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Biology and Epidemiology of Esophageal Carcinoma

Tony E. Godfrey, Virginia R. Litle, Alan G. Casson, David S. Schrump
Biology and Epidemiology of Esophageal Carcinoma is a topic covered in the Pearson's General Thoracic.

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Key Points

  • There are two major histologic types of esophageal carcinoma; esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC). Lymphoma, carcinoids, melanoma and leiomyosarcoma also occur at low frequencies.
  • Squamous cell carcinoma of the esophagus is one of the 10 most frequent malignancies worldwide, with a characteristic geographic variation in incidence and with well-established environmental risk factors.
  • Over the past four decades, a marked change has been reported in the epidemiology of esophageal malignancy in North America and Europe, with an increasing frequency of EAC.
  • Although a strong statistical association between gastroesophageal reflux disease, Barrett’s esophagus, and risk for primary EAC is reported, sociodemographic, dietary, and lifestyle risk factors are less defined for this tumor subtype.
  • Identification of molecular alterations associated with Barrett’s metaplasia-dysplasia-adenocarcinoma progression provides further insight into the molecular pathogenesis of esophageal adenocarcinoma.

Carcinoma of the esophagus is one of the most lethal malignancies wordwide with an estimated 16,000 deaths in the United States[1] and more than 508,000 deaths globally in 2018.[2] The epidemiology of esophageal cancer is characterized by a striking variation in incidence geographically and temporally as well as by ethnicity and gender. These observations distinguish esophageal cancer from many other human solid tumors. ESCC is the most common form of esophageal cancer worldwide with particularly high incidence in Iran, Northern China, India, Japan and Eastern Africa. Chronic irritation and inflammation of the esophagus appear to be important in the etiopathogenesis of ESCC, with smoking and alcohol use being the strongest risk factors, particularly when combined. In the United States, ESCC also has a higher incidence in men than women (~2:1), and in African Americans compared with other racial groups.

Although squamous cell carcinoma remains the most frequent histologic subtype of esophageal cancer globally, there has been a marked increase in the incidence of EAC in North America, Western Europe and Australia over the past four decades. The incidence of adenocarcinoma of the esophagus and esophagogastric junction (cardia) has increased at a rate exceeding that of any other human solid tumor[3] and adenocarcinoma has overtaken squamous cell carcinoma as the most prevalent esophageal malignancy in these regions.[3],[4],[5],[6] The strongest known risk factor for EAC is a metaplastic change in the lower esophageal epithelium from the normal squamous to a columnar cell type known as Barrett’s Esophagus. The presence of BE is associated with an approximately 40-fold increased risk for development of EAC with progression estimates ranging from 0.4 - 1%/year.[7] BE is believed to be a consequence of repeated gastroesophageal reflux (GERD) due to a compromised lower esophageal sphincter and patients with recurring GERD symptoms have a reported 8-fold increased risk of developing EAC.[8] Obesity has also been associated with increased risk of BE and EAC, possibly as a result of increased intra-abdominal pressure and increased reflux. BE is a preneoplastic lesion that can progress to invasive adenocarcinoma through the histologically defined metaplasia – dysplasia – adenocarcinoma sequence.[9] Once thought to be a linear progression, accompanied by accumulation of genetic changes, recent findings have challenged this concept, and in many cases progression appears to be rapid and non-linear.[10]

Despite recent advances in multimodality therapy, esophageal cancers are highly lethal neoplasms, with generally poor outcome.[11] Although improved survival could be achieved with earlier detection through endoscopic surveillance programs for Barrett’s esophagus, an improved understanding of its etiology and tumor biology is required to identify those at risk of progressing from BE to cancer. In this chapter we summarize clinically relevant advances in the biology and epidemiology of esophageal malignancy. Because the premalignant lesion Barrett’s esophagus appears central to our understanding of the molecular pathogenesis of esophageal adenocarcinoma, attention is focused on molecular alterations and environmental risk factors associated with the metaplasia-dysplasia-adenocarcinoma progression.

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Key Points

  • There are two major histologic types of esophageal carcinoma; esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC). Lymphoma, carcinoids, melanoma and leiomyosarcoma also occur at low frequencies.
  • Squamous cell carcinoma of the esophagus is one of the 10 most frequent malignancies worldwide, with a characteristic geographic variation in incidence and with well-established environmental risk factors.
  • Over the past four decades, a marked change has been reported in the epidemiology of esophageal malignancy in North America and Europe, with an increasing frequency of EAC.
  • Although a strong statistical association between gastroesophageal reflux disease, Barrett’s esophagus, and risk for primary EAC is reported, sociodemographic, dietary, and lifestyle risk factors are less defined for this tumor subtype.
  • Identification of molecular alterations associated with Barrett’s metaplasia-dysplasia-adenocarcinoma progression provides further insight into the molecular pathogenesis of esophageal adenocarcinoma.

Carcinoma of the esophagus is one of the most lethal malignancies wordwide with an estimated 16,000 deaths in the United States[1] and more than 508,000 deaths globally in 2018.[2] The epidemiology of esophageal cancer is characterized by a striking variation in incidence geographically and temporally as well as by ethnicity and gender. These observations distinguish esophageal cancer from many other human solid tumors. ESCC is the most common form of esophageal cancer worldwide with particularly high incidence in Iran, Northern China, India, Japan and Eastern Africa. Chronic irritation and inflammation of the esophagus appear to be important in the etiopathogenesis of ESCC, with smoking and alcohol use being the strongest risk factors, particularly when combined. In the United States, ESCC also has a higher incidence in men than women (~2:1), and in African Americans compared with other racial groups.

Although squamous cell carcinoma remains the most frequent histologic subtype of esophageal cancer globally, there has been a marked increase in the incidence of EAC in North America, Western Europe and Australia over the past four decades. The incidence of adenocarcinoma of the esophagus and esophagogastric junction (cardia) has increased at a rate exceeding that of any other human solid tumor[3] and adenocarcinoma has overtaken squamous cell carcinoma as the most prevalent esophageal malignancy in these regions.[3],[4],[5],[6] The strongest known risk factor for EAC is a metaplastic change in the lower esophageal epithelium from the normal squamous to a columnar cell type known as Barrett’s Esophagus. The presence of BE is associated with an approximately 40-fold increased risk for development of EAC with progression estimates ranging from 0.4 - 1%/year.[7] BE is believed to be a consequence of repeated gastroesophageal reflux (GERD) due to a compromised lower esophageal sphincter and patients with recurring GERD symptoms have a reported 8-fold increased risk of developing EAC.[8] Obesity has also been associated with increased risk of BE and EAC, possibly as a result of increased intra-abdominal pressure and increased reflux. BE is a preneoplastic lesion that can progress to invasive adenocarcinoma through the histologically defined metaplasia – dysplasia – adenocarcinoma sequence.[9] Once thought to be a linear progression, accompanied by accumulation of genetic changes, recent findings have challenged this concept, and in many cases progression appears to be rapid and non-linear.[10]

Despite recent advances in multimodality therapy, esophageal cancers are highly lethal neoplasms, with generally poor outcome.[11] Although improved survival could be achieved with earlier detection through endoscopic surveillance programs for Barrett’s esophagus, an improved understanding of its etiology and tumor biology is required to identify those at risk of progressing from BE to cancer. In this chapter we summarize clinically relevant advances in the biology and epidemiology of esophageal malignancy. Because the premalignant lesion Barrett’s esophagus appears central to our understanding of the molecular pathogenesis of esophageal adenocarcinoma, attention is focused on molecular alterations and environmental risk factors associated with the metaplasia-dysplasia-adenocarcinoma progression.

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Last updated: January 24, 2021