Screening for Esophageal Squamous Cell Carcinoma

Introduction and Epidemiology

Esophageal cancer is the eighth most common cancer and the sixth leading cause of cancer death in the world. There are two major histologic subtypes of esophageal cancer: adenocarcinoma and squamous cell cancer. Globally, more than 400,000 deaths were estimated attributable to esophageal cancer in 2012. There is considerable geographic variability in the incidence of esophageal cancer, with the majority of cases (80%) occurring in less-developed parts of the world. Based on recent incidence data, nearly 17,000 new cases of esophageal cancer will be diagnosed in the United States in 2016 (13,460 cases in men and 3,450 cases in women), and there will be 15,690 esophageal cancer-related deaths. On the other hand, more than 290,000 new esophageal cancer diagnoses and more than 218,000 esophageal cancer deaths were estimated in China in 2011.

Overall survival rates for esophageal cancer are poor, with highest mortality rates observed in regions with highest disease incidence, including Eastern Asia, Southern Africa, and Eastern Africa ( Fig. 26.1 ). Even within regions there is substantial geographic heterogeneity in the incidence of disease. Data published nearly four decades ago from the Caspian Cancer Registry, originating from the Caspian Littoral region on the rim of the Caspian Sea, reported annual age-adjusted incidence rates ranging from a low of 20.1 cases per 100,000 population in subregions of lowest incidence to a high of 165.5 cases per 100,000 population in subregions of highest incidence.

FIG 26.1, A, Esophageal cancer incidence in men (2012 data). B, Esophageal cancer mortality in men (2012 data).

Of the two major histologic subtypes of esophageal cancer, the majority of diagnosed cases worldwide are classified as esophageal squamous cell carcinoma (ESCC). A unique trend in Western countries, including the United States, has been a dramatic increase in the incidence of esophageal adenocarcinoma over the past several decades, to the extent that proportionally the majority of esophageal cancers diagnosed currently in the United States are adenocarcinoma rather than ESCC.

Nonetheless, due to the significant morbidity of ESCC, the potential for prevention through early detection and treatment of ESCC and precursor lesions, and the nuances of endoscopic diagnosis of ESCC (with particular attention to the role of chromoendoscopy), understanding and implementing an evidence-based approach to screening for ESCC is essential for health care providers, and particularly the practicing gastrointestinal endoscopist.

Risk Factors for ESCC and Unique Populations at Risk

Common to the pathogenesis of many types of neoplasia, development of ESCC is often a consequence of the interplay between nonmodifiable (genetic) and modifiable (environmental) risk factors for disease.

Worldwide, ESCC incidence rates are more than twofold higher for men than for women. In many countries, including relatively lower-incidence countries in the developed world, alcohol and tobacco use are major risk factors for ESCC. For instance, in a case control study of African-American men in an urban location, the relative risk of esophageal cancer associated with alcohol consumption was 6.4 (95% confidence interval [CI] 2.5–16.4) and the relative risk associated with tobacco use (not controlling for alcohol consumption) was 1.9 (95% CI 1.0–3.0). In this study, consumption of hard liquor was associated with a higher risk of esophageal cancer than beer or wine consumption. In addition, the race-specific incidence of ESCC among US men with exposure to alcohol and tobacco is highest among African-American men compared to other racial and ethnic groups.

The combined effects of alcohol and tobacco are synergistic. In a case control study from Italy, with individuals who were nonsmokers and with moderate weekly alcohol consumption as the reference standard, odds ratios for development of esophageal cancer were 2.6 (95% CI 4–29) for nonsmokers with very heavy alcohol consumption, 8.4 (95% CI 16–41) for heavy smokers with moderate alcohol consumption, and 21.8 (95% CI 6–15) for heavy smokers with very heavy alcohol consumption. Even in higher-incidence regions for ESCC, such as China, smoking has been implicated as a significant risk factor for esophageal cancer as tobacco consumption has increased across the population. And in a case control study from Uganda, the age- and gender-adjusted percentage of cases of ESCC attributable to alcohol and smoking was 13%. Smokeless tobacco use has also been implicated as a risk factor for ESCC. In a study on the global burden of disease, smokeless tobacco use was implicated as the cause of more than 24,000 deaths worldwide due to ESCC, with the majority of these deaths (> 20,000) occurring in Southeast Asia.

Consumption of alcohol and/or tobacco can significantly influence host factors contributing to baseline ESCC risk. For instance, an increased risk of ESCC has been reported in individuals with a family history of esophageal cancer, yet this risk increases substantially for individuals with a family history of esophageal cancer and who are also current smokers and heavy drinkers. In addition, whereas the incidence of ESCC is higher in men than in women, an increasing prevalence of female smokers in the United States can result in comparable incidence between women and men smokers in smoking-related cancers, including ESCC.

Throughout the world, dietary and nutritional factors have been implicated in the pathogenesis of ESCC. Multiple studies have suggested that populations with low dietary intake of fruits and vegetables are at increased risk for ESCC. Micronutrient deficiencies including zinc and selenium may also be associated with increased risk for ESCC. Dietary folate consumption was reported to be inversely associated with risk for ESCC in a European population with high alcohol consumption. On a population health scale, alterations in nutritional habits represent an opportunity to modify ESCC risk. Long-term decline in ESCC mortality in China has been attributed to changes in diet.

Other specific environmental exposures reported to be associated with ESCC risk include exposure to polycyclic aromatic hydrocarbons from not only tobacco smoke but sources including indoor coal stoves and the Brazilian beverage maté; hot tea consumption (in a northern Iranian region); poor oral hygiene; and infection with certain serotypes of human papillomavirus infection.

Unique populations of patients with comorbid illness are at increased risk for ESCC and may be candidates for targeted screening programs. The rare genetic condition tylosis, characterized by cutaneous hyperkeratosis associated with a chromosome 17 abnormality, is associated with a high cumulative lifetime risk of ESCC. Current American Society for Gastrointestinal Endoscopy (ASGE) guidelines recommend screening for ESCC among patients with tylosis beginning at age 30 and repeated at 1 to 3 year intervals thereafter. Targeted screening for ESCC is also recommended in patients who have sustained caustic esophageal injury, typically following lye ingestion, beginning 10 to 20 years after exposure and repeated at 2 to 3 year intervals.

Other populations at increased risk for ESCC include patients with upper aerodigestive (head and neck) squamous cell cancers, among whom high rates of synchronous and metachronous ESCC have been reported, as well as patients with achalasia. However, current ASGE guidelines recommend against screening in patients with upper aerodigestive cancers or achalasia due to a lack of sufficient evidence to suggest that screening confers a benefit with respect to early cancer detection or survival.

Rationale for Population Screening for ESCC

The high mortality rates observed for ESCC reflect the fact that most patients diagnosed with ESCC have advanced disease at the time of diagnosis. The development of luminal obstruction sufficient to cause the cardinal symptom of dysphagia is typically indicative of the presence of invasive carcinoma. A rationale for implementation of a screening program aimed at early cancer detection and, ultimately, improved cancer-specific prognosis and survival must be interpreted in this context. In general, several criteria must be fulfilled for a screening test to be recommended for routine clinical practice:

1.
Screening should enable early detection of an unrecognized (asymptomatic) disease or precursor lesion which, if left undetected and untreated, has the potential to progress and result in significant morbidity and/or burden of suffering.
2.
The test utilized for screening should be accurate, cost-effective, safe, and acceptable to both clinicians and patients undergoing screening.
3.
Effective and acceptable treatment options should be available for patients found to have disease as a result of the screening examination.

Each of these criteria can be examined with respect to ESCC.

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