Ann Thorac Surg 2003;76:1699-1705
© 2003 The Society of Thoracic Surgeons
Original article: general thoracic
Periodic pharyngolaryngoscopy detects early head and neck cancer and improves survival in esophageal cancer
Akihito Watanabe, MD*a,
Masao Hosokawa, MDb,
Masanobu Taniguchi, MDa,
Shigeyuki Sasaki, MDa,b
a Departments of Otolaryngology and Surgery, Keiyukai Sapporo Hospital, Sapporo, Japan
b Division of Medical Science, Health Sciences University of Hokkaido, Hokkaido, Japan
Accepted for publication May 28, 2003.
* Address reprint requests to Dr Watanabe, Department of Otolaryngology, Keiyukai Sapporo Hospital, Kita 1-1, Hondori 14-chome, Shiroishi-ku, Sapporo 003-0027, Japan.
e-mail: akihito-watanabe{at}hokkaido.med.or.jp
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Abstract
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BACKGROUND: Multiple squamous cell carcinomas (SCCs) frequently arise in the upper aerodigestive tract. The purposes of this study were to identify risk factors for SCC of the head and neck in patients with esophageal cancer (EC) and to investigate the value of periodic pharyngolaryngoscopic screening in detecting early SCCs of the head and neck and improving survival.
METHODS: We reviewed the cases of 754 patients with EC treated surgically (n = 545) or nonsurgically (n = 209) from May 1995 to December 1999 in our institution. Of these patients, 541 underwent periodic pharyngolaryngoscopic screening after treatment of EC, whereas 213 did not because of hospital death, dropout from the program, and distance from the hospital. Data were compared between patients in whom SCCs of the head and neck developed synchronously or metachronously (EC + SCC group, n = 70) and patients without SCCs (EC group, n = 684). Survival rates were compared between patients receiving periodic pharyngolaryngoscopy and those followed without endoscopic screening.
RESULTS: In the EC + SCC group, younger patients (p < 0.05), male patients (p < 0.05), and patients with a higher alcohol intake (p < 0.01) were more common than in the EC group. The 5-year survival rate was 40.9% in the EC group and 44.8% in the EC + SCC group (p = not significant). The survival rate of patients receiving periodic pharyngolaryngoscopy was significantly higher than that of patients followed without endoscopic screening (p < 0.001). Periodic pharyngolaryngoscopy was effective in detecting early SCCs of the head and neck and was beneficial for patients with EC in stages I to IV.
CONCLUSIONS: Periodic pharyngolaryngoscopy can provide early detection of SCCs of the head and neck, which arose in 9.3% of patients with EC. Such screening particularly benefits male patients and heavy drinkers, who are at high risk for multiple SCCs. Periodic pharyngolaryngoscopy may prevent reduced survival resulting from associated SCCs of the head and neck and improve overall survival in patients with EC.
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Introduction
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The occurrence of multiple squamous cell carcinomas (SCCs) in the upper aerodigestive tract is a well-known phenomenon. Patients with SCC of the head and neck often have multiple cancers, esophageal cancer (EC) being the most common associated cancer [1–7]. Likewise, patients with EC often have multiple cancers, SCC of the head and neck occurring most often [3, 8–14]. Although endoscopy of the upper gastrointestinal tract before and after treatment proved to be effective in detecting early EC in patients with SCC of the head and neck, it remains to be seen whether pharyngolaryngoscopic screening before and after treatment is effective in detecting early SCC of the head and neck and improving survival in patients with EC [15–17].
We have performed otolaryngologic examination and pharyngolaryngoscopic screening in all patients with EC before and after its treatment since May 1995, when the department of otolaryngology was established at our institution. The purposes of this study were to identify risk factors for the development of SCC of the head and neck in patients with EC and to determine whether periodic pharyngolaryngoscopy after treatment of EC is effective in detecting early SCCs of the head and neck and improving survival in patients with EC.
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Material and methods
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A total of 754 consecutive patients with EC were treated in Keiyukai Sapporo Hospital between May 1995 and December 1999. There were 670 men and 84 women with a mean age of 64.2 ± 0.3 years (mean ± standard error) at diagnosis. Of these patients, 545 underwent surgical treatment, and 209 received nonsurgical treatment (chemoradiotherapy, 94 patients; radiation therapy, 96; chemotherapy, 6; and other, 13). Clinical data collected from the records of the 754 patients until December 2001 were reviewed in this study.
Treatment
All patients with EC underwent otolaryngologic examination and pharyngolaryngoscopic screenings, which were carried out by one otorhinolaryngologist (A.W.) before treatment of EC. Oral cavity, nasal cavity, pharynx (nasopharynx, oropharynx, and hypopharynx), and larynx were checked very carefully with a flexible fiberscope for early SCC of the head and neck. Lugol's iodine staining was performed mainly to detect early cancer of the hypopharynx or floor of the mouth. After conventional examination, the mucosa of the hypopharynx or mouth floor was flushed with water. A 1.5% iodine solution was then sprayed on to coat the hypopharynx or mouth floor. If a distinctly demarcated, unstained lesion measuring 5 mm or more in greatest diameter was detected, a forceps biopsy specimen of the lesion was obtained immediately. The specimen was stained with hematoxylin and eosin and examined histopathologically. When a biopsy was necessary, at least two specimens were taken from slightly reddish lesions.
Pharyngolaryngoscopy after treatment of EC was in principle performed in the same manner in all patients. Patients were screened every 6 months, and those with leukoplakia of the oral cavity were examined every 3 months. Three categories of patients were excluded from this screening program: those who died (operative or hospital death) (n = 76); those who refused or failed to undergo periodic pharyngolaryngoscopy and were regarded as dropouts (n = 70); and those who lived a long distance away and were followed by the local hospital (n = 67). Thus, 541 patients underwent periodic examination and screening of the head and neck after treatment of EC. The 137 patients who were considered dropouts or who lived far away received routine follow-up studies other than periodic endoscopic screening; therefore, follow-up information regarding survival and cause of death was obtained for every patient. The mean follow-up period after the day of discharge was 30.5 ± 0.9 months. The mean number of pharyngolaryngoscopic screenings was 5.0 ± 0.2 per patient.
Treatment strategy was determined by the stage and the location of the tumor and the condition of the patient. When surgical resection was indicated for EC, esophagectomy and three-field lymphadenectomy was generally recommended as the initial treatment for patients with a diagnosis of thoracic esophageal carcinoma excluding mucosal carcinoma. When synchronous SCCs of the head and neck were detected, the therapeutic strategy was determined mainly by the stage and the location of the more advanced tumor, which strongly influence the prognosis. If simultaneous surgical procedures could be performed, the patient received a one-stage operation for EC and SCCs.
Data collection
The following information was collected: demographic data (eg, age, sex, tobacco use, and alcohol use); survival; and stage of EC and SCC of the head and neck if detected (determined by the American Joint Committee on Cancer/International Union Against Cancer TNM classification and stage grouping). To assess the impact of smoking and drinking habits, we used the following indices: alcohol index = daily intake of alcohol (grams per day) x period of drinking (years) and Brinkman index = daily amounts of tobacco (pieces per day) x period of smoking (years). Sequences of the EC and SCC of the head and neck were defined as follows: synchronous cancer was the second cancer detected within 12 months after the diagnosis of the first cancer; metachronous cancer was the second cancer detected 12 months after the diagnosis of the first cancer.
To identify risk factors for the development of both EC and SCC of the head and neck, data were compared between the following two groups: patients with both EC and metachronous or synchronous development of SCCs of the head and neck (EC + SCC group) and patients with EC without SCCs of the head and neck (EC group). If a patient had a history of previous SCCs of the head and neck, he or she was assigned to the EC+SCC group in this section of the study. Survival curves of the two groups were also compared.
To investigate the efficacy of periodic pharyngolaryngoscopy after treatment of EC, data from the patients who had this examination according to the screening program (n = 541) were compared with data from the patients who were followed without endoscopic screening (n = 137). The latter group consisted of patients who dropped out from the periodic screenings (n = 70) and those who lived far away (n = 67), as previously described. Patients who died (operative or hospital death) were not included in this part of the study, as they would have caused a marked decrease in survival in the latter group. Compared data included the incidence and the stage of SCCs of the head and neck during follow-up and survival.
Statistical analysis
All continuous variables are presented as the mean ± the standard error. Univariate analysis was conducted with Student's t test for comparisons of continuous variables and the 
2 test for dichotomous variables. Nonparametric comparisons were done with the Mann-Whitney U test. Survival rates were calculated by the Kaplan-Meier method and compared by log-rank test. All analyses were performed with SPSS software (SPSS Inc, Chicago, IL). A p value of less than 0.05 was considered significant.
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Results
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Of the 754 patients with EC, 40 had the development of primary SCCs of the head and neck after treatment of EC. Thirty other patients had a history of previous SCC of the head and neck before therapy for EC. Thus, a total of 70 patients with both EC and SCC of the head and neck, metachronous or synchronous, were assigned to the EC+SCC group. These 70 patients had 77 SCCs of the head and neck (64 patients, one SCC; 5 patients, two SCCs; and 1 patient, three SCCs). The sites of the 77 carcinomas were as follows: hypopharynx, 32 (41.6%); oral cavity, 18 (23.4%); larynx, 17 (22.1%); oropharynx, eight (10.4%); maxillary sinus, one (1.3%); and external ear canal one (1.3%). The remaining 684 patients with EC but without SCCs of the head and neck were assigned to the EC group.
Comparisons between EC group and EC+SCC group
Table 1
summarizes the data from the EC and EC+SCC groups. The mean age of the EC+SCC group (61.9 ± 1.0 years) was significantly lower than that of the EC group (64.5 ± 0.3 years) (p = 0.020). Male patients were more common in the EC+SCC group than the EC group (p = 0.021). The overall average alcohol index was 2,650 ± 104; it was significantly higher in the EC+SCC group (3,286 ± 336) than in the EC group (2,585 ± 109) (p = 0.006). The average Brinkman index for all patients was 768 ± 23; the difference between the two groups was not significant (p = 0.31). Clinical stage distribution of EC was not significantly different between the two groups (p = 0.27).
The crude survival rates at 1 year, 3 years, and 5 years after treatment of EC for all 754 patients were 68.3%, 47.8%, and 41.2%, respectively. Kaplan-Meier survival curves for the EC group and the EC+SCC group are shown in Figure 1.
The crude 5-year survival rate for the EC group was 40.9% (95% confidence interval [CI], 37.0% to 44.8%) and that for the EC+SCC group, 44.8% (95% CI, 32.6% to 56.9%). The difference in survival curves was not significant by log-rank test.
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Fig 1. Kaplan-Meier survival curves for patients with esophageal cancer without squamous cell carcinoma of the head and neck (EC group) and patients with esophageal cancer and metachronous or synchronous development of squamous cell carcinoma of the head and neck (EC+SCCHN group). There was no significant difference between the two groups.
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We also assessed other clinical factors that might affect survival. These factors included an association with other carcinomas, surgical versus nonsurgical treatment, and periodic pharyngolaryngoscopy versus no such screening. Other primary carcinomas, such as gastric cancer or colorectal cancer, complicated EC in 112 patients in the EC group and 13 patients in the EC+SCC group. The incidence of other primary carcinomas was not significantly different between the two groups (p = 0.61). Kaplan-Meier survival curves for patients without other primary carcinomas in the two groups were also not significantly different by log-rank test.
Surgical resection was undertaken for 489 patients in the EC group and 56 patients in the EC+SCC group. The incidence of surgical resection was not significantly different between the two groups (p = 0.16). Kaplan-Meier survival curves for patients undergoing surgical resection in the EC group and the EC+SCC group are shown in Figure 2.
There was not a significant difference. Periodic pharyngolaryngoscopy was carried out in 541 patients, 484 in the EC group and 57 in the EC+SCC group. Kaplan-Meier survival curves for patients undergoing periodic screening in the two groups are shown in Figure 3,
and again, the curves showed no significant difference.
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Fig 2. Kaplan-Meier survival curves for patients undergoing surgical resection. There was no significant difference between the two groups. (EC group = patients with esophageal cancer without squamous cell carcinoma of the head and neck; EC+SCCHN group = patients with esophageal cancer and metachronous or synchronous development of squamous cell carcinoma of the head and neck.)
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Fig 3. Kaplan-Meier survival curves for patients receiving periodic pharyngolaryngoscopy. There was no significant difference between the two groups. (EC group = patients with esophageal cancer without squamous cell carcinoma of the head and neck; EC+SCCHN group = patients with esophageal cancer and metachronous or synchronous development of squamous cell carcinoma of the head and neck.)
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Table 2
summarizes the univariate analysis of risk factors for the development of both EC and SCC of the head and neck. Male sex (odds ratio, 4.63; 95% CI, 1.11 to 19.2) and alcohol index higher than 3,000 (odds ratio, 1.78; 95% CI, 1.07 to 2.95) were significant risk factors.
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Table 2. Univariate Analysis of Risk Factors for Development of Both Esophageal Cancer and Squamous Cell Carcinoma of the Head and Neck
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Comparisons between patients with periodic pharyngolaryngoscopy and those without screenings
Table 3
summarizes the comparison of data between patients undergoing periodic pharyngolaryngoscopy (complete follow-up group, n = 541) and those not having these screenings (incomplete follow-up group, n = 137). Patients in the complete follow-up group were younger and had surgical resection more often than those in the incomplete follow-up group (both, p < 0.001). Stage distribution of EC tended to be earlier in the complete follow-up group (p = 0.09).
The survival curves of the two groups are shown in Figure 4.
The crude 5-year survival rate was 50.7% (95% CI, 46.1% to 55.3%) in the complete follow-up group and 28.2% (95% CI, 20.0% to 36.4%) in the incomplete follow-up group (p < 0.001). Because the incidence of surgical resection was different between the two groups, probably resulting from the difference in stage distribution of EC, we assessed survival rates only in patients undergoing surgical resection (Figure 5).
Comparison of the two survival curves showed a significant difference (p < 0.01).
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Fig 4. Kaplan-Meier survival curves for patients undergoing periodic pharyngolaryngoscopy (periodical endoscopic screening [+]) and patients without screenings (periodical endoscopic screening [-]). The survival rate for patients receiving screening was significantly better than that for the other group (**p < 0.001).
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Fig 5. Kaplan-Meier survival curves for patients undergoing surgical resection and then followed with (periodical endoscopic screening [+]) or without (periodical endoscopic screening [-]) periodic pharyngolaryngoscopy. Note that only patients who had surgical resection are included. The survival rate for patients undergoing periodic screening was significantly better than that of the other group (**p < 0.01).
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During the follow-up period after treatment of EC, 32 SCCs of the head and neck developed or were detected in the complete follow-up group and six in the incomplete follow-up group (p = not significant). However, stage distribution of these SCCs tended to be earlier in the complete follow-up group (p = 0.08). For reference, we also compared the stage distribution of these 32 SCCs with those of SCCs that developed before treatment of EC, which was recognized in the patient histories of the EC+SCC group. The stage distribution of SCCs of the head and neck in the patient histories before treatment of EC was as follows: stage I, nine; stage II, six; stage III, six; and stage IV, ten. The stage of SCCs in the complete follow-up group was significantly earlier than that recognized in patient histories before treatment of EC (p < 0.01).
To investigate whether periodic pharyngolaryngoscopy benefited patients with advanced EC, survival rates were analyzed in each EC stage (stage 0 to stage IV) for the complete follow-up and incomplete follow-up groups. The 5-years survival rates for stage 0, stage I, stage II, stage III, and stage IV in the complete follow-up group were 88.9%, 72.9%, 48.7%, 41.8%, and 27.2%, respectively, and 76.1%, 46.8%, 29.6%, 17.8%, and 6.7%, respectively, in the incomplete follow-up group. Comparison of survival rates by log-rank test indicated that those of the complete follow-up group were significantly higher than those of the incomplete follow-up group for patients with stage I (p < 0.01), stage II (p < 0.01), stage III (p < 0.05), and stage IV (p < 0.001) EC. In the comparison limited to patients who underwent surgical resection, survival rates in the complete follow-up group were 88.9% for stage 0, 75.9% for stage I, 56.4% for stage II, 54.6% for stage III, and 37.2% for stage IV. These rates were significantly higher than those in the incomplete follow-up group for stage I (46.7%, p < 0.01), stage II (28.6%, p < 0.01), and stage IV (14%, p < 0.001) EC.
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Comment
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Because patients with a primary SCC of the head and neck or EC are at risk for additional malignancies of the upper aerodigestive tract, the value of performing pharyngolaryngoscopy, bronchoscopy, and esophagoscopy for all patients with cancers of this upper tract has been emphasized to identify second cancers. According to the report by Atabek and associates [7], the overall incidence of EC in their patients with head and neck cancer was 2.5%, whereas the incidence of head and neck cancer in patients with EC was 7.1%. On the basis of their report, patients with EC may have a higher risk of multiple cancers than those with other primary cancers of the upper aerodigestive tract. However, endoscopic screening of the head and neck after treatment of EC has not proved to be beneficial, whereas routine esophagoscopy is recommended for patients with SCCs of the head and neck. This is probably due to the short survival of patients with EC, a reported median survival ranging from only 8 to 9 months whether or not there are associated tumors [13].
Thus, not much attention has been focused on the role of endoscopic screening after treatment of EC for patients who might have a poor prognosis. However, there are increasing numbers of patients with early detection of EC and long survival as a result of recent progress in endoscopic methods and diagnostic approaches, such as Lugol's iodine staining and a screening program for individuals at high risk because of alcohol and tobacco abuse [18]. The 5-year survival rate of patients with EC in our institution is 41.2%, which allowed us to carry out the present study on the role of endoscopic screening after treatment of EC.
The incidence of SCCs of the head and neck associated with EC including those that developed before the treatment of EC was 9.3% in the present study. This incidence is higher than the reported incidence [11–13] and might be due in part to the detection of asymptomatic SCCs by periodic endoscopic screening. Data from the EC and EC+SCC groups showed that younger patients, male patients, and heavy drinkers were more common in the EC+SCC group. As shown in Table 2, male patients and heavy drinkers (alcohol index > 3,000) should be intensively followed after treatment of EC or SCC of the head and neck.
In general, the development of another primary cancer exerts a negative effect on survival after treatment of carcinoma during the follow-up period, but the Kaplan-Meier survival curves for the EC group and the EC+SCC group were not significantly different in our series. The crude 5-year survival rates were 40.9% in the EC group and 44.8% in the EC+SCC group, and thus associated SCCs of the head and neck may not have influenced the survival rates in our series. There were no significant differences between the two groups in stage distribution of EC, survival curves excluding patients with other primary carcinomas, or survival curves limited to patients having surgical resection. Thus, early detection of associated cancer by periodic endoscopic screening may have helped prevent decreased survival among our patients.
To examine the effects of periodic pharyngolaryngoscopy after treatment of EC, data from patients undergoing periodic pharyngolaryngoscopic screening and those followed without periodic endoscopic screening were compared. Ideally, patients assigned to two such groups should be randomized, but we were unable to do this in a retrospective study. Patients who dropped out from the periodic screenings and patients who lived far away were used as an alternative group to a control group without periodic endoscopic screening. As shown in Figure 4, the survival curve for patients undergoing periodic pharyngolaryngoscopy was significantly better than that of patients who did not have periodic endoscopic screening. Because patients with earlier stages of EC and patients undergoing surgical resection were more common in the complete follow-up group, we also evaluated the survival curves for patients undergoing surgical resection in the complete and incomplete follow-up groups. Again, survival rate was significantly higher in the complete follow-up group. Our findings suggest that patients undergoing periodic pharyngolaryngoscopy have a longer survival than those followed without such screening.
What caused the difference in survival rate between the complete follow-up group and the incomplete follow-up group? During the follow-up period, 32 SCCs of the head and neck developed or were detected in the complete follow-up group and six, in the incomplete follow-up group. Although the difference in stage distribution did not reach significance, the SCCs in the complete follow-up group tended to be in an earlier stage than those in the other group. The most common SCC of the head and neck in this series was hypopharyngeal cancer; generally, its incidence is lower than that of oral cavity cancer or laryngeal cancer. Because most hypopharyngeal cancers are asymptomatic until they reach an advanced stage, many SCCs of the head and neck including hypopharyngeal cancer would not be detected without endoscopic screening. This is supported by the finding that SCCs arising before treatment of the EC in patients in the EC+SCC group, which were mostly discovered by symptom-directed evaluation, were in a more advanced stage than those detected after EC treatment in the complete follow-up group. Early detection of SCCs of the head and neck by pharyngolaryngoscopy did play an important role in improving survival after treatment of EC.
Which patients would benefit from pharyngolaryngoscopy after treatment of EC? Our results suggest that endoscopic screening of male patients and heavy drinkers would be justified because they are at high risk for the development of associated cancer. According to our analysis of survival rates by stage, pharyngolaryngoscopic screening would be beneficial for patients with stage I to IV EC. The 5-year survival rate of stage IV patients was low, but in the complete follow-up group, it was still 27.2%, and among patients undergoing surgical resection, was 37.2%. We believe these rates are not meaningless, at least for patients undergoing surgical resection. The value of performing pharyngolaryngoscopy is preserved for patients in most stages, including those with advanced EC.
There are some limitations to this study. To determine the value of pharyngolaryngoscopy accurately, a prospective, randomized control study is required. The cost-effectiveness of performing endoscopic screening was not investigated here. We used a group comprising patients who dropped out from periodic screening and patients who lived far away as an alternative to a control group without periodic endoscopic screening. Results from this study can not be extrapolated to those in a general setting, but this study does suggest the value of periodic pharyngolaryngoscopy after treatment of EC.
In conclusion, the incidence of SCCs of the head and neck arising synchronously or metachronously in patients with EC was 9.3% in our series. Periodic examination and pharyngolaryngoscopy can detect SCCs early in patients with primary EC. When performed in select instances, endoscopic screening would benefit male patients and heavy drinkers, who are at high risk for the development of associated cancer. Periodic pharyngolaryngoscopy may improve survival in patients with development of associated SCCs and improve survival in patients with EC. Periodic pharyngolaryngoscopy would be beneficial for patients in most stages, including those with advanced EC.
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Abstract
Introduction
