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Claudin-1 (CLDN1), a major component of tight junction complexes in the epithelium, maintains cellular polarity, and plays a critical role in cell-to-cell communication as well as epithelial cell homeostasis. Although the role of CLDN1 has been widely studied in cancer, its role in the progression and the exact regulatory mechanisms, remain controversial. Using next-generation sequencing, we first analyzed the expression profiles of tumor/non-tumor paired tissue in patients with head and neck squamous cell carcinoma (HNSC) from public and local cohorts and found out that CLDN1 is upregulated in tumors compared to normal tissues. Next, its correlation with lymph node metastasis and poor prognosis was validated in the retrospective cohort, which collectively suggests CLDN1 as an oncogene in HNSC. As expected, the knockdown of CLDN1 inhibited invasive phenotypes by downregulating epithelial-to-mesenchymal transition (EMT) in vitro. To ascertain the regulatory mechanism of CLDN1 in HNSC analysis of GO term enrichment, KEGG pathways, and curated gene sets were used. As a result, CLDN1 was negatively associated with AMP-activated protein kinase (AMPK) and positively associated with transforming growth factor-β (TGF-β) signaling. In vitro mechanistic assay showed that CLDN1 inhibited AMPK phosphorylation by regulating AMPK upstream phosphatases, which led to inhibition of Smad2 activity. Intriguingly, the invasive phenotype of cancer cells increased by CLDN1 overexpression was rescued by AMPK activation, indicating a role of the CLDN1/AMPK/TGF-β/EMT cascade in HNSC. Consistently in vivo, CLDN1 suppression significantly inhibited the tumor growth, with elevated AMPK expression, suggesting the novel observation of oncogenic CLDN1-AMPK signaling in HNSC., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Various enzymes in the one-carbon metabolic pathway are closely related to the development of tumors, and they can all be potential targets for cancer therapy. Serine hydroxymethyltransferase2 ( SHMT2 ), a key metabolic enzyme, is very important for the proliferation and growth of cancer cells. However, the function and mechanism of SHMT2 in head and neck cancer (HNC) are not clear. An analysis of The Cancer Genome Atlas (TCGA) data showed that the expression of SHMT2 was higher in tumor tissue than in normal tissue, and its expression was significantly associated with male sex, aggressive histological grade, lymph node metastasis, distant metastasis, advanced TNM stage, and lymphovascular invasion in HNC. SHMT2 knockdown in FADU and SNU1041 cell lines significantly inhibited cell proliferation, colony formation, migration, and invasion. Additionally, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses using TCGA data revealed that SHMT2 was closely related to cancer stem cell regulation and maintenance. Furthermore, we found that silencing SHMT2 inhibited the expression of stemness markers and tumor spheroid formation compared with a control group. On the contrary, stemness markers were significantly increased after SHMT2 overexpression in HEP-2 cells. Interestingly, we found that knocking down SHMT2 reduced the expression of genes related to the Notch and Wnt pathways. Finally, silencing SHMT2 significantly reduced tumor growth and decreased stemness markers in a xenograft model. Taken together, our study suggests that targeting SHMT2 may play an important role in inhibiting HNC progression.

Background: Despite recent advances in understanding the complex immunologic dysfunction in the tumor microenvironment (TME), fewer than 20% of patients with head and neck squamous cell carcinoma (HNSCC) respond to immune checkpoint blockade (ICB). Thus, it is important to understand how inhibitory IC receptors maintain the suppressed dysfunctional TME, and to develop more effective combination immunotherapy. This study evaluated the immune-modulating effects of Curcumin, which has well-established anti-cancer and chemopreventive properties, and its long-term safety as a phytochemical drug., Methods: We carried out the western blot and small interfering RNA (siRNA) transfection assay to evaluate the effects of Curcumin on IC ligands and IC ligands function in HNSCC. Through T-cell cytotoxicity assay and measurements of cytokine secretion, we assessed the effects of combination of Curcumin with programmed death-ligand 1 (PD-L1) Ab on cancer cell killing. Flow cytometry were used to analyze the effects of Curcumin on the expression of programmed cell death protein 1 (PD-1) and T-cell immunoglobulin and mucin-domain3 (TIM-3) on CD4, CD8 and Treg. Immunofluorescence, immunohistochemistry and western blot were used to detecte the cytokine (IFN-γ, Granzyme B), IC receptors (PD-1 and TIM-3) and its ligands (PD-L1, PD-L2, Galectin-9) in xenograft mouse model and 4-nitroquinoline-1-oxide (4-NQO) oral cancer model., Results: We found that Curcumin decreased the expression of IC ligands such as PD-L1, PD-L2, and Galectin-9 in HNSCC, leading to regulation of epithelial-to-mesenchymal transition-associated tumor invasion. Curcumin also effectively restored the ability of CD8 + cytotoxic T cells to lyse cancer cells. To evaluate the effect of Curcumin on the TME further, the 4-NQO oral cancer model was used. Curcumin increased T-cell proliferation, tumor-infiltrating lymphocytes (TILs), and effector cytokines, and decreased the expression of PD-1, TIM-3, suppressive IC receptors and their ligands (PD-L1, PD-L2, and Galectin-9) in the TME, implying reinvigoration of the exhausted CD8 + T cells. In addition, Curcumin inhibited expression of CD4 + CD25 + FoxP3 + Treg cells as well as PD-1 and TIM-3., Conclusions: These results show that Curcumin reinvigorates defective T cells via multiple (PD-1 and TIM-3) and multi-level (IC receptors and its ligands) IC axis suppression, thus providing a rationale to combine Curcumin with conventional targeted therapy or ICB as a multi-faceted approach for treating patients with HNSCC., (Copyright © 2021. Published by Elsevier GmbH.)

Growth and differentiation factor 15 (GDF15), a divergent member of the transforming growth factor-β (TGF-β) superfamily, has been reported to be overexpressed in different kinds of cancer types. However, the function and mechanism of GDF15 in head and neck cancer (HNC) remains unclear. The Cancer Genome Atlas (TCGA) data show that the expression of GDF15 is significantly associated with tumor AJCC stage, lymph vascular invasion and tumor grade in HNC. In this study, we confirmed that knockdown of GDF15 attenuated: cell proliferation, migration and invasion via regulation of EMT through a canonical pathway; SMAD2/3 and noncanonical pathways; PI3K/AKT and MEK/ERK in HNC cell lines. Furthermore, we found that early growth response 1 (EGR1) was a transcription factor of GDF15. Interestingly, we also demonstrated that GDF15 could regulate the expression of EGR1, which meant a positive feedback loop occurred between these two factors. Moreover, combined inhibition of both GDF15 and EGR1 in a HNC mouse xenograft model showed significantly decreased tumor volume compared to inhibition of EGR1 or GDF15 alone. Our study showed that the GDF15-EGR1 signaling axis may be a good target in HNC patients.

Mitochondrial targeted therapy is a next-generation therapeutic approach for cancer that is refractory to conventional treatments. Mitochondrial damage caused by the excessive accumulation of reactive oxygen species (ROS) is a principle of mitochondrial targeted therapy. ROS in nonthermal plasma-activated media (NTPAM) are known to mediate anticancer effects in various cancers including head and neck cancer (HNC). However, the signaling mechanism of HNC cell death via NTPAM-induced ROS has not been fully elucidated. This study evaluated the anticancer effects of NTPAM in HNC and investigated the mechanism using transcriptomic analysis. The viability of HNC cells decreased after NTPAM treatment due to enhanced apoptosis. A human fibroblast cell line and three HNC cell lines were profiled by RNA sequencing. In total, 1 610 differentially expressed genes were identified. Pathway analysis showed that activating transcription factor 4 (ATF4) and C/EBP homologous protein (CHOP) were upstream regulators. Mitochondrial damage was induced by NTPAM, which was associated with enhancements of mitochondrial ROS (mtROS) and ATF4/CHOP regulation. These results suggest that NTPAM induces HNC cell death through the upregulation of ATF4/CHOP activity by damaging mitochondria via excessive mtROS accumulation, similar to mitochondrial targeted therapy., Competing Interests: The authors have no conflicts of interest to declare., (Copyright © 2021 Chan Oh et al.)

Backgrounds and Purpose: Radiation therapy is an important mode of treatment for patients with head and neck cancers, but some associated complications can reduce the quality of life. We investigated whether N-acetylcysteine inhalation therapy improved the quality of life of such patients., Materials and Methods: We designed a prospective, non-randomized controlled multi-center study involving 10 institutions. We enrolled 120 patients (80 in the experimental group and 40 in the control group). Patients in the experimental group inhaled nebulized liquid N-acetylcysteine (2400 mg daily) for 8 weeks from the start of radiation therapy. Quality of life was assessed using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire H&N 35., Results: N-acetylcysteine inhalation was not associated with any side effect or discomfort. The reduction in painkiller use from the end of N-acetylcysteine inhalation therapy to the 1-month follow-up was greater in the experimental group than in the control group (P = 0.014). Dry mouth symptoms also improved significantly in the experimental group (P = 0.019)., Conclusion: N-acetylcysteine inhalation improves the quality of life of patients with head and neck cancers who are receiving radiation therapy, without any specific side effect.

Background: The acquisition of stem-like phenotype is partly attributed to the induction of epithelial-mesenchymal transition (EMT). Thus, the activation of factors involved in EMT can be linked to cancer stem cell genesis. However, the underlying mechanisms in head and neck squamous cell carcinoma (HNSCC) remain largely unknown. Herein, we investigate whether slug, one of the major effectors of EMT, affects the stemness of HNSCC cells., Methods: We performed in vitro experiments to determine whether slug gene manipulation can influence the stemness phenotypes, including the capacity for self-renewal, expression of putative stemness markers, chemoresistance, and invasion in HNSCC cells. Further, we identified whether Slug knockout attenuates tumorigenicity of HNSCC cells in vivo. Finally, we examined whether prognosis of HNSCC patients after curative treatment may be affected by the level of slug expression., Results: Overexpression of slug promoted self-renewal of HNSCC cells via activation of sphere formation, the expression of stem cell markers, and induction of chemoresistance to cisplatin. Also, slug overexpression increased the migration and invasion of HNSCC cells in vitro and was mainly observed during the invasion in HNSCC xenograft mouse model. By contrast, slug expression knockdown abrogated their self-renewal capacity, stemness-associated gene expression, and cisplatin chemoresistance. Furthermore, high levels of slug expression correlated with poor prognosis of patients with HNSCC., Conclusion: Inhibition of slug expression may represent a novel therapeutic strategy targeting HNSCC stem-like cells., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Purpose: Thunderbeat (TB) is an integrated energy device incorporating ultrasonic and bipolar technology that provides rapid cut and precision dissection and reliable vessel sealing compared with conventional electrosurgery (ES). The present study compared the surgical outcomes of TB and ES for harvesting the anterolateral thigh free flap (ALTFF)., Patients and Methods: The present prospective cohort study compared TB and ES in patients who had undergone head and neck reconstruction using ALTFFs. The baseline characteristics, including age, gender, body mass index, primary tumor site (recipient site), and T stage, were measured. Patients who had undergone reconstruction after previous unsuccessful head and neck cancer treatment using radiation were included in the salvage surgery group. The primary outcome variables were the harvesting time, blood loss, and flap failure. The interval until the start of an oral diet and the percutaneous endoscopic gastrostomy (PEG) insertion rate were analyzed to compare the functional outcomes. After identifying the confounding variables, multivariate approaches were used to adjust for the confounding variables., Results: No significant differences were found in the demographics and disease-related factors such as age, gender, body mass index, anatomic distribution, and T stage of the primary disease, between the 2 groups. The operation time and bleeding volume were reduced by 32.4 and 33.1%, respectively, in the TB group compared with those in the control group. The postoperative drainage volume, duration, flap failure rate, and intensive care unit and total hospital stays were nearly identical between the 2 groups. No statistically significant differences were found in the functional outcomes (PEG insertion and oral diet start day) between the 2 groups., Conclusions: The results of the present study have shown that TB is a useful supportive tool for head and neck reconstruction surgery because it decreases the operation time with surgical outcomes comparable to those with conventional ES., (Copyright © 2020 American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.)

Introduction: Identification of therapeutic targets in head and neck squamous cell carcinoma (HNSCC) is essential because most of the patients with advanced HNSCC have a poor prognosis. Homeobox genes constitute a large cluster of transcription factors with important regulatory roles in mammalian embryonic development and cell differentiation. The oncogenic role of homeobox B5 (HOXB5) in HNSCC has not been investigated., Materials and Methods: We used The Cancer Genome Atlas (TCGA) data to evaluate the correlations between HOXB5 expression and various HNSCC clinicopathological factors. We knocked down HOXB5 expression in HNSCC cell lines and explored the in vitro and in vivo effects on cell proliferation and motility, and HOXB5 signaling., Results: The Cancer Genome Atlas (TCGA) data shows that HOXB5 is overexpressed in HNSCC compared to normal tissues and significantly associates with tumor stage (P = 0.003), lymph node metastasis (P = 0.031), disease stage (P = 0.002), and angiolymphatic invasion (P = 0.004). Our results also show that HOXB5 expression is up-regulated in HNSCC cell lines, and HOXB5 knockdown significantly reduced cell proliferation and tumor growth in vitro and in vivo. Inhibition of HOXB5 decreases cell migration and invasion via suppression of epithelial-to-mesenchymal transition (EMT)-associated proteins expression. Moreover, HOXB5 directly binds to the promoter region of EGFR and consequently regulates the activity of the Akt/Wnt/β-catenin signaling axis., Conclusion: HOXB5 may be a novel therapeutic target as an oncogenic driver by regulating EGFR transcription in HNSCC., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2019 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Background: Head and neck squamous cell carcinomas (HNSCCs) are highly lethal epithelial tumours containing self-renewal cancer stem cells (CSCs). CSCs in HNSCCs are strongly associated with tumour initiation, invasion, and chemoradiation resistance. However, the important factors regulating stemness in HNSCCs remain unclear. Here, we investigated the molecular roles and clinical significance of inhibitor of DNA binding 2 (Id2) protein to determine if it constitutes a novel therapeutic target for ablating HNSCC cells with stemness., Methods: We performed in vitro and in vivo studies of Id2 function and its effects on stemness using HNSCC cells. We also examined whether Id2 expression could be used as a prognostic indicator through immunohistochemical staining of 119 human HNSCC tumours., Results: Expression of Id2 was higher in HNSCC cells with stemness compared with differentiated HNSCC cells. Overexpression of Id2 increased proliferation, self-renewal, and expression of the putative stemness marker CD44 in HNSCC cells in vitro and in vivo. In contrast, silencing of Id2 using short hairpin RNA attenuated the stemness phenotype of HNSCC cells by reducing self-renewal, CD44 expression, cisplatin chemoresistance, and xenograft tumourigenicity. Most importantly, increased expression of Id2 was closely associated with poorer post-treatment survival rates in HNSCC patients., Conclusions: Inhibitor of DNA binding2 represents a novel and promising therapeutic target for treating and improving the clinical outcomes for patients with HNSCC.

The exact regulatory mechanisms of carboxyl-terminal modulator protein (CTMP) and its downstream pathways in cancer have been controversial and are not completely understood. Here, we report a new mechanism of regulation of Akt serine/threonine kinase, one of the most important dysregulated signals in head and neck squamous cell carcinoma (HNSCC) by the CTMP pathway and its clinical implications. We find that HNSCC tumor tissues and cell lines had relatively high levels of CTMP expression. Clinical data indicate that CTMP expression was significantly associated with positive lymph node metastasis (OR = 3.8, P = 0.033) and correlated with poor prognosis in patients with HNSCC. CTMP was also positively correlated with Akt/GSK-3β phosphorylation, Snail up-regulation and E-cadherin down-regulation, which lead to increased proliferation and epithelial-to-mesenchymal transition, suggesting that CTMP expression results in enhanced tumorigenic and metastatic properties of HNSCC cells. Moreover, CTMP suppression restores sensitivity to cisplatin chemotherapy. Intriguingly, all the molecular responses to CTMP regulation are identical regardless of p53 status in HNSCC cells. We conclude that CTMP promotes Akt phosphorylation and functions as an oncogenic driver and prognostic marker in HNSCC irrespective of p53.

Notch1 is associated with the initiation and progression of various solid tumors. However, the exact role of Notch1 expression in head and neck squamous cell carcinoma (HNSCC) remain unclear. We created cells ectopically expressing notch intracellular domain (NICD) from previously established HNSCC cells and examined self-renewal capacity and stem cell markers' expression compared with control cells. In addition, we knocked Notch1 down in primary spheres obtained from HNSCC tumor tissue and assessed the attenuation of stemness-associated traits in these cells in vitro and in vivo. Furthermore, we examined clinical relevance of Notch1 expression in HNSCC patients. Constitutive activation of NICD promoted the self-renewal capacity of HNSCC cells by activating sphere formation and increased the expression of stem cell markers such as Oct4, Sox2, and CD44. In contrast, Notch1 knockdown in primary HNSCC cancer stem cells (CSCs) attenuated CSC traits and augmented the chemosensitizing effects of cisplatin along with the decreased expression of almost all of ABC transporter genes. In addition, Notch1 knockdown in HNSCC CSCs inhibited tumor formation and increased survival of mice in a xenograft model. Also, Notch1 acted upstream of canonical Wnt signaling in HNSCC cells. Finally, elevated Notch1 expression is associated with poor prognosis in patients with HNSCC. In conclusion, Notch1 may be a critical regulator of stemness in HNSCC cells, and inactivation of this pathway could be a potential targeted approach for the treatment of HNSCC.

Objectives: Increasing evidence suggests that epigenetic regulation is responsible for tumor initiation and progression in head and neck squamous cell carcinoma (HNSCC). Although the polycomb group protein enhancer zeste homolog 2 (EZH2) is upregulated and a key epigenetic modifier implicated in various cancers, its molecular mechanism in HNSCC remains unknown. Herein, we investigated the role of EZH2 in HNSCC progression and its clinical implication as an HNSCC risk predictor., Materials and Method: A retrospective analysis was performed on 90 HNSCC patients who had curative surgery between 1999 and 2011. Patients with high and low EZH2 expression were compared by the various clinicopathological factors. Survival rates were estimated by the Kaplan-Meier method and log-rank test was used to determine significance. For functional in vitro analysis, migration/invasion assay and Western blotting were performed after EZH2 knockdown using siRNA. In addition, cell proliferation was measured to clarify the role of EZH2 on cisplatin chemotherapy., Results: In patients with HNSCC, high EZH2 expression was correlated with advanced T stage and poor survival outcome. RNAi analysis revealed that EZH2 silencing increased E-cadherin expression while decreasing that of N-cadherin and Vimentin without altering Snail/Slug signaling, which led to decreased cell migration/invasion. EZH2 is also associated with tumor aggressiveness via regulating the epithelial-to-mesenchymal transition. Furthermore, we show that high EZH2 expression decreases sensitivity to cisplatin-based chemotherapy., Conclusion: Our results indicate that EZH2 may not be only a predictive and prognostic biomarker but also a potential personalized therapeutic target for the treatment of HNSCC., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

We investigated the clinical significance of podoplanin expression in relation to clinicopathological variables in head and neck squamous cell carcinoma (HNSCC), to determine its effectiveness as a marker for high-risk HNSCC patients. Upregulation of podoplanin in HNSCC tissues was examined using immunohistochemistry and clinicopathological analyses. Wound healing and invasion assays were performed using HNSCC cells that were transfected with podoplanin siRNA, podoplanin vector and cotransfection with both the podoplanin vector and VEGF-C siRNA. High podoplanin expression was significantly associated with ~3- and 5-fold increases in the presence of positive lymph node metastasis and poor histological grade, respectively (P<0.05). High levels of podoplanin expression were significantly associated with decreased overall and disease-specific survival rates (P<0.05). Furthermore, upregulation of podoplanin induced cell wound repair activity and invasiveness in the FaDu and SNU-1041 cells, respectively, while downregulation of podoplanin expression through VEGF-C silencing using co-transfection of both the podoplanin vector and VEGF-C siRNA suppressed cell wound healing and invasion abilities in the HNSCC cells. Our findings suggest that high podoplanin expression is associated with aggressive tumor behavior, poor prognosis and metastatic regulation through interaction with VEGF-C, suggesting that podoplanin may be used as a potential prognostic biomarker for HNSCC.

Background: This study investigated the role of p21-activated kinase (PAK)-1 in progression of head and neck squamous cell carcinoma (HNSCC)., Methods: We examined PAK isoforms and explored whether PAK activation enhanced in vitro invasion of the HNSCC cell line. We analyzed the relationship between PAK1 expression and various clinicopathological features and investigated the effect of PAK1 overexpression on survival in 119 patients with HNSCC., Results: PAK1 and PAK2 are predominantly expressed in HNSCC cells and patient tissues. Particularly, PAK1 makes the dominant contribution to increase in cell migration and invasion. There was a statistically significant correlation between PAK1 overexpression and aggressive cancer behavior. Moreover, PAK1 seemed to be a prognostic factor for overall and disease-specific survival in patients. Interestingly, enhancement of PAK1 expression was found in the invasive front of cancer., Conclusion: PAK1 is associated with the aggressive tumor behavior and poor prognosis of head and neck cancer., (© 2014 Wiley Periodicals, Inc.)

Cancer stem cells (CSCs) have been suggested as responsible for the initiation and progression of cancers. Octamer-binding transcription factor 4 (Oct4) is an important regulator of embryonic stem cell fate. Here, we investigated whether Oct4 regulates stemness of head and neck squamous carcinoma (HNSC) CSCs. Our study showed that ectopic expression of Oct4 promotes tumor growth through cyclin E activation, increases chemoresistance through ABCC6 expression and enhances tumor invasion through slug expression. Also, Oct4 dedifferentiates differentiated HNSC cells to CSC-like cells. Furthermore, Oct4(high) HNSC CSCs have more stem cell-like traits compared with Oct4(low) cells, such as self-renewal, stem cell markers' expression, chemoresistance, invasion capacity and xenograft tumorigeneity in vitro and in vivo. In addition, knockdown of Oct4 led to markedly lower HNSC CSC stemness. Finally, there was a significant correlation between Oct4 expression and survival of 119 HNSC patients. Collectively, these data suggest that Oct4 may be a critical regulator of HNSC CSCs and its targeting may be potentially valuable in the treatment of HNSC CSCs.

Accumulating evidence suggests that a distinct subpopulation of cancer stem cells (CSCs) is responsible for tumour initiation and progression in head and neck squamous cell carcinoma (HNSCC). Wnt/β-catenin signalling is essential for stem cell regulation and tumourigenesis, but its molecular mechanism in HNSCC CSCs remains unknown. We investigated whether Wnt/β-catenin signalling regulates self-renewal and tumourigenicity of HNSCC stem-like cells in vitro and in vivo. Cytoplasmic/nuclear β-catenin, a major effector of Wnt/β-catenin signalling, was expressed in a subpopulation of tumour cells in primary HNSCC tissue but in none of normal head and neck tissues. Overexpression of β-catenin increased proliferation of HNSCC cells and induced dedifferentiation of these cells to cells with stem-like features. Knockdown of β-catenin in HNSCC stem-like cells blocked their self-renewal capacity, stemness-associated gene expression, chemoresistance, and in vivo tumourigenicity. Furthermore, β-catenin directly regulates Oct4 transcription in HNSCC stem-like cells. In addition, the effect of shRNA-mediated repression of β-catenin on CSC traits in HNSCC stem-like cells was reversed by overexpression of Oct4. In patients with HNSCC, higher levels of both cytoplasmic/nuclear β-catenin and Oct4 correlated with the worst prognosis. These results suggest inhibition of Wnt/β-catenin signalling as a novel therapeutic strategy for targeting HNSCC stem-like cells., (Copyright © 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.)

Matrix metalloproteinases (MMPs) play an important role in tumor invasiveness and metastasis. The aim of this study was to investigate the expression pattern of MMPs in the primary tumor of head and neck squamous cell carcinomas (HNSCC) with cervical node metastasis and to correlate the expression of MMP in the primary tumor with the presence of extracapsular spread (ECS) in nodes with metastasis. A retrospective study was conducted. Paraffin blocks were obtained from 40 HNSCC patients with cervical node metastasis who underwent surgery as an initial treatment between 2004 and 2011. Expressions of MMP-2, MMP-3, MMP-12, and MMP-14 were investigated immunohistochemically. MMP-2, MMP-3, MMP-12, and MMP-14 were expressed in 27, 47.5, 55, and 57.5 % of cases, respectively. MMP-12 expression was found to be significantly associated with ECS and correlated with nodal metastasis (p = 0.024, 0.011). No relation was found between MMP expression and survival. MMP-12 expressed in the primary tumor is a molecular marker that may be useful for predicting ECS in HNSCC patients with metastatic nodal disease.

Objectives: It is well established that tonsillar squamous cell carcinomas have a high probability of disseminating to the neck. An ipsilateral neck treatment is mandatory during initial treatment of stages II to IV tonsillar carcinomas. However, as of yet, no consensus exists whether to perform elective contralateral neck management., Materials and Methods: A retrospective analysis of 43 N0-3 tonsillar cancer patients with contralateral clinically negative necks from 1992 to 2002 was performed. All patients had a contralateral elective neck dissection. Surgical treatment was followed by postoperative radiotherapy in 33 patients. The follow-up period ranged from 2 to 120 (mean 38) months. The Kaplan-Meier method and log-rank test were used to calculate the disease-specific survival rates and prognostic significance of contralateral occult lymph node metastasis., Results: Clinically negative, but pathologically positive, contralateral lymph nodes occurred in 16% (7 of 43). Of the 33 cases with an ipsilateral node positive neck, contralateral occult lymph node metastases developed in 21% (7 of 33), in contrast with 0% in ipsilateral N0 necks. On the basis of the clinical staging of the tumor, 5% (1 of 22) of the cases showed lymph node metastases in T2 tumors, 36% (5 of 14) in T3, and 25% (1 of 4) in T4. None of the T1 tumors (3 cases) had pathologically positive lymph nodes (T1 + T2 vs. T3 + T4, P < .05). Patients with no evidence of contralateral nodal cancer had significantly improved disease-specific survival over patients with any pathologically positive nodes (5 year disease-specific survival rate 92% vs. 28%, P = < .05)., Conclusion: The risk of contralateral occult neck involvement in above T3 staged tonsillar squamous cell carcinomas with unilateral metastases was high (approximately 21%), and patients who present with a contralateral metastatic neck have a worse prognosis than those who are staged as N0. Therefore, we advocate an elective contralateral neck treatment in tonsillar squamous cell carcinoma patients with ipsilateral node metastases.