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Annals of Surgical Oncology 10:551-557 (2003)
© 2003 Society of Surgical Oncology

NEW APPROACHES TO THE TREATMENT OF HEPATIC MALIGNANCIES

Squamous Cell Carcinoma of the Head and Neck in Nonsmokers and Nondrinkers: An Analysis of Clinicopathologic Characteristics and Treatment Outcomes

Sam M. Wiseman, MD, FRCS(C), Helen Swede, PhD, Daniel L. Stoler, PhD, Garth R. Anderson, PhD, Nestor R. Rigual, MD, Wesley L. Hicks, Jr, DDS, MD, Wade G. Douglas, MD, Dongfeng Tan, MD and Thom R. Loree, MD

From the Departments of Head and Neck Surgery (SMW, NRR, WLH, WGD, TRL), Experimental Pathology (HS, DLS), Cancer Genetics (GRA), and Pathology (DT), Roswell Park Cancer Institute, Buffalo, New York.

Correspondence: Address correspondence and reprint requests to: Thom R. Loree, MD, Department of Head and Neck Surgery, Roswell Park Cancer Institute, Elm & Carlton Streets, Buffalo, NY 14263; Fax: 716-845-8646; E-mail: thom.loree{at}roswellpark.org

ABSTRACT

Background: The objective of this study was to describe the clinicopathologic manifestations of disease and outcomes of treatment among individuals without a history of smoking tobacco or consuming alcohol who develop head and neck cancer.

Methods: Of 1648 invasive head and neck cancer cases treated between 1970 and 2001 at Roswell Park Cancer Institute, 40 patients were identified as never having smoked tobacco or consumed alcohol during their lifetime. These cases were reviewed to gather data on multiple clinicopathologic variables.

Results: Mean age at presentation of nonsmoker/nondrinker head and neck cancer patients was 60 years (range, 27 to 90 years), and 78% (n = 31) of the patients were women. The distributions of tumor sites were 75.0% oral cavity (n = 30), 20.0% oropharynx (n = 8), and 5.0% larynx (n = 2). Sixteen patients (40%) experienced a recurrence of disease during the follow-up period, and 10 patients (25.0%) developed a second primary tumor a median of 6 years after their initial diagnosis.

Conclusions: The nonsmoker/nondrinker head and neck cancer patient tends to be elderly and female, have oral cavity primary tumors, and be predisposed to second primary tumor development.

Key Words: Head and neck cancer • Nonsmoker • Nondrinker • Squamous cell carcinoma

Squamous cell carcinoma of the upper aerodigestive tract has been clearly linked to the use of tobacco products and alcohol consumption. However, a small minority of patients do not use either of these substances. Currently, the underlying etiology of head and neck cancer evolution in this patient population remains unclear. Also not well understood is the biological behavior of these tumors in this population (i.e., the pattern of disease recurrences and chances of second primary tumor development), and their response to current treatment modalities (surgery, radiation, and chemotherapy) is also currently unknown. The objective of this study was to gain an appreciation of the clinical manifestation of disease and the results of treatment, with the ultimate goal of improving the treatment outcomes in this unique head and neck cancer patient population.

PATIENTS AND METHODS

We conducted a case-series investigation of 40 nonsmoking/nondrinking (NSND) patients treated for invasive squamous cell carcinoma of the head and neck at Roswell Park Cancer Institute, Buffalo, NY, between January 1970 and December 2001. These patients were selected from the population of 1648 consecutive patients treated during the study period as listed in the hospital’s tumor registry. The selected patients were all those who had reported a definitive history of no cigarette smoking, as documented in the registry, and who also reported a history of no alcohol use in a self-administered epidemiological survey. Alcohol-use data were gathered from the Patient Epidemiologic Data System (PEDS), a database of 30,000 patients who completed a 16-page self-administered questionnaire at the time of hospital admission. Smoking status identified in the tumor registry was confirmed with the PEDS database. With the data from the tumor registry, PEDS, and a medical chart review, criteria for inclusion in our study population were the following: (1) history of no tobacco use (cigarette smoking, pipe smoking, cigar smoking, or tobacco chewing), (2) history of no alcohol consumption, (3) no history of head and neck irradiation, (4) no history of betel nut chewing, (5) no current or previous history of immunosuppression (disease or treatment related), and (6) no prior history of head and neck cancer. All staging was performed in accordance with the 1999 American Joint Committee on Cancer guidelines for staging head and neck cancer.1 Medical records of all 40 patients were reviewed by a physician. Vital status was obtained for all 40 patients. All gross disease was removed from patients treated surgically, and for all patients, intraoperative frozen-section margins were negative. One patient refused treatment because of advanced-stage disease. We excluded this patient from analyses of recurrence. All patients in this study had primary disease presentations, and all patients underwent their treatment and follow-up at Roswell Park Cancer Institute.

We compared recurrence rates and the incidence of second primary tumors according to histological subtype by using Fisher’s exact {chi}2 test. Among patients with tumors of the oral cavity (n = 27), we compared recurrence rates across treatment groups by using Fisher’s exact {chi}2 test and examined overall survival by the method of Kaplan and Meier. Recurrence was defined as a pathologically confirmed incidence of head and neck cancer at a local, regional, or distant site. A second primary tumor was defined in accordance with the criteria of Warren and Gates.2 In accordance with these criteria, second primary tumors were defined in the following manner: (1) each of the tumors must present a definite picture of malignancy, (2) each must be distinct, and (3) the probability of one being a metastasis of the other must be excluded.2 Survival time was calculated from the date of diagnosis to date of last follow-up or death. The median follow-up time for survivors was 7.2 years, with a range of 8.0 months to 23.3 years. Approximately 85.7% of those who survived were followed up clinically for >=1 year, and 75.0% were followed up for >=2 years.

RESULTS

Patient and Primary Tumor Characteristics
The mean age at presentation of the NSND patients was 60 years (range, 27–90 years), which was comparable to the overall patient population, which had a mean age of 60 years (range, 18–97 years). The female to male ratio in the NSND population was 3:1, with 30 female patients and 10 male patients. This is in contrast to the patient sex distribution in the general population, which was predominantly male (68%). In the NSND patient population, all patients but one were white (97.5%). The racial distribution in the general population was 92.2% white, 7.4% black, .4% other racial group, and .1% unavailable. Six NSND patients had a history of another primary malignancy. The location of these other primary tumors was breast (n = 2), cervix (n = 1), ovary (n = 1), colon (n = 1), and skin (n = 1). No NSND patients developed cancers of either the lung or esophagus during follow-up. Ten patients (25.0%) reported a family history of cancer in either a first- or second-degree relative. Of these 10, 1 patient reported a family member with a head and neck malignancy.

Table 1 shows the distribution of tumor sites and stages. The breakdown of tumor sites was 75.0% oral cavity (n = 30), 20.0% oropharynx (n = 8), and 5.0% larynx (n = 2). Most patients presented with advanced-stage disease (55.0%). Tumors of 17.5% of patients were stage I (n = 7), 27.5% were stage II (n = 10), 15.0% were stage III (n = 7), and 40% were stage IV (n = 16) at initial diagnosis. Eighteen patients (45%) had evidence of cervical lymph node metastases at initial presentation. No patient had distant metastatic disease at the time of their initial diagnosis.


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  		TABLE 1. Disease stage by tumor site in 40 nonsmoking, nondrinking patients with head and neck cancer
 
Overall Survival, Recurrence Rates, and Second Primary Tumors
Five-year survival for the 40 patients was 69.5% ± 15.4% (Fig. 1). Seven patients (17.5%) died from their head and neck malignancy, 2 patients (5.0%) died of other causes, 3 patients (7.5%) are alive with disease, and the remaining 28 patients (70.0%) are alive with no evidence of disease. The pattern of disease recurrence is listed in Table 2. Sixteen patients (40.0%) experienced a relapse in a local or regional (neck) site (seven local; six regional; one local and regional; one distant; and one local, regional, and distant). As seen in Table 3, 10 patients (25.0%) in the study population went on to develop second primary tumors (range, 1–3) of the head and neck. In this study, second primary tumors are defined by the criteria of Warren and Gates.2 All subsequent primary tumors, even when located within the same head and neck anatomical site, were distinct and separate from the original primary tumor and other subsequent primary tumors. The subsite breakdown and side of the subsequent primary tumors are listed in Table 4. When subsequent primary tumors were located on the same side and within the same anatomical subsite as the original primary tumor, as was the case for three patients (30% of second primary tumors), the diagnosis was made a mean of 12 years after diagnosis of the primary tumor. Four patients in the oral cavity primary tumor patient population developed third primary tumors, and one patient in this group went on to develop a fourth primary tumor. All third and fourth primary tumors were located in the oral cavity. Neither of the laryngeal cancer patients went on to develop second primary malignancies. The median time to second primary tumor development was 5 years 3 months. Two (28.6%) of the seven patients who eventually died of head and neck cancer died after the development of a second primary tumor. Five patients developed third and fourth primary tumors.



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  		FIG. 1. Kaplan-Meier survival curve of 40 nonsmoking, nondrinking head and neck cancer patients. The overall 5-year survival was 69.5% ± 15.4%.

 

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  		TABLE 2. Disease recurrence in 39 treated nonsmoking, nondrinking patients with head and neck cancer
 

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  		TABLE 3. Incidence of subsequent head and neck tumors in 39 treated nonsmoking, nondrinking patients with head and neck cancer
 

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  		TABLE 4. Pattern of subsequent head and neck tumors in 39 treated nonsmoking, nondrinking patients with head and neck cancer
 
Oral Cavity Cancer
Of the 30 patients with a malignancy at this site, the most frequent subsite (41.4%) was the oral tongue (n = 12), followed in frequency by buccal mucosa (n = 6), alveolar ridge (n = 5), floor of mouth (n = 3), and lip (n = 2). As seen in Table 1, 17 patients (56.7%) with cancer of the oral cavity had early-stage disease (stage I and II), and 13 (43.3%) patients had advanced-stage disease (stage III and IV). As seen in Table 5, of the 29 patients undergoing treatment, 20 (70.0%) were treated with surgery alone, 7 (24.1%) were treated with surgery and postoperative adjuvant radiation, and 2 (6.9%) were treated with radiotherapy alone. Patients treated with surgery alone tended to have early-stage disease compared with patients who received both surgery and postoperative radiation, yet their rate of disease recurrence was higher (45.0% vs. 28.6%, respectively; P = .13).


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  		TABLE 5. Disease recurrence in 29 treated nonsmoking, nondrinking patients with oral cavity cancer
 
Table 5 summarizes the recurrence pattern in patients with cancers of the oral cavity. In the surgery-alone treatment group, most of the disease recurrences were local (7 of 12), compared with the surgery and radiation group, in which no disease recurrences were local. Of the surgery-alone treatment group, five (25%) patients eventually died of disease. Fourteen patients in this group remain alive, 1 patient with further recurrent disease and 13 patients without evidence of disease. One patient in this group died of other causes with no evidence of disease. In the surgery and postoperative adjuvant radiation group, no patient died of disease. Six patients in this group remain alive, two patients with further recurrent disease and five patients without evidence of disease. One patient in this group died of other causes with no evidence of disease. The two patients in this group who developed regional recurrences were salvaged by neck dissections, and they remain alive with no evidence of disease.

When comparing the overall survival of the surgery-alone group (65%) with the overall survival of the surgery and adjuvant radiation group (57%), there was only an 8% survival difference, even though most patients who underwent surgery alone tended to have early-stage (stage I and II) disease when compared with patients undergoing surgery and adjuvant radiation (65% vs. 28%, respectively).

Oropharyngeal Cancer
The most common oropharyngeal disease subsite in our patient population was the base of the tongue (n = 5), followed by the tonsillar fossa (n = 3). All patients were diagnosed with advanced-stage disease, yet there was only one regional recurrence during the study period. All patients remain alive with no evidence of disease after a median follow-up of 6 years 10 months.

DISCUSSION

The vast majority of individuals who develop squamous cell carcinoma of the upper aerodigestive tract have a history of smoking tobacco.3 Many of these individuals also consume alcohol regularly.4,5 The increased risk for developing head and neck cancer in these individuals has been well established by large epidemiological studies.4–10 Not only have the smoking of tobacco and the drinking of alcohol each been demonstrated to be independent risk factors for the development of head and neck cancer, but together they have been shown to increase patient cancer risk in a multiplicative manner.5–7 The potentiation of the carcinogenic effects of tobacco by alcohol may be a consequence of its solvent properties or its toxicity to the respiratory epithelial enzyme systems.11,12 Alcohol is also able to induce hepatic microsomal enzymes that are capable of transforming proximate carcinogens to ultimate carcinogens.11,12 Other factors that are believed to contribute to the carcinogenic effect of alcohol include nutritional deficiencies that occur in heavy drinkers and contaminants and congeners that are present in alcohol.11,12 Most oral cavity cancers (75%) are located in a horseshoe-shaped area that extends from the anterior floor of the mouth and includes the tonsillar pillar/retromolar trigone complex. It has been suggested that concentrated carcinogens suspended in saliva are pooled in these areas, encouraging carcinogenesis.13 Unfortunately, smoking and drinking are social behaviors that commonly occur together, with smokers being drinkers and vice versa.5 Examination of the anatomical sites predisposed to manifesting head and neck cancers have demonstrated that the risks of developing oral, pharyngeal, and laryngeal cancers are especially high in individuals who both smoke tobacco and drink alcohol.7–10,12,14 Individuals who both smoke tobacco and drink alcohol tend to develop head and neck cancer at a younger age. Bross and Coombs15 reported on a cohort of 145 women treated for oral cavity cancer at our institution between 1957 and 1966. They concluded that use by women of both substances leads to the onset of oral cancer >=15 years earlier than in NSND women.

However, there remains a small minority of the head and neck cancer patient population who have no history of either smoking tobacco or drinking alcohol. In this study, these patients represented 2.4% of the individuals treated for invasive head and neck cancer at our institution over a 31-year period. This small proportion of head and neck cancer patients is consistent with the current literature.5,16 In a multicenter North American epidemiological study examining a cohort of 1114 oral and pharyngeal cancer patients, the NSND population (defined in this study as no history of smoking and less than one glass of alcohol per week) made up 3.9% of the patient population.5

Although a growing number of reports exist that examine head and neck cancers in nonusers of tobacco16–18 and head and neck cancer in young patients,19 the current literature examining the adult NSND head and neck cancer patient population is limited.20–24 When this literature is evaluated, special attention must be given to the authors’ definitions of nonsmoker and nondrinker, because these definitions may vary considerably from one study to another.16–18,20–24 Early work examining the NSND head and neck cancer patient population focused on large cohorts of Seventh-Day Adventists because they neither smoke nor drink because of their religious beliefs. Deaths from oral and pharyngeal cancers were eight times lower in the Adventist population when compared with the smoking and drinking general population.22 However, when these data were further analyzed and the Adventist population was compared with the nonsmoking general population, mortality differences suggested that these populations were different and that confounding variables, such as dietary differences, were present, making it difficult to apply these results to the general population.23

Constantinides et al.20 described a cohort of 10 NSND elderly head and neck cancer patients. In this group, the site of the primary tumors was oral cavity (n = 6), oropharynx (n = 3), and larynx (n = 1). Nine of the patients in this study were women. Inclusion criteria for this study included age >59 years. The age range in this study was 60 to 87 years (median, 75 years). Three patients developed disease recurrences (30%), and two patients in this study developed second primary tumors (20%). The authors concluded that recurrences in these patients were often local and aggressive and, along with second primary tumors, were the major determinants of patient survival. Agudelo et al.21 described a cohort of 31 laryngeal cancer patients with no history of tobacco or alcohol use. These patients made up 3.3% of 933 cases of laryngeal cancer at their institution. They demonstrated that the NSND laryngeal cancer patient population, compared with the smoking and drinking laryngeal cancer population, was an average of 10 years older and showed a male predominance, and their tumors were primarily glottic in location. The two NSND laryngeal cancer patients in our study had glottic tumors; one patient was male and the other female. In a study from The Netherlands, de Boer et al.24 examined a cohort of 303 women aged >=40 years. Of this group, 125 patients were nonsmokers (never smoked or stopped 10 years previously) and nondrinkers (never or occasionally drink alcohol). They found that NSND head and neck cancer patients tended to present 15 years later than smokers and drinkers. Also, of the NSND group, 91 patients (73%) presented with oral cavity tumors, and 24 patients (27%) presented with oropharyngeal tumors.

There are a number of studies that evaluate small cohorts of nonsmoking head and neck cancer patients.16–18 These patients seem to share many characteristics with the NSND head and neck cancer patient population. Hodge et al.17 described a cohort of 33 head and neck cancer patients with no history of tobacco use. Most cases arose in older women in their oral cavity, and of these cases, most (79%) had early-stage disease. Alcohol consumption was not a factor evaluated in this study. These authors concluded that conservative initial surgical treatment was responsible for a higher than expected rate of treatment failure. They recommend an aggressive surgical approach in managing head and neck cancers in this patient population. In a French study, Panis et al.18 reported on a cohort of 158 women treated for head and neck cancer at their institution. Forty-two (27%) of the 158 women were nonusers of tobacco (not specifically defined in this report). These authors concluded that women tobacco nonusers who develop head and neck cancer are significantly older and have a significantly greater proportion of oral cavity tumors than their smoking counterparts. No significant differences were observed when the smoker group’s treatment outcomes were compared with the nonsmoker group’s treatment outcomes.

Koch et al.16 described a cohort of 46 nonsmoker patients with head and neck cancer. These authors defined nonsmokers as individuals who never used tobacco on a regular basis. This group was compared with smokers and former smokers (quit smoking a minimum of 10 years previously). When compared with the smokers, a disproportionately large proportion of the nonsmoker group was female. The nonsmoker group also had a larger proportion of patients at extremes of age compared with the other groups. Also, the nonsmoker group contained a significantly higher percentage of oral cavity tumors and a significantly lower percentage of laryngeal and hypopharyngeal tumors than the other groups. Of the 46 nonsmokers in this study, 37 patients (84%) were also nondrinkers. The overall length of survival of the patients in this study did not vary significantly with either smoking history or drinking history.

Singh et al.25 performed comparative genomic hybridization to screen for genetic aberrations in a cohort of 71 head and neck cancer patients stratified by tobacco and alcohol exposure history. Although the overall pattern of abnormalities did not vary significantly by the extent of tobacco and alcohol exposure, gains of 1p and amplification of 3q were significantly more common in the smoking and drinking patients. Koch et al.16 also performed multiple molecular analyses in the smoker and nonsmoker groups and were able to demonstrate multiple differences between these groups. The differences found when the nonsmokers were compared with smokers were that nonsmokers had a lower rate of p53 mutation, nonsmokers had a higher rate of human papilloma virus (HPV) infection, and nonsmokers had a lower rate of loss of heterozygosity at multiple chromosomal loci. Other authors have also suggested a role for HPV in the development of head and neck cancer in the NSND patient population.26–30 Other factors that include gastrointestinal reflux disease31 and lichen planus32 have also been hypothesized to play a role in head and neck cancer development.

Individuals with Plummer-Vinson syndrome, characterized by dysphagia, iron-deficiency anemia, and esophageal webs, are predisposed to developing hypopharyngeal carcinoma.33,34 Several series have reported rates ranging from 3% to 15% for postcricoid carcinoma development.33,34 Affected individuals are typically elderly white women from Northern countries.33,34 Thus, patients with this syndrome share some epidemiological characteristics with the NSND patient population. Although the pathogenesis of Plummer-Vinson Syndrome is controversial, the iron deficiency is believed to play an important role, and iron repletion usually leads to symptom resolution. The mucosal changes arising from the iron deficiency may be premalignant.33,34 Thus, nutritional factors may play an important role in the pathogenesis of upper aerodigestive tract cancers. The role of nutrition in cancer development in NSND patients is currently unknown.

The results of our study are consistent with the current literature evaluating the NSND head and neck cancer patient population.16,20,21,24 In North America and Europe, squamous cell carcinoma of the upper aerodigestive tract in NSND head and neck cancer patients tends to present as an oral cavity primary tumor in elderly women. In this report, we have focused on the NSND oral cavity tumor patients that make up our study population. The incidence of cancers outside the upper aerodigestive tract (15.0%) and cancers in close family members (17.5%) in our NSND patient population is comparable to the current literature.16 The incidence of second primary tumors (28%) in our NSND patient population is high when compared with the current literature.16 At our institution, Kotwall et al.35 reviewed the incidence of second primary tumors at autopsy in a cohort of head and neck cancer patients treated between 1961 and 1985. These authors found second primary tumors of the upper aerodigestive tract in 150 (18%) of 832 patients. In 1953, Slaughter et al.36 were among the first to recognize that "field cancerization" occurred in head and neck cancer patients. These authors described the squamous mucosa of head and neck cancer patients as being "condemned." Despite a lack of exposure to tobacco and alcohol, and for reasons that are currently unknown, the squamous mucosa of the NSND head and neck cancer patient is also condemned. The risk of second primary head and neck tumors, especially located in the oral cavity, in the NSND head and neck cancer patient is significant.

CONCLUSIONS

Head and neck cancer is a distinct clinical entity in individuals with no history of smoking tobacco or drinking alcohol. Our experience suggests that these individuals tend to be elderly and female and have oral cavity primary tumors and that they are predisposed to second primary tumor development. Our results indicate that in patients with oral cavity tumors, aggressive surgery and adjuvant radiotherapy offers these individuals the best chance of cure of their cancer. Further study of the NSND head and neck patient population seems warranted. Potential factors that may contribute to head and neck cancer development in NSND individuals include nutritional deficiency, HPV infection, gastrointestinal reflux disease, and lichen planus. Evaluation of these factors, along with the molecular mechanisms that underlie tumorigenesis and tumor progression in this minority of head and neck cancer patients, may provide investigators with clues fundamental to their understanding of the biology of the disease in the greater patient population.

Footnotes

Review of the clinicopathologic characteristics of 40 nonsmoking and nondrinking individuals diagnosed with invasive squamous cell carcinoma of the head and neck suggests that this malignancy tends to present in elderly women, with a predisposition for second primary tumor development, as oral cavity primary tumors.

Received for publication September 11, 2002. Accepted for publication January 3, 2003.

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