Ann Thorac Surg 1995;59:1604-1609
© 1995 The Society of Thoracic Surgeons
Collective Review
Achalasia and Squamous Cell Carcinoma of the Esophagus: Analysis of 241 Patients
John M. Streitz, Jr, MD,
F. Henry Ellis, Jr, MD, PhD,
S. Peter Gibb, MD,
Gerald M. Heatley, MS
Duluth Clinic, University of Minnesota School of Medicine, Duluth, Minnesota, Deaconess Hospital, Harvard Medical School, Boston, Massachusetts, and Lahey Clinic, Burlington, Massachusetts
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Abstract
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Achalasia of the esophagus is presumed by many to be a premalignant lesion leading to an increased risk of squamous cell carcinoma. There is disagreement, however, as to the precise risk of malignant degeneration and there is no consensus as to either the need for close surveillance of achalasia patients or the surveillance technique that should be employed. A review of the available literature on the subject has disclosed a wide range of reported cancer risks in achalasia patients, from zero to 33 times that of the normal population. Cancers, when discovered, are often unresectable and the median survival when they are resectable is low. A personal experience with 241 achalasia patients treated during the past quarter of a century disclosed that 9 had carcinoma, for a prevalence of 3.7%. Carcinoma developed in 3 of these 9 while they were under our observation. This translates into one cancer per 1,138 patient-years of follow-up, an incidence of 88 per 100,000 population, and a risk 14.5 times that of the age-adjusted and sex-adjusted general population. Because of the low postresection survival rate if treatment is delayed until carcinoma of the esophagus becomes symptomatic, closer surveillance of achalasia patients is recommended than has been the case. Because it seems unlikely that close endoscopic surveillance will prove to be cost-effective, periodic (every 2 to 3 years) blind brush biopsy warrants further study as a means of surveillance.
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Introduction
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There is disagreement regarding the premalignant nature of esophageal achalasia. Although it is generally believed that there is an increased risk of squamous cell carcinoma developing in patients with this disease, this presumption is based on indirect and uncertain data, and has never resulted in a consensus being reached regarding the need for long-term surveillance in these patients. In fact, some believe that the incidence of malignant change is so low that surveillance is not indicated [1, 2]. This situation prompted us to reexamine the cancer risk faced by patients with achalasia, to evaluate the results of treatment of carcinoma when it develops, and to assess the need for long-term surveillance of patients with esophageal achalasia to thereby permit earlier and presumably more effective treatment.
Among the questions we attempted to answer were: If achalasia is truly a premalignant lesion, what is the precise risk of the subsequent development of squamous cell carcinoma of the esophagus in such patients?, Is a screening test available to facilitate early detection of malignant degeneration in patients with achalasia of the esophagus?, Will it result in improved survival, and has close surveillance of achalasia patients been shown to be cost-effective? In an effort to answer these questions, we undertook an in-depth review of the literature on this topic and the controversy surrounding it, and compared these findings with our own experience in 241 patients with esophageal achalasia treated during the past quarter of a century.
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Review of the Literature
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Prevalence and Incidence
Two hundred years after Willis' description [3] of a patient with the disorder that later became known as esophageal achalasia, the first case of squamous cell carcinoma arising in association with this disorder was reported by Fagge in 1872 [4]. Since then, there have been numerous reports of the coincidence of the two conditions, and these reports were well analyzed in a 1988 review by Matthews and Pattison [1].
It is important to distinguish between the terms prevalence and incidence in addressing the problem of the relationship between achalasia and carcinoma. Prevalence data are the number of cases of carcinoma in a defined population of achalasia patients and are dependent on the referral patterns of the reporting institution. It is understandable, then, why the reported prevalence rates range widely from 2% to 8.6% [5–11] (Table 1
). These data, of course, significantly overstate the risk or incidence of the disease. In fact, the figures of 20% to 29% are cited frequently in the literature as indicative of the close association between carcinoma and achalasia. Some authors have implied that these numbers represent the ``incidence'' of malignant degeneration of the achalasic esophagus [5, 10, 11], whereas they are actually based on the prevalence of esophageal carcinoma noted at autopsy of patients dying with achalasia [12]. The true incidence or risk is the number of patients with a diagnosis of achalasia without carcinoma in whom, during a variable follow-up period after diagnosis or treatment, depending on the report, carcinoma subsequently develops. Even these data are soft, for some include adenocarcinoma of the esophagus or cardia, or both-cancers not considered related to achalasia. The adenocarcinoma developing in Barrett's esophagus is the result of gastroesophageal reflux after dilation or operation, or both [13–15], and is not caused by achalasia. Those studies that have indeed determined the incidence or risk of esophageal cancer developing in patients with previously benign achalasia are listed in Table 2, the incidence being substantially lower than that suggested by prevalence data. The risk ranges from zero per 953 patient-years of follow-up to 1 per 293 patient-years [2, 9, 16–18]. The data reported in the literature are further complicated by variation in the way in which the follow-up interval is determined, as some studies use the time of onset of symptoms as the starting point for the follow-up interval and others consider the time of origin to be when the patient was first treated by them. Thus, the cancer incidence per 100,000 population varies from zero to 340. This translates into a risk of from zero to 33 times that of the age-adjusted and sex-adjusted population. Because the number of cases of carcinoma discovered in any one study is small, the confidence interval for cancer rates is quite large. In the study of Peracchia and associates [9], the incidence of 18.6 per 100,000 population has a 95% confidence interval ranging from 0.45 to 100 cases. A prospective endoscopic follow-up study conducted by Meijssen and colleagues [16] revealed a cancer rate of 340 per 100,000 population, 33 times the expected incidence.
Clinical and Pathologic Features
Much of the evidence for an association between carcinoma and achalasia has been inferred from indirect clinical data, such as mean patient age and location of the tumor, rather than gleaned from a prospective evaluation of the incidence of malignant degeneration. In collective reviews, the mean age of patients with achalasia and carcinoma has been significantly lower than that of patients in the general population with carcinoma of the esophagus without achalasia. In two reports, the mean age of presentation with cancer and achalasia was 51 and 52 years, roughly 10 years younger than the usual age of presentation of squamous cell carcinoma of the esophagus in the general population. This suggests a causal relationship between long-standing achalasia and the development of carcinoma [1, 19]. Others, however, have not confirmed this finding, for they have reported mean ages of presentation with carcinoma and achalasia similar to those of patients without achalasia, ranging from 60 to 68 years [10, 16]. Similarly, it has been suggested that esophagomyotomy serves a protective role in preventing the subsequent development of carcinoma, but this concept, too, has been refuted by others, and, in fact, there have been many reports of carcinoma developing after a successful myotomy. Viard and associates [20] reviewed the literature up to 1978 and found 25 such cases. Since then, other cases [21, 22] have been reported even as late as 23 years postoperatively [23].
In Matthews and Pattison's collective review [1], the clinical features of 281 patients with carcinoma arising in association with achalasia were described. Two hundred fifty-five of these individuals were white, 21 were Japanese, and 5 were black. The male-to-female ratio was 3.75:1, and the ages ranged from 8 to 72 years (mean, 52 years) at the time of the development of carcinoma. There was a wide range in the intervals from the onset of symptoms of achalasia to the time of treatment, if any, and to the time of development of carcinoma. The mean interval from the time when the symptoms of achalasia appeared to the time of treatment either by dilation or myotomy was 11.3 years; the interval from the time of treatment to the development of carcinoma was 9.2 years. In 20% of the cases for which it could be calculated, the total time from the onset of achalasia symptoms to the development of carcinoma ranged from 1 to 42 years (mean, 20.5 years). There was no difference in this time interval between those patients treated by esophagomyotomy and those treated by forceful dilation.
The site in the esophagus at which carcinoma arises in patients with achalasia is seen as indirect evidence of an association between the two conditions. The middle third of the esophagus is the most common site for cancers to arise in patients with achalasia. It was found in this location in 67% of Matthews and Pattison's 168 cases. This compares with the roughly 50% incidence of carcinoma in the middle third of the esophagus in patients without this associated disease. However, this finding is not confirmed by individual reports that cite a 33% to 58% incidence of tumors in the middle third of an achalasic esophagus [5, 9, 11]. Thus the reported data are conflicting, some supporting and others negating a causal relationship between the two conditions.
Results of Treatment
In the first reported case of squamous cell carcinoma developing in a patient with achalasia, the findings were made at autopsy [4]. Since then, there has been little improvement in survival, as patients in whom carcinoma develops in an achalasic esophagus present late for treatment for a number of reasons. They are accustomed to many years of varying degrees of dysphagia, and therefore are slow to report changes in their swallowing patterns. The dilated nature of their esophagus is such that a malignant lesion must obtain substantial size before causing dysphagia, or the ultimate bulky nature of the tumor results in necrosis or symptoms of bleeding, bringing the patient to clinical attention. Finally, surveillance with contrast esophagography or endoscopy may be difficult because of the presence of retained food and debris, making a detailed and accurate examination of the entire mucosa difficult.
The advanced stage of carcinoma arising in the achalasic esophagus is reflected in the uniformly poor survival after therapy. In most patients, the cancer is inoperable or unresectable at the time of presentation due to the advanced stage of the disease. The mean survival in the reported cases is less than 1 year and often less than 6 months. Of those patients who undergo resection, only a few have been reported to survive more than 5 years (Table 3) [9, 16, 20]. Early stage patients, such as those with carcinoma in situ, have been reported but are extremely rare [24, 25].
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Personal Experience
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Clinical Material
Between January 1970 and January 1992, we treated 241 consecutive patients with esophageal achalasia. Six had carcinoma of the esophagus when first seen by us. Of the remaining 235 patients, some underwent more than one form of therapy, but the initial treatment given by us was esophagomyotomy in 181; forceful dilation in 30; vagotomy, antrectomy, and Roux-en-Y diversion in 15; and a variety of operative procedures in 9 to correct for a prior failed antireflux operation done elsewhere for an incorrect diagnosis of reflux. In addition to the 6 patients with squamous cell carcinoma at the time of initial presentation, it subsequently developed in 3 while they were under observation, for a total of 9 patients and a prevalence rate of 3.7%. Barrett's esophagus developed in 1 patient after forceful dilation, and then subsequently adenocarcinoma of the esophagus arose. He is not included among the 9 patients with cancer related to achalasia.
Follow-up evaluation of the patients' status was carried out within 2 years of the termination date of enrollment of the patients in the study group. Ten patients died of unrelated diseases, and they are included in the follow-up data. Although 22 patients were lost to follow-up, the status of 10 who were followed up for more than 10 years after treatment are included. The 6 patients who had carcinoma when first seen by us are not included, leaving a total of 223 patients for the analysis as to the risk of the subsequent development of squamous cell carcinoma of the esophagus. These patients were followed up for 3,415 patient-years. Carcinoma of the esophagus developed in 3 patients 4.5, 18, and 19 years after treatment and 15.5, 20, and 39 years after the onset of esophageal achalasia. This translates into an incidence of one cancer per 1,138 patient-years of follow-up, an incidence of 88 per 100,000, and a risk 14.5 times that of the age-adjusted and sex-adjusted general population [26].
Cancer and Achalasia
Clinical data on the 9 patients with cancer and achalasia, in 3 of whom it developed while they were under observation by us and in 6 who were first seen by us when the cancer had already developed in an achalasic esophagus, are given in Table 4. The diagnosis of esophageal achalasia was made in 6 on the basis of classic symptoms and upper gastrointestinal radiographic contrast study findings (Fig 1). Three patients had also undergone esophageal manometry that disclosed the classic pattern of esophageal achalasia. There were 6 male and 3 female patients with ages ranging from 40 to 77 years (median, 67 years). Seven of the 9 patients had been treated for achalasia before the development of carcinoma. One had been treated by forceful dilation, with good results. Six had undergone esophagomyotomy, 1 on two occasions. In 2 of these 6 patients, the esophagomyotomy was performed by us. One of those who had undergone a prior esophagomyotomy elsewhere subsequently underwent vagotomy, antrectomy, and Roux-en-Y diversion performed by us 2 years after the myotomy, followed by a Belsey antireflux procedure because of a reflux stricture. The interval between the onset of symptoms and the development of carcinoma ranged from 3 to 52 years, with a median of 28.25 years. The location of the malignancy in the thoracic esophagus was in the upper esophagus in 5, the midesophagus in 3, and the lower esophagus in 1. In 1 patient with midesophageal involvement, nearly the entire intrathoracic esophagus was involved by tumor (see Fig 1).
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Fig 1. . Esophagogram (A) and gross specimen (B) of the surgically removed esophagus from patient 9. (Courtesy of Dr Douglas J. Mathisen.)
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Six of the 9 patients were considered to be surgical candidates; 5 underwent resection. The operative finding of vertebral body involvement in 1 led us to perform palliative intraoperative prosthetic intubation. Four of the five resections were performed by the Ivor Lewis route; 1 of the patients required a cervical esophagogastrostomy. The fifth patient had a transhiatal resection. Two of the 3 patients not considered surgical candidates had tracheobronchial involvement by the tumor and were treated by radiotherapy and, in one instance, also by prosthetic intubation. The third patient whose general status precluded surgical intervention was treated with chemoradiation therapy. It was possible to stage the lesions accurately only in those patients undergoing surgical exploration. The lesion in 1 patient who showed a complete response after neoadjuvant therapy was stage 0. One lesion was stage IIa, and the remaining four tumors were stage III.
There were no hospital deaths. Two of the patients undergoing resection are alive, 6 and 42 months postoperatively. The other 3 patients who had resection succumbed to their disease 6, 7, and 22 months postoperatively. None of the 4 patients not treated by resection survived more than 1 year.
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Comment
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Despite the widely disparate figures reported concerning the prevalence and incidence rates of squamous cell carcinoma and esophageal achalasia, with only one recent exception [2], they are in agreement that there is an association between the two conditions. Our finding of a 3.7% prevalence rate of squamous cell cancer among 241 achalasia patients treated by us over nearly a quarter of a century is consistent with this view. Although the reported risk of carcinoma developing in a patient with achalasia ranges from zero to 33 times the risk of the general population, our calculated risk of 14.5 times that of a comparable age-adjusted and sex-adjusted population also supports the potentially precancerous nature of esophageal achalasia. To be sure, it is a lower risk than that reported by some, but a risk twice that cited by Wychulis and associates [18] from the Mayo Clinic, a figure based on the largest number of achalasia patients yet reported.
Regional differences in esophageal cancer incidence might account for this twofold difference. Our estimates are, if anything, overly conservative, as we included patients who were followed up for only 10 years, whereas the average reported interval from the onset of symptoms of achalasia to the development of carcinoma is in the neighborhood of 20 years. We may have easily underestimated the true risk. On the other hand, by eliminating other types of cancer from our calculation, specifically the adenocarcinoma that develops in the setting of Barrett's esophagus and carcinoma of the cardia, which in all likelihood have no relationship to esophageal achalasia, our data are probably more specific as far as the precancerous nature of achalasia is concerned than is true of some of the reports in the literature that do not make these exclusions. Furthermore, we believe that, in calculating incidence rates, the interval before the development of carcinoma should begin with the onset of symptoms, not with the time when achalasia was diagnosed or the time when therapy was initiated. This results in an incidence rate lower than that cited in some other reports. The supposed protective role of esophagomyotomy in preventing the subsequent development of carcinoma is likewise disproved both by our literature review, which has disclosed numerous reports of cancer developing after myotomy, and by our own experience. Of our 9 patients with esophageal achalasia in whom squamous cell cancer developed, 6 had undergone a prior esophagomyotomy, 1 of them 23 years before the development of carcinoma [23].
The reported results of surgical therapy for carcinoma developing in patients with esophageal achalasia have been extraordinarily poor because of the advanced stage of the disease at the time of diagnosis, with associated lower operability and resectability rates. We have only been able to identify three 5-year survivals after resection [9, 16, 20]. Only 1 of our patients, who experienced a complete response to neoadjuvant therapy, in that no tumor was found in the resected specimen, appears to have a chance of surviving 5 years, for he is currently well 3.5 years after resection.
The increased risk of cancer developing in achalasia patients and the advanced stage at which it is usually diagnosed raise the question of whether close surveillance in patients with achalasia is indicated, and, if so, what form it should take. The literature on this point is widely divergent. Surveillance has been deemed ``unwarranted'' [2], some say it should be employed on a ``regular basis'' [17], some recommend periodic endoscopic surveillance alone [16, 24, 27], and some advocate radiographic, endoscopic, and cytologic examinations performed every 1 to 2 years [20, 28]. Surprisingly, the American Society of Gastrointestinal Endoscopy, in their official guidelines for clinical application [29], states that there is no need for endoscopic surveillance in achalasia patients after effective dilation or myotomy, or both, and that the role of surveillance in those treated later in the disease has yet to be determined.
For a screening test to be of value, it must be able to reliably detect an abnormality, the compliance of the patient must be high, and the technique of surveillance must be cost-effective. In a study conducted by Meijssen and associates [16], not only were the potential benefits of endoscopic screening shown, but its pitfalls were also pointed up. Carcinoma was apparently missed in 1 of their patients, and 2 of 3 patients delayed their endoscopy for a year more than the time required by the protocol. The cost of this surveillance must also be examined. Although not so stated, it can be inferred from their data that approximately 732 endoscopic examinations were required to detect three cancers over the 15-year study period, for a total cost of $585,000, or a cost of $195,000 per cancer detected. In contrast, the calculated cost for cancer detection in a patient with Barrett's esophagus is estimated to be $31,000 [30]. Furthermore, the glandular epithelium of Barrett's esophagus usually exhibits dysplasia as an early signal of malignant degeneration, allowing early, and therefore often curative, resection of the esophagus [31]. This early histologic marker of malignant change is not present in achalasia, and gross evidence of tumor is usually necessary for a malignancy to be detected.
Although it seems evident that there is a large measurable increase in the risk of squamous cell carcinoma developing in patients with achalasia, the absolute incidence of these tumors is small compared with that of more common tumors, such as carcinoma of the lung, for which routine screening has been shown to be ineffective in prolonging life [18, 32] (Table 5). However, the Chinese experience with periodic screening using brush cytologic studies in high-risk asymptomatic individuals in a region where esophageal cancer is endemic suggests an alternative to costly endoscopic screening. This approach proved to be 80% accurate and led to a 90% 5-year survival rate after resection [34]. Periodic screening every 1 to 2 years is thought to permit detection of esophageal cancer at a potentially curable stage, for the findings yielded by endoscopic studies suggest that it may take 3 to 4 years for carcinoma in situ of the esophagus to progress to a far advanced stage [35]. Therefore, although the role of surveillance in achalasia patients remains to be determined as far as providing an early diagnosis of cancer, the use of brush cytologic studies every year or 2 may well prove to be a cost-effective surveillance method in such patients.
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Footnotes
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Address reprint requests to Dr Streitz, Department of Thoracic and Cardiovascular Surgery, Duluth Clinic, 400 East Third St, Duluth, MN 55805.
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Top
Abstract
Introduction
