Epidemiology and Biology of Esophageal Cancer

Abstract

In the United States and other Western countries, there has been a remarkable change in the epidemiology of esophageal cancer over the past 50 years. Adenocarcinoma of the esophagus and gastroesophageal junction has replaced squamous cell as the most common type of esophageal cancer in the United States, and the incidence of esophageal adenocarcinoma is increasing faster than that of any other malignancy. Risk factors include gastroesophageal reflux disease and obesity. The increasing incidence of esophageal adenocarcinoma and a greater understanding of its underlying biology provide opportunities to devise treatment strategies that maximize survival and minimize morbidity. However, rational use of available endoscopic procedures, esophagectomy, and chemotherapy and radiotherapy requires a comprehensive understanding of the disease.

OVERVIEW OF THE SCOPE OF THE PROBLEM

Worldwide, esophageal cancer is a significant and increasing health problem. In 2005, there were 497,700 new cases, and the prevalence is expected to increase by approximately 140% by 2025.¹ It also remains a deadly disease, with 416,500 people estimated to have died from esophageal cancer in 2005. Of the two major types, squamous cell is most common worldwide, but in the United States and many Western countries, adenocarcinoma has surpassed squamous cell to become the most prevalent form of esophageal cancer. In one of the most dramatic epidemiologic shifts ever recorded, esophageal adenocarcinoma has gone from a disease that was not thought to exist until the 1950s, to the fastest increasing cancer in America in the 2000s.^2–4 From 1975 to 2000, the relative rates ofmost common cancers including breast, colon, and lung remained stable or decreased in the United States. There were increases in both prostate cancer and melanoma, but these pale in comparison to the six-fold increase in esophageal adenocarcinoma incidence during that same period.⁵ The latest Surveillance Epidemiology and End Results (SEER) statistics indicate that this alarming increase is continuing in the United States, with a more than 460% increase in incidence in white males from 1975 to 2004.⁴ The increase has been noted in white females also—at a rate of 335% over the same period.⁴ The rising incidence is occurring across all disease stages and all age groups, but the greatest increase (> 600%) is in men over 65 years old. Most cases are diagnosed in white males, but Hispanic, Japanese, Chinese, and African-American people also get esophageal cancer.¹ In the US in 2008, it is projected that 16,470 new patients will be diagnosed with esophageal cancer, and more than 50% of cases will be adenocarcinoma.⁴ A similar trend has been reported in other Western countries including the Netherlands.⁶ The United Kingdom has the highest incidence of esophageal adenocarcinoma globally, at 7 cases per 100,000 population.^7,8 By comparison, the average incidence in the US is 2.5 per 100,000, although in some regions the incidence in white males is as high as 5.3 per 100,000.^7,9,10 These numbers do not include adenocarcinoma of the gastroesophageal junction (GEJ), which many believe represents esophageal cancer in most patients.

ADENOCARCINOMA OF THE DISTAL ESOPHAGUS VS. GE JUNCTION

The incidence of adenocarcinoma of the cardia or GEJ has also increased significantly since the mid 1970s.¹¹ However, the average rate stabilized in the US after the late 1980s and perhaps is beginning to decline slightly.⁹ The incidence of adenocarcinoma of the GEJ is greatest in white males, as seen in esophageal adenocarcinoma; but unlike esophageal adenocarcinoma, the incidence does not differ significantly between white and African American females and is similar in African Americans and Asians. Further, the rate of adenocarcinoma of the GEJ is double that of esophageal adenocarcinoma in these groups.^10,12 The overall incidence of adenocarcinoma of the GEJ (3.1 per 100,000) previously exceeded that of esophageal adenocarcinoma in the US, but the most recent data indicate that esophageal adenocarcinoma incidence has surpassed that of adenocarcinoma of the cardia.^5,9

ETIOLOGY OF ESOPHAGEAL AND GEJ ADENOCARCINOMA

The etiologies of adenocarcinoma of the esophagus and squamous cell cancer are different. While squamous cancer is associated with alcohol and tobacco use, esophageal adenocarcinoma develops as a consequence of gastroesophageal reflux disease.¹³ There is some association with the use of medications that reduce the lower esophageal sphincter pressure (and worsen reflux), use of acid suppressionmedications, and obesity, but gastroesophageal reflux remains the major culprit.^13–18 The etiology of adenocarcinoma of the GEJ, or cardia, has been investigated as well. Evidence shows that GEJ adenocarcinoma develops from gastroesophageal reflux in some patients and secondary to Helicobacter pylori and gastric intestinal metaplasia in others.^19–21 Although Siewert and Stein suggested a classification system that distinguished between adenocarcinoma of the distal esophagus and the gastroesophageal junction,²² we have shown that the biologic behavior of these tumors is similar and esophagectomy is appropriate therapy for tumors at both locations (S. DeMeester, et al, unpublished data, 2009).

The increasing incidence of esophageal adenocarcinoma in combination with routine endoscopic surveillance in patients with the precursor lesion for this cancer, Barrett’s esophagus, has led to the detection of high-grade dysplasia and earlystage adenocarcinoma in an increasing number of patients. The progression of Barrett’s esophagus through dysplasia to invasive adenocarcinoma is a complex process that even today remains incompletely understood. Despite years of investigation and the investment of large sums of research dollars, we remain unable to predict with certainty which patients are most likely to progress to cancer. The best studied and validated markers are the presence and degree of histologic dysplasia and aneuploidy or abnormal cell DNA, yet even these are imperfect. Dysplasia, particularly low-grade dysplasia, is subject to substantial intra- and inter-observer variation among pathologists. While there is less variation in the pathologic interpretation of high-grade dysplasia, Schnell et al and others have suggested a low rate of progression to cancer once an incident cancer has been carefully excluded, while others report progression to cancer in approximately 10% of patients a year.^23,24 In surgical series, intramucosal cancers have been reported in approximately 30% of resected esophagi thought to have only high-grade dysplasia based on thorough preoperative endoscopic biopsies.^25,26 Additional factors that participate in the complexity of this condition include whether the dysplasia is unifocal or multifocal and the length of the Barrett’s.

BIOLOGY OF ESOPHAGEAL ADENOCARCINOMA

Recently, the biology of esophageal adenocarcinoma has become better understood. Once believed to be systemic at the time of diagnosis, it is now clear that esophageal cancer follows a pattern more consistent with other gastrointestinal cancers where lymphatic metastases precede systemic disease in most patients. Clear evidence for this comes from studies demonstrating that intramucosal cancer is curable in nearly all patients and is associated with a low prevalence of lymph node metastases. ^27–29 We recently showed that survival was excellent and equivalent for patients with intramucosal adenocarcinoma whether they were treated with an esophagectomy with extensive lymphadenectomy or a less morbid vagal-sparing procedure in which no or few lymph nodes were resected.³⁰ Until recently, cure of these lesions was reliably accomplished only with esophagectomy, but new technologies now allow endoscopic therapy with esophageal preservation in appropriate patients. Data from Pech and colleagues show excellent survival for patients with intramucosal adenocarcinoma treated with endoscopic resection and/or mucosal ablation without esophagectomy.³¹

STAGING ESOPHAGEAL CANCER

Endoscopic ultrasound (EUS) is the best method for local/regional staging of esophageal adenocarcinoma. Standard 7.5 and 12 MHz endoscopic ultrasound probes can accurately assess the depth of invasion once the tumor has gone through the submucosa, and also provide information on the presence of abnormal or enlarged lymph nodes. However, neither the standard probes nor newer high-resolution 20 MHz probes are able to accurately distinguish intramucosal from submucosal tumor invasion.³² Currently, endoscopic mucosal resection (EMR) is the only method that accurately and reliably determines the depth of invasion of a small visible lesion. EMR excises a disc of esophageal (or gastric) wall down to the muscularis propria and provides a specimen for histologic review that includes both mucosa and submucosa. In this way, EMR can reliably determine the “T” stage of early esophageal lesions.³³ Other standard staging studies include computed tomography (CT) scans of the chest and abdomen; positron emission tomography (PET) scans are increasingly being used, although the added value over CT and EUS remains unclear.^34–36

LYMPH NODES AND TYPE OF RESECTION FOR ESOPHAGEAL ADENOCARCINOMA

Evidence clearly shows that the depth of tumor invasion predicts the risk of lymph node metastases, but the presence and extent of lymph node involvement is the major determinant of survival in patients with esophageal adenocarcinoma. The risk of lymph node involvement increases from a low 2% to 4% for intramucosal tumors to 30% for submucosal tumor invasion and more than 80% with intramural and transmural invasion.^29,37–39 While systemic disease is rare in patients without an involved lymph node, it becomes nearly universal once more than eight lymph nodes are involved.⁴⁰ Consequently, an extensive lymphadenectomy as part of esophagectomy for patients with adenocarcinoma is only useful in the subgroup with ≤ 8 involved nodes. On the other hand, data from both retrospective and prospective studies have shown that survival in these patients is improved with the systematic lymphadenectomy that accompanies an en bloc resection compared to a transhiatal esophagectomy.^40,41 Further, single-center and multi-center Surveillance Epidemiology and End Results (SEER) data analysis has shown that survival improves with increasing numbers of resected nodes, even in node-negative patients.^42–44 These studies support the use of an en bloc esophagectomy as the preferred surgical therapy for esophageal adenocarcinoma, and numerous series have shown 40% to 50% rates of overall long-term survival for patients undergoing this procedure.^45–47

NEOADJUVANT THERAPY FOR ESOPHAGEAL ADENOCARCINOMA

In an attempt to improve survival for patients with esophageal cancer, Walsh and colleagues studied use of preoperative chemoradiotherapy, results of which, published in 1996, showed a survival advantage for neoadjuvant treatment.⁴⁸ These findings changed the management approach for many esophageal cancer patients. While the trial has been criticized for poor staging, unusual exclusions in the multimodal therapy arm, and very poor survival in the surgery arm, the biggest concern is the inaccurate survival curves from which the improved survival was calculated. ^19,49 Further, every other randomized trial, with the exception of a recently reported trial that closed prematurely due to poor recruitment, found no survival difference for patients treated with surgery alone vs. neoadjuvant chemoradiotherapy followed by surgery.^19,50 What was demonstrated is that use of neoadjuvant therapy reduced risk of local-regional recurrence; however, this applied primarily to patients who had an inferior transhiatal resection, which is associated with higher localregional recurrence rates than en bloc resection.^{46,47,51–55}

The benefit of an en bloc resection is also seen after neoadjuvant therapy, even in patients with residual disease, a group often dismissed as being incurable. We reported absolute 5-year survival rates of 35% for those undergoing en bloc resection vs. no survivors with transhiatal resection for patients with residual disease after neoadjuvant treatment.⁵⁶ These results support the use of an en bloc esophagectomy after neoadjuvant therapy, even in the setting of residual disease.

The application of neoadjuvant chemoradiotherapy has not been associated with a reduction in systemic disease.⁵¹ Improvements in chemotherapy are sorely needed to control the systemic component of disease in patients treated optimally for their local-regional disease by en bloc esophagectomy.

CONCLUSIONS

There has been an alarming increase in the incidence of esophageal adenocarcinoma. Reasons for this increase are unclear, but it is related to gastroesophageal reflux disease and Barrett’s esophagus. Through careful surveillance endoscopy, an increasing number of patients are being diagnosed with high-grade dysplasia or intramucosal adenocarcinoma, which are potentially curable in the majority of patients. The major determinant of survival in patients diagnosed with esophageal cancer is the presence and number of lymph node metastases. Patients with more than nine involved nodes almost always have systemic disease, and there is limited evidence for efficacy of chemotherapy in reducing risk of death in these patients. The increasing incidence of esophageal cancer should lead to more studies of optimal management strategies. Prevention should also be a focus of research and educational efforts. It is also hoped that the application of ablation techniques for dysplastic Barrett’s mucosa will alter the natural history of this disease.