Molecular staging of head and neck squamous carcinoma

The staging system of head and neck cancer is a Tumor-Node-Metastases system that was developed by the American Joint Committee on Cancer. The stage of the head and neck cancer defines the extent of the lesion and is determined by physical examination, radiologic studies, and pathologic examination. Accurate staging of head and neck cancer is critical since it will determine the treatment modalities used to cure the disease. Recent advances in the field of molecular genetics have allowed clinicians to detect occult cancer cells previously missed by physical examination and standard histopathologic techniques. Molecular assays are 500 times more sensitive in identifying cancer cells than standard techniques and provide more objective analyses with fewer sampling errors. Consequently, these techniques are currently being used to perform molecular staging of head and neck cancer patients. Preliminary results show that molecular staging will accurately identify those patients at significantly increased risk for recurrence of their head and neck cancer.     

Molecular classification of head and neck squamous cell carcinoma using cDNA microarrays

Squamous cell carcinomas of the head and neck constitute an anatomically heterogeneous group of neoplasms that share in common a causal association with tobacco and alcohol exposure. The clinical course of these neoplasms is difficult to predict based on established prognostic clinicopathological criteria. Given the genetic complexity of head and neck cancers, it is not surprising that correlations with individual genetic abnormalities have also been disappointing. Several authors have suggested that global gene expression patterns can be used to subgroup patients with cancer. Here we report the use of cDNA microarrays containing 9216 clones to measure global patterns of gene expression in these neoplasms. We have used a statistical algorithm to identify 375 genes, which divide patients with head and neck tumors into two clinically distinct subgroups based on gene expression patterns. Our results demonstrate that gene expression profiling can be used as a predictor of outcome.     

头颈部鳞癌手术切缘分子标记物

手术是头颈部鳞癌治疗的主要方法之一,阴性切缘对于手术治疗的效果十分关键.研究显示,分子生物学检测较常规病理检查可更早期、更准确地对手术切缘进行评估,为术后治疗策略的制定和预后预测提供更佳的依据.     

Re-irradiation for head and neck squamous cell carcinoma

Introduction

Local recurrences after curative treatment have a potential for cure with salvage surgery or with re-irradiation.

Molecular and cytogenetic subgroups of oropharyngeal squamous cell carcinoma.

PURPOSE: The aim of this study was to acquire further insights into the pathogenetic pathways of head and neck squamous cell carcinomas (HNSCC) that may be useful for identifying new biomarkers instrumental in developing more specific treatment approaches. EXPERIMENTAL DESIGN: Cell cycle regulators and epidermal growth factor receptor (EGFR) and BRAF genes were analyzed in a series of 90 oropharyngeal SCCs of a cohort of surgically treated patients from a single institution, and the results were matched with the presence of high-risk human papillomavirus (HR-HPV) DNA and the TP53 status. RESULTS: At least four distinct groups of tumors were identified sharing a common histology but displaying different molecular/cytogenetic patterns: (a) 19% were HPV-positive SCCs whose lack of alterations of the investigated genes could explain their particular natural history, which requires less aggressive treatment; (b) 37% were HPV-negative SCCs carrying TP53 mutations, which may be more effectively treated by drugs acting through p53-independent apoptosis; (c) 34% were HPV-negative SCCs carrying wild-type TP53 and loss of 9p21 (p16INK4a and p15INK4b) and/or cyclin D1 overexpression that justify treatment with DNA-damaging drugs followed by cell cycle inhibitors; and (d) 10% were HPV-negative lacking tumor suppressor genes and cell cycle alterations. The second, third, and fourth groups also showed an increased copy number of EGFR and chromosome 7 (43%) that might justify the additional or alternative use of EGFR inhibitors. CONCLUSIONS: Our findings suggest that assessing HPV, TP53, 9p21, and EGFR status may be crucial to finding more tailored and beneficial treatments for oropharyngeal SCCs.     

PIK3CA mutations in head and neck squamous cell carcinoma.

PURPOSE: Recent studies have reported high frequencies of somatic mutations in the phosphoinositide-3-kinase catalytic alpha (PIK3CA) gene in several human solid tumors. Although gene amplifications of PIK3CA have been reported in head and neck squamous cell carcinoma (HNSCC), small mutation of the gene has not been evaluated in HNSCC previously. In this study, we examined the mutation frequency of PIK3CA in HNSCC. EXPERIMENTAL DESIGN: More than 75% of the somatic mutations of PIK3CA are clustered in the helical (exon 9) and kinase domains (exon 20). To investigate the possible role of PIK3CA in HNSCC tumorigenesis, exons 1, 4, 5, 6, 7, 9, and 20 of the gene were analyzed by direct genomic DNA sequencing in 38 HNSCC specimens. RESULTS: We identified four missense mutations in the seven exons of PIK3CA from 38 HNSCC specimens (11%). Three of the four mutations (i.e., H1047R, E542K, and E545K) have been previously reported as hotspot mutations. The remaining novel mutation, Y343C, is identified at exon 4 nucleotide 1028 A --> G. Three of the four mutations were shown to be somatic, whereas the fourth mutation (H1047R) was identified in a cell line. Interestingly, three of the four mutations identified were in pharyngeal cancer samples. CONCLUSIONS: These data provide evidence that oncogenic properties of PIK3CA contribute to the carcinogenesis of human head and neck cancers, especially in pharyngeal cancer. A specific kinase inhibitor to PIK3CA may potentially be an effective therapeutic reagent against HNSCC or pharyngeal cancer in particular.     

Functional surgery for head and neck squamous cell carcinoma

Surgery for head and neck squamous cell carcinoma can alter speech, swallowing, and cosmoses. Recent tendency is to avoid mutilating surgery unless the tumour is aggressive or resistant to chemotherapy and or radiotherapy. Functional surgery is being widely employed, and for example it may vary between conventional partial surgery and endoscopic laser surgery for small sized vocal cord cancers. Various new reconstructive procedures have been developed to help early functional restoration. Loco-regional flaps can be used to replace gums and avoid dental extractions. Free flaps with micro-vascular anastomosis can be employed for immediate reconstruction of extensive surgical defects involving pharyngeal wall, tongue, mandible and mid-face to restore better function and cosmoses. Few recently developed techniques can be also employed in selected cases of laryngo-pharyngeal cancers to avoid permanent laryngeal mutilation. Another goal of functional surgery is to decrease the postoperative radiotherapy or chemo-radiotherapy sequelae, and obtain successful postoperative functional rehabilitation.     

Identification of new minimally lost regions on 18q in head and neck squamous cell carcinoma

Loss of heterozygosity (LOH) on 18q predicts poor survival in head and neck squamous cell carcinomas (HNSCCs). Several putative tumor suppressor genes, such as DCC, DPC4/Smad4, and MADR2/Smad2, are mapped to 18q, but thus far, the important gene locus in HNSCC is not known. To identify possible gene loci on 18q, we performed LOH studies using tumor DNA from 57 HNSCC primary tumor cell lines and DNA isolated from fibroblasts or lymphoblastoid cells from the same patients. Forty-two highly polymorphic microsatellite markers spaced not more than 5 cM apart (mean distance, 1.82 cM) spanning the region from D18S44 in 18q11.1 to D18S1141 in 18q23 were used. D18S71 in 18p11.21 on 18p was also used to determine whether the short arm was retained. Forty-three of 57 (75%) HNSCC lines showed LOH or isolated allelic imbalance (AI) for at least one locus on 18q. Although many of the cell lines had large distal 18q deletions with a breakpoint between 18q11.1 and 18q12.2 to qter, three loci were identified that were lost in 70% or more of the cases. The minimally lost regions (MLRs) range in size from 1.5-15.79 cM. The most proximal is centered on D18S39 (1.56 cM) in band 18q21.1, with LOH or isolated AI in 28 of 38 (74%) of informative cases. The largest (15.8 cM) begins at D18S61 (28 of 40; 70%) in band 18q22.2 and extends through D18S50 in 18q23. The third is centered on D18S70 (30 of 40; 75%) in band 18q23 (3.67 cM). Of these MLRs, only the one centered on D18S39 has been implicated previously in HNSCC. D18S70, the most frequently lost marker, was the only marker consistently lost in three tumor cell lines with very minimal losses, UM-SCC-19, UM-SCC-67, and UM-SCC-73A. In addition, UM-SCC-91 exhibited AI only at this locus, and UT-SCC-4 had AI at D18S70 and D18S39 only. Close physical mapping of these three regions may pinpoint one or more previously unidentified tumor suppressor genes.     

AKT3 is a key regulator of head and neck squamous cell carcinoma

The phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway plays a vital role in cell proliferation, apoptosis, metabolism, and angiogenesis in various human cancers, including head and neck squamous cell carcinoma (HNSCC). In the present study, we aimed to clarify the role of AKT, which is a major downstream effector of the PI3K-AKT-mTOR pathway, in HNSCC. We first investigated the mRNA expression of AKT isoforms using RNA-sequencing data from The Cancer Genome Atlas database. We observed a specific elevation of AKT3 expression in HNSCC tissues when compared with that in normal tissues. Furthermore, AKT3 expression correlated with genes related to the immunosuppressive microenvironment more than the other AKT isoforms and PIK3CA. Accordingly, we focused on AKT3 and performed a knockdown approach using an HNSCC cell line. AKT3 knockdown cells exhibited impaired proliferation, a shift in the cell cycle from G2/M to G1/G0 phase, an increase in apoptotic cells, and downregulation of gene expression related to immunosuppression, as well as the knockdown of its upstream regulator PIK3CA. We also performed immunohistochemistry for both AKT3 and PIK3CA using surgical specimens from 72 patients with HNSCC. AKT3 expression in tumor cells correlated with immune cell infiltration and unfavorable prognosis when compared with PIK3CA. These findings suggested that AKT3 expression is a potential biomarker for predicting the immunoreactivity and prognosis of HNSCC. Furthermore, the isoform-specific inhibition of AKT3 could be developed as a novel cancer therapy that efficiently suppresses the PI3K-AKT-mTOR pathway.     

Docetaxel and squamous cell carcinoma of the head and neck

Chemotherapy in head and neck carcinoma is used as palliative treatment but also as induction treatment or combined treatment with concurrent radiation therapy. Platinum and 5-fluorouracil are the most commonly used cytotoxic agents. Docetaxel is an active drug for treating head and neck carcinoma. For patients with recurrent or metastatic disease, docetaxel could be used either as a second line chemotherapy or a first line for patients who received previously platinum or 5FU. In combination with platinum and 5FU, used as induction chemotherapy the TPF regimen is a very active treatment with an overall response rate of 85 to 90% with a manageable acute toxicity rate. This approach is under investigation in terms of ability to obtain more larynx preservation compared to the standard approach with platinum and 5FU. Docetaxel is a radiosensitizer. Concurrent radiochemotherapy using docetaxel alone is feasible, Trials are needed to define the optimal regimen for combining radiation, platinum and docetaxel.     

Chemoprevention of squamous cell carcinoma of the head and neck

PURPOSE OF REVIEW: The aim of this article is to summarize progress in understanding of the biology of squamous cell carcinoma of the head and neck and of trials to prevent malignant conversion of oral premalignant lesions and the development of second primary tumors in those already treated for squamous cell carcinoma of the head and neck. RECENT FINDINGS: The understanding of squamous cell carcinoma of the head and neck biology is rapidly evolving. Clinical trials for chemoprevention are involving more diverse regimens, following disappointing results of retinoid monotherapy. In-vitro and animal studies form the rationale for the next generation of studies, employing combination, synergistic treatments. SUMMARY: Based on trial data to date, no recommendation for intervention with a chemopreventive agent can be made. It is clear, however, that smoking cessation is an effective intervention for preventing oral premalignant lesions and second primary tumors. Promising trials are being conducted and designed currently. The future of this area of study will involve rational choice of multidrug regimens based on current understanding of the biology of squamous cell carcinoma of the head and neck.     

Role of cytokines in head and neck squamous cell carcinoma

Head and neck squamous cell carcinoma is one of the most frequent cancers and standard treatment has only marginally improved the 5-year survival rate of patients with this disease in the last few decades. It is supposed that cytokine alterations in immune, inflammatory and angiogenetic regulatory routes within the head and neck squamous cell carcinoma microenvironment play a critical role in tumor aggressiveness, its response to chemo- and radiation therapies, as well as the development of immune escape mechanisms.     

Role of miRNA in head and neck squamous cell carcinoma

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common malignancy worldwide. Evidence suggests that miRNAs play an important role in progression, recurrence, metastasis and postoperative survival of HNSCC. Studies have investigated the utility of miRNAs as diagnostic/prognostic tools and as potential therapeutic targets and biomarkers that may improve the management and outcomes of HNSCC. The aim of this article is to review the current literature on aberrant expression profiles of miRNAs in biopsy samples of HNSCC and their role in cancer development, metastasis, prognosis and survival of these patients. This review gives an overview that miRNAs deregulation play major role in the development of HNSCC. They offer the potential to be used as biomarkers or novel therapeutic targets. Future research is required to test their use in both of these fields.     

Role of cytokines in head and neck squamous cell carcinoma

Head and neck squamous cell carcinoma is one of the most frequent cancers and standard treatment has only marginally improved the 5-year survival rate of patients with this disease in the last few decades. It is supposed that cytokine alterations in immune, inflammatory and angiogenetic regulatory routes within the head and neck squamous cell carcinoma microenvironment play a critical role in tumor aggressiveness, its response to chemo- and radiation therapies, as well as the development of immune escape mechanisms.