Esophageal cancer screening in achalasia: is there a consensus?

Introduction

Achalasia is an important but relatively uncommon disorder, with an estimated incidence of 1 in 100 000 and prevalence of 1 in 10 000.¹ Long-term effective treatment aims to lower lower esophageal sphincter (LES) pressure, principally via pneumatic dilation or Heller myotomy. Recent studies have demonstrated that these treatments are both effective and durable.^2–5 Nonetheless, irrespective of treatment, esophageal cancer remains a long-term potential complication of achalasia. This risk is likely related to multiple pathophysiologic mechanisms. Squamous cell carcinoma (SCC) may arise because of esophageal food retention with resultant bacterial fermentation and stasis esophagitis. The associated inflammation has been purported to progress to dysplasia as well as increase epithelial susceptibility to bacterial produced carcinogens.^6–9 Alternatively, the risk of esophageal adenocarcinoma may relate directly to gastroesophageal reflux and poor clearance in the aperistaltic esophagus. Indeed Barrett's esophagus has been reported in up to 14% of achalasia patients following therapies targeted at lowering LES pressure.^10–13 In addition, Barrett's esophagus has been described in untreated achalasia, potentially relating to stasis esophagitis.^14,15

However, despite these proposed mechanisms, the precise risk of developing esophageal cancer in patients with achalasia remains unclear. Several studies have examined the risk of esophageal cancer in this population, with largely variable results. In a Dutch cohort of 448 patients with achalasia, 3.3% developed esophageal cancer over a mean follow up of 9.6 years.¹⁶ These findings contrast with a Swedish study of 2896 patients with achalasia in which only 22 esophageal cancers developed over a mean follow up of 9.9 years.¹⁷ Similarly, Eckardt et al. identified only two cases of esophageal SCC in a cohort of 253 achalasia patients over a median follow up of 9.3 years.¹⁸ Additional studies have similarly yielded conflicting results, with estimated risks ranging from those similar to the general population to as high as 6%.^11,19–23

Because of these discrepancies, the role of cancer surveillance in achalasia remains controversial. The current American Society of Gastrointestinal Endoscopy (ASGE) and American College of Gastroenterology (ACG) practice guidelines do not recommend endoscopic surveillance in achalasia.^24,25 This is largely based on the lack of data demonstrating the efficacy of endoscopic surveillance. This is illustrated by a Swedish study that demonstrated the need for 406 endoscopies in men and 2220 in women to detect one cancer with annual surveillance.²⁶ However, some studies have suggested reasonable efficacy with surveillance strategies.^27,28 A study from the United Kingdom followed a cohort of 36 treated achalasia patients with biannual chromoendoscopy surveillance for a cumulative total of 74 patient years. In this cohort, two superficial SCCs were detected.²³ Similarly, a prospective study of 195 treated achalasia patients with 874 collective years of annual endoscopic surveillance detected three esophageal squamous cell cancers. Most notably, in two cases, early stage squamous cell cancer (stage I and IIa) was detected, with curative outcome. In the last, the patient refused further endoscopic surveillance and presented when symptomatic with stage IV esophageal cancer.²⁹ However, the small number of subjects in these studies does not allow for general surveillance recommendations in achalasia. Some have advocated for more selective screening in achalasia. They note that studies have demonstrated that esophageal cancer is most likely to occur in patients with symptom durations of greater than 10 years or those with significant esophageal dilation, suggesting that surveillance should be limited to this population.^16–18,20 However, a paucity of data exists to confirm or refute the efficacy of such a strategy. Given these issues, we sought to identify current practice among experts in the field. Our goal was to ascertain whether consensus exists around general recommendations and identification of risk factors regarding endoscopic surveillance for esophageal cancer in patients with achalasia.

Methods

A survey designed to assess current practices regarding screening for esophageal cancer in achalasia was designed and sent to 28 recognized experts in the area of achalasia. The survey consisted of 10 multiple choice questions (Fig. 1). Surveys were sent via electronic mail with an explanation of the study. A subsequent message was sent 2 weeks after the initial mailing to non-responders. Expert gastroenterologists were identified based on their published work and recognition in the field. Participants had a mean of 200 publications and specific expertise in the field of esophageal motility, with a mean of 18 publications in the field and a history of invited lectures on achalasia at major society meetings. Responses to the survey were recorded by a single investigator (K. R.). Assessment of agreement among responders was done utilizing the Fisher's exact test.

Results

Survey responses were received from 17 of 28 (61%) contacted experts. Participants came from throughout the world, with seven (41%) from the United States, eight (47%) from Europe and Australia, and two (12%) from Asia. All participants reported relatively high achalasia patient volumes, with 15 (88%) seeing more than 50 patients annually with achalasia in their practice and the remaining two with 20–50 achalasia patients (Table 1).

Screening for esophageal cancer in achalasia was highly variable, with nine (53%) experts advocating routine screening for cancer while eight experts (47%) did not. The location of the experts did not influence the decision to perform surveillance with 3/7 (43%) US experts, 4/8 (50%) European or Australian experts, and both Asian experts employing routine esophageal cancer screening in achalasia (P = 0.64). Practice was also not dependent on patient volume, with 53% of experts seeing a high volume (>50 achalasia patients) and 50% seeing intermediate volume (20–50 achalasia patients) routinely screening for esophageal cancer.

Similarly, perceptions regarding the risk of esophageal cancer in achalasia were inconsistent. Three experts counseled patients that the risk of esophageal cancer in achalasia was no different than the general population. Among those who did believe the risk of cancer was increased, there remained high rates of variability. A lifetime risk of 0.1–0.5% was reported by seven experts, 0.5–1% by three experts, and three experts reported risks of 1–2% and 3–5% respectively each. These differences were independent of regional differences with four of seven (57%) US experts, three of eight (38%) European or Australian experts, and one of two (50%) Asian experts endorsing a lifetime risk for esophageal cancer of 0.1–0.5% (P = 0.80). Interestingly, these variations did not reliably correlate with screening practices. One of three (33%) experts who did not believe the risk of cancer was increased in achalasia still endorsed routine screening, while routine screening was performed by seven (70%) who endorsed a risk of 0.1–1% and one (33%) who reported a risk of greater than 1% (P = 0.47) (Table 2).

Among experts who did perform routine screening, practice remained variable. All experts utilized esophagogastroduodenoscopy for screening, with only one combining this was esophagram. However, screening intervals were highly variable. Only one respondent each began screening at or within 1 year of diagnosis, while three each (33%) began screening 5 and 10 years after symptom onset, respectively. One respondent did not report when they initiated screening. Further, after initiation, screening was performed every 2 years in four (44%), every 3 years in four (44%), and every 5 years in one (11%) respondent's practice. None of the experts used the Chicago classification criteria to determine screening practice while only one considered esophageal diameter (Table 2).

Interestingly, significant practice variation in the general approach to therapy of achalasia was also seen. Pneumatic dilation was the initial therapeutic approach among five (29%) experts, Heller myotomy in eight (47%) experts, and peroral endoscopic myotomy among two (12%) experts while two did not identify a single performed therapeutic modality. Heller myotomy was the preferred approach across all geographic areas, endorsed by four of seven US and four of eight European or Australian experts. However, pneumatic dilation was more frequent in European and Australian practice, endorsed by three of eight (38%) compared with only one of seven (14%) US experts (P = 0.57). In addition to initial clinical management, variation was also seen in long-term monitoring of achalasia patients. Long-term follow up was recommended by 14 of 17 (82%) expert gastroenterologists; however, the interval periods varied. Annual follow up was recommended by eight gastroenterologists, while three each recommended follow up every 3–6 months and on a biannual basis, respectively (Table 2).

Discussion

One of the most feared long-term complications of achalasia remains esophageal carcinoma. However, while the link between these two conditions has biological and observational validity, the role of surveillance in achalasia remains unclear. Our findings reinforce this uncertainty, with a nearly even division among experts regarding the need for cancer screening in achalasia. This debate would seem to center around the perceived risk of cancer in these patients, with significant differences of opinion seen in this study. Nearly half of experts estimated the lifetime risk of esophageal cancer in achalasia to be between 0.1% and 0.5%. However, among the remaining experts, there was an even distribution among those who believed that the risk was no different than the general population and those who believed the risk was 1–5% over their lifetime.

Interestingly though, these differences in perceived risk did not correlate with the practice of screening and surveillance in this study. This finding is somewhat surprising, given screening practices for other premalignant conditions, most notably Barrett's esophagus. The estimated risk of cancer in non-dysplastic and low-grade Barrett's esophagus has recently been estimated at 0.1% and 0.3% per patient year, respectively.^30,31 This risk is similar to that reported in achalasia, with several studies reporting a risk of 0.3–0.4% per patient year.^14,20,29 However, although many of our experts endorsed a similar risk of cancer in achalasia and Barrett's, the recommendation for screening was highly variable and inconsistent. The reasons for these differences in perception are unclear and likely based on the paucity of data dictating clear recommendations and factors that increase cancer risk in achalasia. Identification of these factors may help frame a consensus regarding screening practices in achalasia.

While upper endoscopy was universally chosen as the method for screening, practices among those who endorsed screening were nonetheless highly variable. Interestingly, none of the experts utilized the Chicago classification, and only one considered esophageal diameter when initiating cancer surveillance. Perhaps most striking, there was no consensus regarding timing of initiation of screening and frequency of surveillance. This is despite the fact that the risk of cancer in achalasia appears to increase with the duration of disease. In fact, in nearly all series examining the risk in achalasia, esophageal cancer was not described earlier than 10 years after symptom onset.^16,17,20 Furthermore, Eckardt et al. found a 2.6% prevalence of esophageal cancer in a cohort of patients with median symptom duration of 22 years compared with no occurrences within a cohort with a median duration of 9.3 years.¹⁸ This and similar findings would suggest that a subset of high-risk achalasia patients exist in whom screening may be beneficial. Further consensus regarding identification of this group is likely essential to establish screening practices in achalasia.

Finally, discordance regarding initial treatment of achalasia was seen. This is not surprising considering recent data suggesting that Heller myotomy and pneumatic dilation have comparable therapeutic outcomes, challenging a prevalent opinion that myotomy is the best long-term treatment of choice.⁵ As such, these discrepancies may simply reflect practice variation dependant on local expertise. Nonetheless, the lack of consistency regarding management and follow up of these patients further underscores the general lack of agreement in the management of achalasia.

This study has several limitations. Only a small number of experts were included, not allowing for assessment of general practice among community gastroenterologists. However, our intent was to establish whether consensus exists among experts in achalasia through which a standard practice could be established. The finding of high variability among this group suggests that similar practice variation would exist among a larger cohort of gastroenterologists. In addition, utilization of a multiple choice questionnaire did not allow for more specific detail regarding clinical practice in achalasia. It is possible that a more detailed assessment of practices would have yielded greater consensus. However, the variation found in this study establishes the fact that greater discussion and consensus is required.

Nonetheless, this study documents a large degree of practice variation in the long-term management of achalasia among expert esophagologists. Despite the ASGE and ACG guidelines against cancer screening, the majority of experts still employ esophageal cancer screening and surveillance in their achalasia practice. Furthermore, no consensus exists regarding how endoscopic surveillance should be structured. These differences may reflect the limited data available regarding the efficacy of surveillance strategies. Indeed, the ACG clinical guidelines note a potential benefit to surveillance beyond early detection of cancer, but conclude that further studies are required to determine if surveillance strategies are effective. Consequently, while insufficient data may exist upon which clinical guidelines for endoscopic surveillance can be made, many experts may still employ a surveillance program in patients suspecting that this may improve long-term clinical outcomes. Interestingly, the lack of consensus on cancer screening parallels a lack of agreement on initial treatment of achalasia. These findings suggest that experts should initiate an attempt to foster greater homogeneity of clinical practice in the face of the current guidelines regarding management of long-standing achalasia and cancer screening. Most importantly, this study underscores the need to collect more meaningful data on this subject to establish more reliable and agreed upon recommendations.

References

Author notes