Oral Oncology

Editorial Board/Aims & Scope

2010-02-01

Contemporary reconstruction of the mandible

Mathew Bak, Adam S. Jacobson, Daniel Buchbinder, Mark L. Urken — 2009-12-28

Summary: Reconstruction of the mandible has evolved significantly over the last 40years. Early attempts were often disfiguring and wrought with complications but with the introduction of free tissue transfer of well vascularized bone in the 1970’s there was a significant improvement in outcomes. In recent years the harvest, inset, and microvascular anatomosis have been refined to the point that success rates are reported as high as 99% throughout the literature. Focus has now shifted to optimizing functional and aesthetic outcomes after mandible reconstruction. This paper will be a review defect classification, goals of reconstruction, the various donor sites, dental rehabilitation, new advances, and persistent problems.Reconstruction of segmental mandibular defects after ablative surgery is best accomplished using free tissue transfer to restore mandibular continuity and function. Reestablishing occlusion and optimizing tongue mobility are important to post-operative oral function. Persistent problems in oro-mandibular reconstruction relate to the effects of radiation treatment on the native tissue and include xerostomia, dysgeusia, osteoradionecrosis and trismus. These problems continue to plague the oral cancer patient despite the significant advances that allow a far more complete functional restoration than could be accomplished a mere two decades ago.

Taste disorders in cancer patients: Pathogenesis, and approach to assessment and management

Joel B. Epstein, Andrei Barasch — 2009-12-28

Summary: Taste dysfunction in cancer patients impacts quality of life and impairs oral intake, which may have broader implications consisting of weight loss and nutritional compromise. These consequences may in turn affect broad symptom clusters including tissue healing, energy levels and mood. Patient evaluation and management should include a complete patient history and examination, and may require special tests. Patient-reported outcomes together with taste and smell testing are often necessary for diagnosis and management of taste disorders. Understanding, prevention and management of taste disorders in cancer patients requires continuing study. Current practice and recommendations are based on limited evidence. Due to its potentially significant impact on quality of life during and following cytotoxic therapy, and considering the increase in cancer survivorship, further research on this topic is imperative.

Maté drinking and oral and oro-pharyngeal cancer: A systematic review and meta-analysis

Ananda P. Dasanayake, Amanda J. Silverman, Saman Warnakulasuriya — 2009-12-28

Summary: In Latin America, maté is consumed as a beverage regularly. Among the cancers that are associated with maté drinking is oral and oro-pharyngeal cancer, incidence of which is high in the region. In order to further understand this association between maté drinking and the risk of oral and oro-pharyngeal cancer, we performed a systematic review and meta-analysis of related studies. All relevant studies published in English as original articles up to June 2009 were identified through a literature search using PubMed and Medline and by reviewing the references from the retrieved articles. Four case–control studies done in Latin America were identified. There were 879 maté users and 1128 non- or low-maté users in those studies with a total of 566 oral and oro-pharyngeal cancers. The adjusted association between maté drinking and oral and oro-pharyngeal cancer was significant within 3 of those studies. Meta-analysis yielded a significant summary odds ratio (OR) of 2.11 (95% confidence interval=1.39–3.19). Population Attributable Risk for maté drinking was 16%. While the epidemiological data indicate that maté users have an increased risk of oral and oro-pharyngeal cancer, little is known about whether this increased risk is due to the high temperature of the beverage when it is consumed or due to certain carcinogenic constituents that are present in maté. More human and animal studies are needed before a conclusion can be made on the oral and oro-pharyngeal carcinogenic risk of maté to humans.

Assessment of preoperative ultrasonography of the neck and elective neck dissection in patients with oral squamous cell carcinoma

B.M. Wensing, M.A.W. Merkx, P.C. De Wilde, H.A.M. Marres, F.J.A. Van den Hoogen — 2010-01-11

Summary: Estimating the value of our preoperative workup in the treatment of patients with clinically N0 (cN0) squamous cell carcinoma of the oral cavity. Retrospective analysis. Results of preoperative palpation, ultrasound (US) and ultrasound-guided fine needle aspiration cytology (FNAC) were compared to the histological findings after unilateral or bilateral elective selective neck dissection of level I–III (SND I–III) in patients with cN0 squamous cell carcinoma of the oral cavity. Occult metastases were detected by in 50 (22%) out of the 224 cN0 patients. No metastases were found beyond level III in extended neck dissections. T1N0M0 tumors and T2N0M0 tumors metastasized in 8 out of 77 cases (10%) and 32 out of 112 (29%) cases, respectively. Staging of the cN0 neck by palpation and US (±ultrasound-guided FNAC) missed occult lymph node metastases in 22% of the patients with oral cavity squamous cell carcinoma. The use of SND I–III therefore still is warranted. Frozen section sampling seemed to be redundant in this selected group of patients, because no additional metastases were found in extended neck dissection specimens. It might not be necessary to perform elective neck dissection in patients with T1 tumors.

Head and neck cancer surgery in the elderly – Does age influence the postoperative course?

2009-12-28

Summary: There are few data focusing on postoperative course after major head and neck cancer surgery in the elderly compared with the younger population. The aim of this study was to assess the impact of age on postoperative outcomes.At hospital admission, we prospectively collected data from 261 patients separated into two groups with regard to their age (those ⩾70years and those <70years). Twenty-nine of them were over 70years old. Median length of stay was similar in both populations (22 vs. 21days, p=0.66). Incidence of severe postoperative complications was similar: surgical site infection (6/29 vs. 89/232, p=0.77), pneumonia (4/29 vs. 29/232, p=0.13) and infection caused by multi-resistant pathogens (1/29 vs. 14/232, p=0.08). There was no significant increase in postoperative deaths (4/29 vs. 6/232, p=0.12).The impact of age on postoperative deaths was assessed after adjustment for potential risk factors. In a logistic regression model, postoperative death risk remained insignificantly increased in the elderly (adjusted Odds Ratio=3.3 [0.7–14.9], p=0.22).In our experience, the postoperative course in elderly patients is not significantly different from that than in younger patients.

Chromosomal numerical aberrations in apparently normal oral mucosa of heavy smokers affected by lung cancer

2009-12-10

Summary: Cigarette smoke creates a field of injury in the epithelial lining of the entire respiratory tract causing an increased risk for the development of malignant lesions. It is conceivable, therefore, that early genetic alterations, can be detected in oral mucosa of heavy smokers mainly those affected by lung cancer. As aneuploidy was shown to be an early event in oral carcinogenesis, we aimed to investigate the prevalence of aneuploid cells (ACs) in samples obtained from apparently normal looking oral mucosa of heavy smokers affected by lung cancer (LC). Two brush samples were collected from the oral mucosa of 152 subjects; 31 heavy smokers with LC, 59 heavy smokers without LC and 62 never-smokers. The samples were simultaneously analyzed for morphology and fluorescent in situ hybridization (FISH) using chromosomes 2 and 8 centromeric probes. Over 2% ACs were found in 23% of heavy smokers with LC compared to 12% in heavy smokers without LC and 5% of the never-smokers group (P=0.015). A trend was also noticed when comparing the group of heavy smokers without LC with the never-smokers (P=0.198). We conclude that heavy smokers harbour detectable chromosomal numerical aberrations in oral epithelial cells of normal looking mucosa. These aberrations are more frequently found in heavy smokers affected by LC.

Moderate predictive value of demographic and behavioral characteristics for a diagnosis of HPV16-positive and HPV16-negative head and neck cancer

2009-12-28

Summary: Patients with HPV-positive and HPV-negative head and neck squamous cell carcinoma (HNSCC) are significantly different with regard to sociodemographic and behavioral characteristics that clinicians may use to assume tumor HPV status.Machine learning methods were used to evaluate the predictive value of patient characteristics and laboratory biomarkers of HPV exposure for a diagnosis of HPV16-positive HNSCC compared to in situ hybridization, the current gold-standard.Models that used a combination of demographic characteristics such as age, tobacco use, gender, and race had only moderate predictive value for tumor HPV status among all patients with HNSCC (positive predictive value [PPV]=75%, negative predictive value [NPV]=68%) or when limited to oropharynx cancer patients (PPV=55%, NPV=65%) and thus included a sizeable number of false positive and false negative predictions. Prediction was not improved by the addition of other demographic or behavioral factors (sexual behavior, income, education) or biomarkers of HPV16 exposure (L1, E6/7 antibodies or DNA in oral exfoliated cells).Patient demographic and behavioral characteristics as well as HPV biomarkers are not an accurate substitute for clinical testing of tumor HPV status.

Chemoprevention of oral cancer in animal models, and effect on leukoplakias in human patients with ZengShengPing, a mixture of medicinal herbs

Zheng Sun, Xiaobing Guan, Ning Li, Xiaoyong Liu, Xiaoxin Chen — 2009-12-21

Summary: ZengShengPing (ZSP), a mixture of six medicinal herbs, has been reported to prevent esophageal squamous cell carcinoma (SCC) in human patients with dysplasia. This study was designed to investigate the chemopreventive effects of ZSP on oral cancer in animal models and human patients. In the 7,12-dimethylbenz[a]anthracene (DMBA)-induced hamster cheek pouch model, ZSP (6g/kgBW/day by gavage for 10 weeks) significantly reduced the number of visible tumor, the tumor volume, and the incidence of SCC (P<0.01). Two biomarkers associated with cell proliferation, silver stained nucleolar organizer region (AgNOR) and proliferating cell nuclear antigen (PCNA)-labeling index, were also significantly suppressed by ZSP treatment (P<0.01). In the 4-nitroquinoline 1-oxide (4NQO)-induced oro-esophageal cancer model in mice, ZSP (10% in diet) also significantly reduced the incidence of tongue SCC from 55.2% (16/29) to 22.2% (6/27) (P<0.05), and slightly reduced the incidence of esophageal SCC from 34.5% (10/29) to 22.2% (6/27). Furthermore, in a randomized clinical trial on patients with oral leukoplakia, ZSP (4 tablets, 3 times per day for 8–12months) reduced the size of oral lesion in 67.8% (40/59) patients, whereas the placebo was effective in 17% (9/53) patients (P<0.01). Such an effect was associated with significant decrease of AgNOR and PCNA-labeling index. In summary, our studies have demonstrated the chemopreventive effects of ZSP on two animal models of oral cancer, and human patients with oral leukoplakia.

Effect of local hyperthermia on lymphangiogenic factors VEGF-C and -D in a nude mouse xenograft model of tongue squamous cell carcinoma

2009-12-28

Summary: It is widely accepted that tumor-induced lymphangiogenesis driven by vascular endothelial growth factor (VEGF)-C- and/or VEGF-D-induced activation of VEGF receptor (VEGFR)-3 could promote lymphatic metastasis. In this study, tumor growth and intratumoral expression level of VEGF-C and -D following administration of local hyperthermia was evaluated in nude mice model of tongue squamous cell carcinoma (SCC). The data demonstrated that the size of tumor in local hyperthermia was 26.5% of control group, and that local hyperthermia markedly suppressed the mRNA and protein expression of VEGF-C and -D as determined by quantitative real-time RT-PCR, Western blot and immunohistochemistry (P<0.05). These results suggest that, accompanying with tumor growth inhibition, local hyperthermia may act as an anti-lymphangiogenic role by suppressing the expression of tumor VEGF-C and -D, and thereby inhibiting cancer cell lymphatic metastasis in tongue SCC.

A basal-cell-like compartment in head and neck squamous cell carcinomas represents the invasive front of the tumor and is expressing MMP-9

2009-12-28

Summary: Head and neck squamous cell carcinomas (HNSCCs) are the most frequent malignancies of the upper aerodigestive tract. The cancer stem cell (CSC) hypothesis concludes that CSCs constitute the dangerous tumor cell population due to their ability of self-renewal and being associated with relapse of tumor disease, invasiveness and resistance to chemo(radio)therapy. The aim of this study was to look for CSC candidates and expression of MMP-9 that previously was implicated in HNSCC invasiveness.Immunohistochemical, immunofluorescence and Western blot analysis were performed on HNSCC tumor specimens using antibodies specific for MMP-9, CD44, ALDH1 and CK14. Gelatinolytic activity was assessed by zymography. Pearson correlation analysis was used for statistical comparison.Immunohistochemical analysis found CD44 and MMP-9 to co-localize in tumor cells at the invasive front. Western blot analysis demonstrated a significant correlation (p=0.0047) between CD44 and MMP-9 in the tested tissues. In addition gelatinolytic activity of HNSCC tissues was found to significantly correlate (p=0.0010) with MMP-9 expression. The CD44+ invasive front of the tumor was also positive for ALDH1 and CK14, all of them being typically expressed by cells in the basal cell layer of normal stratified squamous epithelia that also harbors the epithelial stem cells.The observations point to a role of a MMP-9 positive basal-cell-like cell layer in the process of HNSCC invasiveness. This compartment likely contains CSCs since it is expressing the putative CSC markers CD44, ALDH1 and CK14. This cell layer therefore should be considered a major therapeutic target in the treatment of head and neck cancer.

Evaluation of cornulin, keratin 4, keratin 13 expression and grade of dysplasia for predicting malignant progression of oral leukoplakia

2009-12-28

Summary: Oral leukoplakia is defined as a white patch in the oral cavity that cannot be diagnosed as any other known disorder. These lesions carry an increased risk of malignant progression, and approximately 2–3% per year do progress to cancer. At present biopsies are histopathologically graded for dysplasia to assess the risk of progression, but this grading is somewhat subjective and of limited use for the individual patient.In a previous study we discovered by a comprehensive proteomics approach that compared to normal mucosa, protein expression of cornulin, keratin 4 and keratin 13 is decreased in tumors and severe dysplasia, preneoplastic tissue with a high risk of malignant progression. Here, we studied whether loss of expression of these proteins can predict malignant transformation of oral leukoplakia. Biopsies of 12 progressing and 36 non-progressing leukoplakia lesions were analyzed for cornulin, keratin 4 and keratin 13 expression by immunohistochemistry, and graded for dysplasia. Kaplan–Meier analysis showed that loss of expression of neither cornulin (p=0.075), keratin 4 (p=0.789) nor keratin 13 (p=0.732) was significantly associated with malignant transformation of leukoplakia lesions. However, decreased expression of these proteins was significantly associated with the presence of hyperkeratosis. Only dysplasia grading correlated significantly with malignant progression of leukoplakia (p=0.024).Despite the promising outlook that decreased cornulin, keratin 4 and keratin 13 expression in the oral mucosa is associated with a premalignant state, these markers do not predict malignant transformation of leukoplakia lesions. The most likely explanation is that the aberrant differentiation state of hyperkeratotic leukoplakia lesions already causes a decreased expression, obscuring the putative association with malignant transformation. Our results support the significance of dysplasia grading for the prediction of malignant transformation.

Influence of class M1 glutathione S-transferase (GST Mu) polymorphism on GST M1 gene expression level and tumor size in oral squamous cell carcinoma

F.P. Koch, P.W. Kämmerer, P. Kämmerer, B. Al-Nawas, J. Brieger — 2010-01-08

Summary: Glutathione S-transferases (GST) are antioxidant enzymes and oxidative stress markers in oral carcinogenesis. They present a system of polymorphic proteins. Some variants are associated with increased sensitivity to toxic compounds, as it is known for the GSTM1-null variant allele. However, the influence of the GSTM1 allele variant genotype on GSTM1-mRNA quantity in oral squamous cell carcinoma (OSCC) and normal mucosa as well as the impact on prognosis remains unclear. The genotype for GSTM1 (mutation vs. wild type) was determined by polymerase chain reaction (PCR) using genomic DNA extracted from peripheral blood from 28 OSCC patients. From the same patients, 28 pairs of OSCC cells and normal oral mucosal cells were obtained by brush biopsy. mRNA was extracted from these paired samples and the expression levels of GSTM1 were examined by real-time reverse transcriptase qPCR (RT-qPCR). The mRNA expression of the OSCC samples was normalized against an external standard, as well as to the corresponding normal mucosa. The coincidence of GSTM1 genotype and GSTM1-mRNA-expression level was examined. In 15 patients (54%), the null genotype GSTM1 was present. In the GSTM1-null allele group, the GSTM1 gene expression level was determined at 1.63 (mean: 3.08; SD 3.4) folds vs. 3.6 (mean: 10.5; SD 14.2) folds in the group with the positive genotype (p=0.06), if calibrated vs. individual normal mucosa. More T3 and T4 OSCCs (+38%), higher UICC stadia (+38%) and more lymphatic metastasis (+28%) were seen in the group with the negative allele. Furthermore, positive GSTM1 genotype and enhanced GSTM1 gene expression was accompanied with increased tumor size, lymphatic metastasis status and UICC stadium. A coincidence of null type GSTM1 and lowered GSTM1 gene expression was observed. The larger tumors and more frequent lymph node metastases in this group could be explained by the insufficient cell protection by GST.