An intronic poly (AT) polymorphism of the DNA repair gene XPC and risk of squamous cell carcinoma of the head and neck: a case-control study.

Inherited polymorphisms of DNA repair genes may contribute to variations in DNA repair capacity and genetic susceptibility to cancer. In a hospital-based case-control study of 287 non-Hispanic white patients with newly diagnosed SCCHN and 311 control subjects matched on age, sex, ethnicity, and smoking status, we investigated the role of a newly identified variant allele of XPC, XPC-PAT+. We found that the frequency of the XPC-PAT+ allele was higher in the cases (0.409) than in the controls (0.333; P = 0.007). Fifty cases (17.4%) and 37 controls (11.9%) were XPC-PAT+/+, and 135 (47.0%) cases and 133 controls (42.8%) were XPC-PAT+/-. XPC-PAT+/- and XPC-PAT+/+ subjects were at significantly increased risk for SCCHN [adjusted odds ratios = 1.44 and 1.85, respectively (95% confidence intervals, 1.01-2.05 and 1.12-3.05, respectively; trend test, P = 0.007)]. We did not find ethnic difference in the frequency of XPC-PAT+ allele among four groups aged between 19 and 75 years: non-Hispanic whites, 294; African-Americans, 178; Hispanic-Americans, 103; and native Chinese, 119 (0.333, 0.281, 0.296, and 0.353, respectively). The case-control findings support the hypothesis that the XPC-PAT+ allele may contribute to the risk of developing SCCHN.

Evaluation of topical gene therapy for head and neck squamous cell carcinoma in an organotypic model.

The organotypic (raft) culture system has been shown to be a useful model for examining the effects of biochemical manipulations on various epithelial cell types, using in vitro conditions that simulate the in vivo environment of the tissue of origin. To investigate this method as a model for topical gene therapy, we cultured the oral head and neck squamous cell carcinoma cell line TR146 on fibroblast-containing collagen gels at the air-medium interface and assessed the efficiency of transduction of a topically applied adenoviral vector containing beta-galactosidase cDNA. Diffuse expression of -galactosidase activity in multiple cell layers demonstrated effective penetration of the vector. Transduction efficiency and therapeutic activity of a replication-defective recombinant adenovirus containing wild-type p53 cDNA linked to a FLAG marker (AdCMV-p53-FLAG) were then assessed in TR146 organotypic cultures transduced by topical application. Twenty-four, 48, and 72 h after transduction, the cultures were harvested, and residual cell number and FLAG peptide expression were determined. The number of cells in p53 transduced cultures was significantly reduced in comparison to controls at all three time points (P < 0.001), which resulted from the induction of apoptosis as determined by in situ DNA end labeling. In addition, the FLAG peptide was expressed diffusely in the residual cells, further confirming effective transduction and expression of the exogenous gene products throughout multiple layers. We conclude that the organotypic culture is an effective in vitro model for assessing the efficacy of topically applied gene therapy on head and neck squamous carcinomas and premalignancies.

Mutagen sensitivity to benzo(a)pyrene diol epoxide and the risk of squamous cell carcinoma of the head and neck.

Genetic susceptibility appears to modulate an individual's risk of tobacco-induced carcinoma. One biomarker of such susceptibility, chromatid breaks induced in vitro in lymphocytes by the mutagen bleomycin, is an independent risk factor for several malignancies. To date, the more etiologically appropriate mutagen benzo(a)pyrene diol epoxide (BPDE) has only been used in one lung cancer study. Our objective was to evaluate the association between the BPDE-induced chromatid breaks per cell (b/c) values and the risk of squamous cell carcinoma of the head and neck (SCCHN) in a pilot case-control study. Blood samples were obtained from 60 SCCHN patients and 112 healthy controls matched for age, sex, ethnicity, and smoking status. After incubation and exposure to BPDE, metaphase spread slides were created, and the average b/c values were determined. Univariate analysis identified elevated BPDE-induced b/c values as a significant risk factor [P < 0.05, crude odds ratio (OR)=1.94, 95% confidence interval (CI)=1.00-3.74]. On multivariate analysis using logistic regression models and including age, sex, ethnicity, and smoking status, BPDE-induced b/c values remained an independent risk factor for disease (P < 0.05, adjusted OR=2.36, 95% CI=1.17-4.79). Furthermore, when b/c values were divided based on control values into low, medium, and high tertiles, there was a dose-response relationship: an adjusted OR of 1.28 (95% CI=0.49-3.33) for the middle tertile and an adjusted OR of 4.09 (95% CI=1.67-10.0) for the high tertile (trend test, P < 0.001). These findings suggest that high BPDE-induced b/c values in lymphocytes are an independent risk factor for SCCHN and a marker for genetic susceptibility to tobacco-induced carcinogenesis.

Reduced DNA repair capacity in head and neck cancer patients.

Head and neck cancers (HNCs) are malignancies that can be induced by tobacco use, although host-specific factors such as the DNA repair capacity (DRC) may modulate individual susceptibility to tobacco carcinogenesis. To test the hypothesis that genetically determined DRC modulates HNC susceptibility, we measured the DRC in the peripheral blood lymphocytes of 55 patients with newly diagnosed, previously untreated HNC and 61 healthy controls by the host-cell reactivation assay using a reporter gene damaged by benzo(a)pyrene diol epoxide, an ultimate tobacco-related carcinogen. The mean DRC was significantly lower in cases (8.6%) than it was in controls (12.4%; P < 0.001). The DRC was an independent risk factor for HNC (P < 0.01); those in the middle and lowest tertiles of DRC had increased odds ratios [2.17 (95% confidence interval, 0.74-6.39) and 4.27 (confidence interval, 1.45-12.5), respectively] for HNC. These findings suggest that individuals with reduced DRC may be at increased risk of developing HNC.

Alcohol dehydrogenase 3 genotype is not associated with risk of squamous cell carcinoma of the oral cavity and pharynx.

Alcohol is one of the major risk factors for oral and pharyngeal cancer. The rate-limiting step in alcohol metabolism is the oxidation (activation) of ethanol to acetaldehyde by the alcohol dehydrogenases (ADHs). It has been hypothesized that individuals who are homozygous for the fast allele (ADH(1-1)(3)) are at greater risk for alcohol-related cancers. To test this hypothesis, we investigated the association between the ADH3 genotype and oral and pharyngeal cancer risk in a large racially homogeneous case-control study of 229 patients and 575 matched control subjects with frequency matching on age, sex, and smoking status. Although the smoking status was matched between cases and controls, current and former alcohol use remained a significant risk factor, compared with never use (odds ratio, 2.08; 95% confidence interval, 1.37-3.17; odds ratio, 1.97; 95% confidence interval, 1.25-3.09; and odds ratio, 1.00, respectively). The ADH1(3) allele frequency of controls was 57.4%, consistent with reports of similar racial groups (50-60%). The genotype distribution in controls was also consistent with the Hardy-Weinberg equilibrium (P = 0.51). However, the ADH1(3) allele frequency and ADH(1-1)(3) genotype frequency were not significantly different between cases and controls [55.5% versus 57.4% (P = 0.52), and 30.6% versus 31.3% (P = 0.91), respectively]. There was no association between ADH3 genotypes (ADH(1-1)(3), ADH(1-2)(3), and ADH(2-2)(3)) and risk of oral and pharyngeal cancer (odds ratios, 1.00; 0.96; 95% confidence interval, 0.68-1.37; and odds ratio, 1.23; confidence interval, 0.78-1.93, respectively). Therefore, we found no evidence that supports a main effect of ADH3 genotype or a combined effect of alcohol and ADH3 genotype on risk of cancer of the oral cavity or pharynx.

Reduced expression of hMLH1 and hGTBP/hMSH6: a risk factor for head and neck cancer.

Head and neck cancer, like lung cancer, is considered a paradigm of an environmentally induced disease. Genetically determined variation in DNA repair capacity is thought to contribute to susceptibility to tobacco-related cancers. In this molecular epidemiology study, we investigated the association between DNA mismatch-repair (MMR) gene expression and the risk of head and neck cancer. Using our newly developed multiplex reverse transcription-PCR assay, we simultaneously evaluated the relative expression levels of five MMR genes (hMSH2, hMLH1, hPMS1, hPMS2, and hGTBP/hMSH6) in the peripheral blood lymphocytes of 78 patients (mean age = 59.6 +/- 12.4 years) with newly diagnosed head and neck cancer and 86 healthy controls (mean age = 58.2 +/- 12.9 years). The relative MMR gene expression was not correlated with disease stage or tumor site in the cases or with smoking and alcohol use in the controls. The expression levels increased with age in both cases and controls, but the mean expression of hMLH1, hPMS1, and hGTBP/hMSH6 was significantly lower in the cases than in the controls (P < 0.05). Using the median expression level in controls as the cutoff value, significantly increased odds ratios (ORs) were associated only with low expression of hMLH1 (OR = 4.4; 95% confidence interval = 2.1-9.1) and hGTBP/hMSH6 (OR = 2.1; 95% confidence interval = 1.1-4.1) after adjustment for age, sex, ethnicity, smoking status, and alcohol use. The results suggest that low hMLH1 and hGTBP/hMSH6 expression is associated with an increased risk of head and neck cancer. Additional studies with a larger number of subjects are warranted to confirm these findings.

Postoperative radiotherapy for malignant tumors of the submandibular gland.

PURPOSE: This retrospective study assessed the outcome and patterns of failure for patients with malignant submandibular tumors treated with surgery and postoperative radiation. METHODS AND MATERIALS: Between 1965 and 1995, 83 patients aged 11-83 years old received postoperative radiotherapy after resection of submandibular gland carcinomas. The most common radiation technique was an appositional field to the submandibular gland bed using electrons either alone or mixed with photons. Primary tumor bed doses ranged from 50 to 69 Gy (median, 60 Gy). Regional lymph nodes (ipsilateral Levels I-IV) were irradiated in 66 patients to a median dose of 50 Gy. Follow-up time ranged from 5 to 321 months (median, 82 months). RESULTS: Actuarial locoregional control rates were 90%, 88%, and 88% at 2, 5, and 10 years, respectively. The corresponding disease-free survival rates were 76%, 60%, and 53%, because 27 of 74 patients (36%) who attained locoregional control developed distant metastases. Adenocarcinoma, high-grade histology, and treatment during the earlier years of the study were associated with worse locoregional control and disease-free survival. The median survival times for patients with and without locoregional control were 183 months and 19 months, respectively. Actuarial 2-, 5-, and 10-year survival rates were 84%, 71%, and 55%, respectively. Late complications occurred in 8 patients (osteoradionecrosis, 5 patients). CONCLUSIONS: High-risk cancers of the submandibular gland have a historic control rate of approximately 50% when treated with surgery alone. In the current series, locoregional control rates for high-risk patients with submandibular gland cancers treated with surgery and postoperative radiotherapy were excellent, with an actuarial locoregional control rate of 88% at 10 years.

Great auricular nerve: anatomy and imaging in a case of perineural tumor spread.

We present the imaging and clinical findings of a case of recurrent cutaneous squamous cell carcinoma of the face in which CT and MR imaging revealed perineural tumor spread along the great auricular nerve. The great auricular nerve is a superficial cutaneous branch of the cervical plexus, providing sensory innervation to the skin of the parotid and periauricular region. Our purpose was to familiarize the reader with the anatomy of this nerve and imaging's potential role in the diagnosis of perineural tumor spread along this seldom seen structure.

Differential effects of retinoic acid and N-(4-hydroxyphenyl)retinamide on head and neck squamous cell carcinoma cells.

Both retinoic acid (RA) and the synthetic retinoid N-(4-hydroxyphenyl)retinamide (4HPR) have shown efficacy in head and neck cancer chemoprevention trials. To compare their activity and mechanism of action, the 1483 oral head and neck squamous cell carcinoma (HNSCC) cell line was grown in organotypic culture, an in vitro system that allows cellular stratification and simulates carcinoma in situ, and was exposed to 10 micromol/L of either RA or 4HPR. Extensive apoptosis, as evidenced by in situ deoxyribonucleic acid end-labeling, occurred in 4HPR-treated cultures after 9 days, with >80% cell loss (P< .001). In contrast, the growth of cultures treated with RA was inhibited by only 32%, with no evidence of apoptosis. Because 4HPR has low systemic toxicity and is a potent inducer of apoptosis in HNSCC cells, its role in chemoprevention of head and neck cancers, including cancers that are resistant to RA-induction therapy, warrants further investigation.

Prognostic factors affecting outcome in lower gingival carcinoma.

Squamous cell carcinoma of the lower gingiva is a rare lesion that frequently invades the mandible. To determine the factors that affect local disease control and overall survival, a retrospective review of 155 previously untreated patients was performed. Primary lesions larger than 3 cm (P = .021) and persistently disease-positive surgical margins (P = .027) were found to be associated with decreased local control rates. Survival was adversely affected by advanced T stage (P = .001), positive initial and final surgical margins (P = .004), mandibular invasion (P = .014), and cervical metastases (P<.001). Extent of mandibular resection, tumor extension beyond the lower gingiva, recent dental extractions in the region of the primary, perineural invasion, and histologic grade did not affect local control or survival. Although lower gingival carcinoma tends to involve the mandible, our findings indicate that tumor size is more important than mandibular invasion in predicting local disease control. Larger tumors that have a greater propensity for local recurrence and poorer survival require a more extensive surgical resection.

An unusual metastasis to the thumb in a laryngectomized tracheoesophageal speaker.

Neoplastic spread by tumor cell implantation into adjacent or distant traumatized tissues is a well-documented phenomenon but is a rare mechanism of tumor dissemination. In patients with head and neck squamous cell carcinoma, mechanical implantation of tumor cells into tracheotomy and percutaneous endoscopic gastrostomy sites has been described, but hematogenous dissemination occurs far more commonly, typically resulting in pulmonary disease. Digital metastases, either by implantation or by hematogenous spread, have never been documented, to our knowledge. We report a case of metastasis to the thumb used for digital occlusion during tracheoesophageal speech in a laryngectomized patient with lung metastases. Although this may have been a manifestation of either hematogenous dissemination or direct neoplastic seeding from contaminated pulmonary secretions, we propose that repeated trauma from digital stomal occlusion predisposed this site to metastatic spread.

Isotretinoin therapy for recurrent respiratory papillomatosis.

Retinoic acid has been advocated for use in several premalignant and malignant epithelial lesions of the head and neck, including benign recurrent respiratory papillomatosis, with varying results. We describe a 24-year-old man with extensive tracheoesophageal and bronchoalveolar papillomatosis that degenerated into squamous cell carcinoma. Multiple endoscopic carbon dioxide laser excisions, at one point performed on a weekly basis, as well as a prolonged trial of interferon, failed to control the progression of his disease. Isotretinoin (13-cis-retinoic acid) therapy (1 mg/kg per day) was instituted, with dramatic clinical, radiographic, and functional improvement. The patient experienced no significant toxic effects and required no endoscopic procedures over a 6-month period. We propose that isotretinoin may be an effective adjuvant therapy for aggressive respiratory papillomatosis.

A comparative study of the fallopian canal at the meatal foramen and labyrinthine segment in young children and adults.

If entrapment is a critical factor in pathogenesis, the lower incidence of Bell's palsy in children compared with adults may have an anatomical basis. Histologic sections of 20 temporal bones from children younger than 2 years were examined to determine the diameter of the facial nerve and fallopian canal at the meatal foramen and in the labyrinthine segment. No statistically significant difference in the nerve/canal ratios in these areas was found. Comparisons were made with similar data from 10 adult temporal bones. The nerve/canal ratios in the labyrinthine portion were similar in both age groups; however, the ratio at the meatal foramen was significantly smaller in children. This may be due, in part, to growth of the vertical crest, which was found to increase considerably in length and width by adulthood. These results suggest that the facial nerve is not as tightly contained at the meatal foramen in children and provides a possible explanation for the relative infrequency of Bell's palsy in this age group.

Lower gingival carcinoma. Clinical and pathologic determinants of regional metastases.

OBJECTIVE: To determine which clinical and pathologic features are associated with regional metastases in patients with lower gingival squamous cell carcinoma. PATIENTS AND METHODS: The medical charts of 155 previously untreated patients seen between 1970 and 1990 were retrospectively analyzed. All patients underwent surgical resection of the primary tumor. In addition, 66 patients underwent elective neck dissection, while a therapeutic neck dissection was performed in 28. Sixty-one patients who had clinically N0 neck disease did not undergo treatment of the cervical lymphatics. RESULTS: T stage (P = .01), radiologic (P = .03) or histologic (P = .01) evidence of mandibular invasion, and decreased tumor differentiation (P = .004) significantly correlated with the presence or evolution of regional metastases. In addition, tumors involving the symphyseal region were associated with an increased incidence of nodal metastases, although the relationship did not achieve statistical significance (P = .08). Occult regional disease was found in 18% of patients who underwent elective neck dissection, and the presence of metastases was pathologically confirmed in 68% who underwent a therapeutic dissection. Six patients with clinically N0 neck disease did not undergo elective dissection and later developed regional metastases. In all patients, survival was adversely impacted by the presence or later development of regional metastases (P < .001). Two- and 5-year survival rates for patients with no cervical metastases were 0.91 and 0.85, respectively, while for those with cervical metastases, the survival at 2 and 5 years declined to 0.72 and 0.59. More importantly, the 2- and 5-year survivals of patients with clinically N0 necks who were found to have lymph node metastases histologically after neck dissection were 1.00 and 0.78. This contrasts with the 0.50 survival rate at 2 and 5 years for those who did not undergo elective dissection and later developed cervical metastases (P = .36). CONCLUSIONS: Patients with adverse clinical and pathologic features, even in the absence of demonstrable neck disease, are at risk for harboring regional metastases. Elective treatment of the cervical lymphatics should be considered for patients with primary tumors that overlie the mandibular symphysis, moderately or poorly differentiated tumors, or radiographic or histologic evidence of mandibular invasion.

Surgical management of cervical lymph node metastases.

Surgical management of regional metastases from upper aerodigestive tract malignancies has shifted from the traditional radical resection to more conservative procedures that are tailored to the extent of nodal disease and to the location of the primary tumor. When the primary tumor is treated surgically, a selective neck dissection is now performed routinely in the patient with a clinically negative neck who has a significant risk of developing regional disease. Future directions of research should emphasize clinicopathologic and molecular predictors of occult metastases in the N0 neck to allow selective, therapeutic, and cost-effective treatment of the cervical lymphatics.

Levator claviculae muscle presenting as a neck mass: CT imaging.

We describe the imaging and clinical features of a patient presenting with a posterior cervical space mass. The only abnormality identified on CT was a variant muscle, the levator claviculae. Radiologists are cautioned to be familiar with this muscle and its appearance to avoid misdiagnosing it as pathologic.

The importance of peer group ("crowd") affiliation in adolescence.

Many researchers have speculated about the role peer groups play in adolescent development, but few have examined teenagers' own perspective on the importance of group affiliations. The two studies reported here, involving 1,300 7th to 12th graders in three Midwestern U.S. communities, assessed teenagers' valuation of belonging to a "crowd" as well as the reasons they cited to support or oppose crowd affiliation. The importance of crowd affiliation declined across age. Younger adolescents generally favored membership, emphasizing the crowd's ability to provide emotional or instrumental support, foster friendships and facilitate social interaction. Older respondents expressed dissatisfaction with the conformity demands of crowds and felt their established friendship networks obviated the need for peer group ties. The importance of crowd affiliation was not related to the strength of respondents' sense of identity but did vary significantly with their willingness to conform to peers and the centrality of their position in peer groups or the type of crowd to which they belonged. Findings emphasized that adolescent peer groups can serve multiple functions, whose salience shifts with age.

Surgical outcomes in head and neck cancer patients 80 years of age and older.

BACKGROUND: Elderly patients over 80 years of age represent a growing population, some of whom have complex medical problems that are compounded by the presence of upper aerodigestive tract cancer. METHODS: Forty-three patients, aged 80 years and older, who were initially seen with head and neck squamous cell carcinoma from 1986 to 1992 at a tertiary-care center were compared with 79 similar patients, aged 65 years or younger, in a retrospective, case-control study. RESULTS: Median overall survival for the patients over 80 years of age was significantly lower than that for the controls (p = .001). However, their overall survival was similar to the actuarial survival for the general octogenarian population. Advanced age also adversely affected local control (p < .001) and disease-specific survival (p = .041). Although the older age group had a higher frequency of morbid preoperative conditions, there were no significant differences in perioperative or postoperative complications between the two groups. CONCLUSIONS: Careful preoperative staging and evaluation of associated medical illnesses, as well as skillful perioperative and postoperative management, are essential for reducing operative morbidity and mortality in the octogenarian patient. Successful outcome depends upon appropriate surgical management, treatment of concurrent illnesses, and minimization of postoperative complications. Individualized surgical management of the elderly head and neck cancer patient is effective, well tolerated, and clinically indicated for upper aerodigestive tract malignancies.

Glutathione-S-transferase polymorphisms and risk of squamous-cell carcinoma of the head and neck.

Differences in genetic susceptibility to tobacco-induced carcinogenesis appear to modulate an individual's risk of squamous-cell carcinoma of the head and neck (SCCHN). Risk for SCCHN may be associated with the null alleles of the carcinogen-metabolizing genes glutathione-S-transferase (GST) T1 and GSTM1. In this study, we evaluated the association between GSTM1 and GSTT1 null genotypes and risk of SCCHN in a matched case-control study of 162 patients with SCCHN and 315 healthy controls. Our results showed that 53.1% of cases and 42.9% of controls were null for GSTM1, whereas 32.7% of cases and 17.5% of controls were null for GSTT1 (p < 0.05 and p < 0.001, respectively). Furthermore, 19.8% of cases but only 7.9% of controls were null for both genes (p < 0.001). Multivariate analysis using logistic regression models, including age, sex, ethnicity, smoking status, alcohol status and GST genotypes, showed that both of these genotypes remained independent risk factors for disease [adjusted odds ratios (ORs) = 1.50 and 2.27, respectively; 95% confidence intervals (CIs) = 1.01-2.23 and 1.43-3.60, respectively). When the genotypes were divided into neither null, either null or both null, there was a dose-response relationship (adjusted OR = 1.50, 95% CI = 0.98-2.30) for the either-null group and (adjusted OR = 3.64, 95% CI = 1.94-6.84) for the both-null group (p < 0.001, trend test). Our findings suggest that the GSTM1 and GSTT1 null genotypes are independent risk factors for SCCHN and markers for genetic susceptibility to tobacco-induced carcinogenesis.

XPD/ERCC2 polymorphisms and risk of head and neck cancer: a case-control analysis.

DNA repair capacity is central in maintaining normal cellular functions. Variants of several DNA repair genes,including the nucleotide excision repair gene XPD, have been described recently. Because we previously reported that patients with squamous cell carcinoma of the head and neck (SCCHN) had lower DNA repair capacity than healthy controls, we hypothesized that inherited polymorphisms of XPD may contribute to genetic susceptibility to SCCHN, a tobacco-related cancer. To test this hypothesis, we conducted a hospital-based case-control study of 189 SCCHN patients and 496 cancer-free controls who were frequency-matched on age, gender and smoking status. All subjects were non-Hispanic whites. Two XPD polymorphisms (C22541A and A35931C) were typed using the restriction enzymes TfiI and PstI, respectively. Multivariate logistic regression analysis was performed to calculate adjusted odds ratios (ORs) and 95% confidence intervals (CIs). In the controls, the frequencies of the variant 22541A and 35931C alleles were 44.7% and 33.8%, respectively. The frequency of the 22541A homozygous genotype (22541AA) was lower in cases (15.9%) than in controls (20.4%) but was not associated with risk (adjusted OR = 0.90; 95% CI = 0.52-1. 56) for SCCHN. The frequency of the 35931C homozygous genotype (35931CC) was higher in cases (16.4%) than in controls (11.5%) and associated with a borderline increased risk (adjusted OR = 1.55; 95% CI = 0.96-2.52) for SCCHN. The risk was higher in older subjects (OR = 2.22; 95% CI = 1.03-4.80), current smokers (OR = 1.83; 95% CI = 0.79-4.27) and current drinkers (OR = 2.59; 95% CI = 1.25-5.34) in the stratification analysis. These results suggest a gene-environment interaction, but this did not reach statistical significance. The findings are limited due to the relatively small numbers in the subgroups and need to be verified by further investigations.