Are elderly patients presenting with squamous cell carcinoma of the oral cavity given the appropriate treatment?

Objectives

There is no consensus for the specific management of elderly patients presenting with oral cavity squamous cell carcinomas (OC SCC). We report our findings in the treatment of primary OC SCC, for patients of 70 years of age or more, in a French university hospital center.

p53 and Ki-67 as predictive markers for radiosensitivity in squamous cell carcinoma of the oral cavity? an immunohistochemical and clinicopathologic study

PURPOSE: Previously published data relating the expression of p53 and Ki-67 to radiation response in head and neck cancer are conflicting. This may be due to differences in patient selection and treatment modalities. In this study of a homogenous population of patients with oral cavity cancer, Ki-67 and p53 indices were correlated with histopathologically assessed tumor regression after preoperative radiochemotherapy and longterm outcome. METHODS AND MATERIALS: Eighty-eight patients with squamous cell carcinoma of the oral cavity and treated between September 1985 and November 1995 by preoperative radiochemotherapy and definitive surgery were included in this analysis. By immunohistochemistry (IHC) the pre-irradiation expression of p53 and of Ki-67 were analyzed and correlated with the histopathologically proven tumor regression, overall survival and local control. RESULTS: The overall 2- and 5-year survival rates were 76.5% and 63%, the locoregional control rates were 84% and 79%, respectively. After preoperative radiochemotherapy 29 patients (33%) showed complete tumor regression (ypT(0) classification). Survival and local control rates were significantly higher for patients showing ypT(0) classification than ypT(1-4) classification (p < 0.01). This effect was independent of pretreatment tumor classification in multivariate analysis. Pre-irradiation p53 status and Ki-67 index had no influence on tumor regression and clinical outcome in these patients. CONCLUSION: Complete tumor regression after preoperative treatment is related to an improved outcome in combined modality treatment of oral cavity cancer. The presented study could not demonstrate an influence of p53 and Ki-67 status as detected by immunohistochemical staining on survival, local control, or tumor regression after radiochemotherapy.     

Elective supraomohyoid neck dissection for oral cavity squamous cell carcinoma: is dissection of sublevel IIB necessary?

Spinal accessory nerve (SAN) dysfunction and related shoulder disability are common consequences of supraomohyoid neck dissection (SOHND). Nerve dysfunction is usually attributed to excessive nerve traction or devascularization during clearance of the lymph nodes posterior and superior to the SAN (sublevel IIB). The need for routine dissection of this sublevel with elective neck dissection has recently been questioned. This review article discusses whether preserving sublevel IIB lymph nodes is justified in elective SOHND for patients with squamous cell carcinoma (SCC) of the oral cavity. A review of the literature was conducted on studies of sublevel IIB dissection in elective SOHND for SCC of the oral cavity. Only two studies have prospectively investigated the incidence of lymph node metastasis in patients with clinically N0 SCC of the oral cavity. Data from these two prospective pathologic and molecular analyses of neck dissection specimens, including 122 patients with N0 oral cancer, revealed 7.3% with positive neck nodes at sublevel IIB for oral cancer in general, and 12% for tongue cancer in particular. When considering the merits of preservation of sublevel IIB, the benefit of preservation of SAN function has to be weighed against potentially reduced oncologic control.     

Is the human papillomavirus a mutual aetiological agent in oral and cervical squamous cell carcinoma?

BACKGROUND: Oncogenic HPV-types are the most important risk factor in cervical SSC and have also been implicated in the aetiology of OSSC. This evidence of infection at different anatomical sites suggests systemic susceptibility that implies that different expressions of disease should more or less correlate over long periods of time. MATERIALS AND METHODS: This was undertaken to establish whether any correlation could be found between the incidence of cervical SCC and OSCC in females and OSSC in males in South Africa, over a ten-year period, 1986 to 1995. RESULTS: Several moderate to strong correlations, which ranged from significant (p < 0.05) to highly significant (p < 0.01), between the incidence of cervical SSC and OSSC in the Black and Coloured populations, and OSSC in the White male population, were found. CONCLUSION: These results support the idea of systemic susceptibility, and infection through a common agent such as HPV, contributing to the cause of SSC.     

Pheophorbide a-mediated photodynamic therapy induces apoptotic cell death in murine oral squamous cell carcinoma in vitro and in vivo

Photodynamic therapy (PDT) with several photosensitizers is a promising modality for the treatment of cancer. In this study, the therapeutic effect of PDT using the synthetic photosensitizer pheophorbide a (Pa-PDT) was examined in AT-84 murine oral squamous cell carcinoma (OSCC) cells. The MTT assay revealed that Pa-PDT induced cell growth inhibition in a dose- and time-dependent manner. Pa-PDT treatment significantly induced intracellular ROS generation, which is critical for cell death induced by Pa-PDT. Cell cycle analysis showed the increased sub-G1 proportion of cells in Pa-PDT-treated cells. Induction of apoptotic cell death was confirmed by DAPI staining and the reduction of mitochondrial membrane potential (ΔΨm) on Pa-PDT-treated cells. The changes in apoptosis-related molecules were next examined using western blotting. Cytochrome c release and cleavage of caspase-3 and PAPR were observed in AT-84 cells, whereas Bcl-2 protein levels were decreased. To determine the therapeutic effect of Pa-PDT in vivo, a murine OSCC animal model was used. Treatment of mice with Pa-PDT significantly inhibited tumor growth, especially PDT with Pa intravenous administration (i.v. Pa-PDT), and increased proliferative cell nuclear antigen (PCNA) levels and TUNEL-stained apoptotic cells compared to vehicle-treated controls. The data demonstrate that the in vitro effects of Pa-PDT on the inhibition of tumor cell proliferation and induction of apoptosis correlate to the anticancer activity of Pa-PDT in vivo. Our findings suggest the therapeutic potential of Pa-PDT in OSCC.     

Targeting thiamine-dependent enzymes for metabolic therapies in oral squamous cell carcinoma?

Purpose

Thiamine-dependent enzymes (TDEs) linking glycolysis with the tricarboxylic acid cycle (TCA) pyruvate dehydrogenase (PDH), of the pentose phosphate pathway transketolases (TKTs), the TCA alpha-ketoglutarate deydrogenase (KGDH)/2-oxoglutarate dehydrogenase (OGDH) complex, and the amino acid catabolism branched-chain alpha-ketoacid dehydrogenase (BCKDH) complex are crucial factors for tumor metabolism. The expression of these enzymes has not been analyzed for carcinogenesis of oral squamous cell carcinoma (OSCC) with special focus on new targeted metabolic therapies as yet.

Methods

TDEs PDH, KGDH (OGDH), and BCKDH were analyzed in normal oral mucosa (n = 14), oral precursor lesions (simple hyperplasia, n = 21; squamous intraepithelial neoplasia, SIN I–III, n = 35), and OSCC specimen (n = 46) by immunohistochemistry and western blot (WB) analysis in OSCC tumor cell lines.

Results

Although the total numbers of PDH and KGDH (OGDH) positive samples decreased in OSCC, both enzymes were significantly overexpressed in the carcinogenesis of OSCC compared with normal tissue. BCKDH has been demonstrated to be significantly overexpressed in the carcinogenesis of OSCC. Specificity of the antibodies was confirmed by WB analysis.

Conclusions

This is the first study showing increased expression of TDEs in OSCC. Metabolic targeting of TDEs (including TKTs) by antagonistic compounds like oxythiamine or oxybenfothiamine may be a useful strategy to sensitize cancer cells to common OSCC cancer therapies.

     

Overexpression of macrophage inflammatory protein-3α in oral cavity squamous cell carcinoma is associated with nodal metastasis

We examined the role of macrophage inflammatory protein (MIP)-3α on oral cavity squamous cell carcinoma (OSCC) and whether it was involved in modulating OSCC cell functions. The study population was comprised of 102 patients with OSCC. MIP-3α levels in tissues were examined by immunohistochemistry and quantitative real-time RT-PCR. Effects of MIP-3α on OSCC cell function were investigated by cell proliferation assays, trans-well migration/invasion assays, and RNA interference. We found that MIP-3α was overexpressed in OSCC tumor cells. MIP-3α expression was significantly higher in tumor cells vs. normal epithelial cells, as determined by both quantitative real-time RT-PCR and immunohistochemistry. Overexpression of MIP-3α was significantly correlated with positive pN status (P=0.036). Nevertheless, there were no correlations related to patient age, pT status, overall pathological stage, cell differentiation, or perineural invasion. The long-term disease-specific survival for patient subgroups stratified by the absence or presence of MIP-3α overexpression was 70.9% vs. 54.7% (P=0.041). Multivariate analysis indicated that MIP-3α overexpression had a significantly lower disease-specific survival (hazard ratio: 2.158; P=0.037). Additionally, in vitro suppression of MIP-3α expression in OECM-1 cells using specific interfering RNAs attenuated cell migration and invasiveness. These findings suggest that MIP-3α overexpression in OSCC is associated with a poorer prognosis for patient survival and contributes to tumor metastasis.     

Prognostic and predictive factors in oral squamous cell cancer: important tools for planning individual therapy?

An escalation in the incidence of oral cancer and its attributable mortality has been observed in recent decades in Europe; oral cancer is expected to become a public health problem in the foreseeable future. However, survival rates have remained at a disappointingly stable level despite significant development in the multimodality treatment of the disease. Additionally, due to the limited prognostic value of conventional prognostic factors and the uniformity of treatment strategies, several patients are still over- or under-treated with significant personal and socio-economical impact. Here we review some promising prognostic and predictive markers that can help the clinician to improve prognostic accuracy and define the most appropriate management for the individual patient with oral cancer.     

Loss of expression of DNA repair enzyme MGMT in oral leukoplakia and early oral squamous cell carcinoma. A prognostic tool?

MGMT is a specific DNA repair enzyme that removes alkylating lesions and therefore plays an important role in maintaining normal cell physiology and genomic stability. Loss of expression of MGMT is associated with increased carcinogenic risk and sensitivity to methylating agents in different types of tumours. The expression of MGMT was immunohistochemically assessed in 12 normal oral mucosa, 38 oral leukoplakias and 33 early oral squamous cell carcinomas. The results were correlated with clinicopathological data. We found a significant loss of MGMT protein expression from leukoplakia when compared with early squamous cell carcinoma. We also observed a statistically significant relationship between smoking and the loss of MGMT protein expression. Loss of MGMT expression could be considered an early event in oral carcinogenesis with possible prognostic implications.     

Upregulation of β2-microglobulin expression in progressive human oral squamous cell carcinoma

The aim of the present study was to investigate β2-microglobulin (β2-M) expression in normal oral mucosa and progressive oral squamous cell carcinoma (OSCC) and to assess the clinical significance of β2-microglobulin expression. The study included 10 cases of normal oral mucosa epithelium specimens, 55 cases of primary OSCC specimens, and 25 cases of OSCC metastasis specimens. Immunohistochemistry was used to determine β2-M expression, and its correlation with clinicopathological factors in progressive OSCC was evaluated. Immunohistochemistry showed that strong β2-M expression was significantly asscociated with tumor size (T3, T4 vs. T1, T2; P=0.001), positive node status (N positive vs. N negative; P=0.000) and advanced clinical stage (Ⅲ, Ⅳ vs. Ⅰ, Ⅱ, P=0.000) in primary OSCC lesions. Compared to primary OSCC lesions, the frequency of β2-M expression was significantly increased in metastatic OSCC lesions (P=0.02). In addition, in vitro results from Western blotting showed increased β2-M expression in the two OSCC lines studied. Therefore, we speculate that the up-regulation of β2-M expression may contribute to the oncogenesis of human oral mucosa, tumor invasion and metastasis.     

Radiation therapy for squamous cell carcinoma of the tonsillar region: a preferred alternative to surgery?

PURPOSE: There are no definitive randomized studies that compare radiotherapy (RT) with surgery for tonsillar cancer. The purpose of this study was to evaluate the results of RT alone and RT combined with a planned neck dissection for carcinoma of the tonsillar area and to compare these data with the results of treatment with primary surgery. PATIENTS AND METHODS: Four hundred patients were treated between October 1964 and December 1997 and observed for at least 2 years. One hundred forty-one patients underwent planned neck dissection, and 18 patients received induction (17 patients) or concomitant (one patient) chemotherapy. RESULTS: Five-year local control rates, by tumor stage, were as follows: T1, 83%; T2, 81%; T3, 74%; and T4, 60%. Multivariate analysis revealed that local control was significantly influenced by tumor stage (P =.0001), fractionation schedule (P =.0038), and external beam dose (P =.0227). Local control after RT for early-stage cancers was higher for tonsillar fossa/posterior pillar cancers than for those arising from the anterior tonsillar pillar. Five-year cause-specific survival rates, by disease stage, were as follows: I, 100%; II, 86%; III, 82%; IVa, 63%; and IVb, 22%. Multivariate analysis revealed that cause-specific survival was significantly influenced by overall stage (P =.0001), planned neck dissection (P =.0074), and histologic differentiation (P =.0307). The incidence of severe late complications after treatment was 5%. CONCLUSION: RT alone or combined with a planned neck dissection provides cure rates that are as good as those after surgery and is associated with a lower rate of severe complications.     

Human FAT1 cadherin controls cell migration and invasion of oral squamous cell carcinoma through the localization of β-catenin

FAT1 [Homo sapiens FAT tumor suppressor homolog?1 (Drosophila)] is an intrinsic membrane protein classified as a member of the cadherin superfamily. The FAT1 gene is a tumor suppressor in humans as well as being the pivotal gene for cell morphogenesis and migration. Deletion of this gene could play a role in the characteristics of oral squamous cell carcinomas (OSCCs), involving cell adhesion, migration and/or invasion. This study investigated the mechanisms by which FAT1 is involved in the biological behavior of OSCCs. First, a rat monoclonal antibody was developed against a FAT1 intra-cellular domain epitope, and used for an immunohistochemical study of FAT1 in clinically obtained OSCC samples. FAT1 was localized at lamellipodial edges or cell-cell boundaries in normal cells and well differentiated OSCCs, but showed a diffuse cytoplasmic and nuclear distribution in moderately-poorly differentiated OSCCs. FAT1-siRNA was transfected into OSCCs resulting in a drastic inhibition of cell migration and invasion based on the suppression of FAT1 expression and disorganized localization of β-catenin which is associated with cell polarity and migration. These results suggested that FAT1 may be involved in the migration and invasion mechanisms of OSCCs and, therefore, it could be an important target for the development of new therapeutic strategies.     

ACR appropriateness criteria® adjuvant therapy for resected squamous cell carcinoma of the head and neck

Locoregional recurrence following surgical resection alone for stage III/IV head and neck cancer is common. Adjuvant radiotherapy has been shown to improve post-operative locoregional control when compared to pre-operative radiotherapy for head and neck cancers. Following surgical resection, adverse pathological features determine the need for adjuvant therapy. High-risk pathologic features include extranodal tumor spread and involved surgical margins. Other adverse pathologic features include T 3-4 tumors, perineural invasion, lymphovascular space invasion, low neck adenopathy, and multiple tumor involved cervical lymph nodes. The standard adjuvant therapies are post-operative radiation therapy or post-operative chemoradiotherapy. Post-operative chemoradiotherapy yields superior locoregional control, progression-free survival, and in some studies, overall survival compared to post-operative radiotherapy for high-risk patients in multiple randomized studies. Pooled analyses of randomized data demonstrate that post-operative concurrent chemoradiotherapy is associated with overall survival benefits for patients with involved surgical margins as well as those with extranodal tumor spread. Post-operative radiotherapy concurrent with cisplatin at 100 mg/m(2) every 21 days is the current standard chemoradiotherapy platform adjuvant head and neck cancer treatment. Post-operative radiotherapy and post-operative chemoradiotherapy radiation treatment volumes are not standardized and should be designed based on the risk of recurrence and clinically occult involvement of head and neck subsites and nodal regions. Evidence supports a post-operative radiotherapy and chemoradiotherapy radiation dose of at least 63 Gy for high-risk patients and at least 57 Gy for low risk patients.