Introduction
Less than 15% of patients diagnosed with esophageal cancer are cured, with approximately half of patients presenting with unresectable or metastatic disease. This chapter reviews the natural history and treatment of esophageal cancer, including anatomy, risk factors, patterns of spread and failure, staging, results of current therapeutic approaches, radiation planning techniques, toxicity data, and future treatment strategies.
Anatomy
The esophagus is a thin-walled, hollow tube approximately 25 cm in length. It is lined with stratified keratinized squamous epithelium, extending from the cricopharyngeus muscle at the level of the cricoid cartilage superiorly to the gastroesophageal junction inferiorly. The lower one-third (5 to 10 cm) of the esophagus may contain glandular elements. Replacement of the stratified squamous epithelium with columnar epithelium is referred to as Barrett's esophagus, often occurring in the lower one-third. The Z-line refers to the endoscopically visible junction of the squamous and glandular epithelium. The esophageal wall is composed of three layers: the mucosa, submucosa, and muscularis propria (Fig. 53.1). The mucosal layer contains the epithelium, lamina propria, and muscularis mucosae. The epithelium is separated from the lamina propria by a basement membrane. In the portion of esophagus containing columnar-type epithelium, the muscularis mucosae may consist of two layers. The mucosa may be divided into distinct layers, including M1 (epithelium), M2 (lamina propria), and M3 (muscularis mucosae). Similarly, the submucosal layer may be divided into inner (SM1), middle (SM2), and outer (SM3) layers. The muscularis propria consists of a circular inner layer and longitudinal outer layer. The adventitia (periesophageal connective tissue) lies directly on the muscularis propria.1 No serosa is present, facilitating extraesophageal spread of disease.
Although somewhat arbitrary, the esophagus is frequently divided into cervical and thoracic components. The most recent American Joint Committee on Cancer (AJCC) report divides the esophagus into four regions: cervical, upper thoracic, midthoracic, and lower thoracic (Fig. 53.2).1 The cervical esophagus begins at the cricopharyngeus muscle (approximately the C7 level or 15 cm from the incisors) and extends to the thoracic inlet (at approximately the T3 level or at approximately 20 cm from the incisors, at the level of the suprasternal notch), and therefore lies within the neck. The thoracic esophagus extends from approximately the level of T3 (beginning at about 20 cm) to T10 or T11.1,2 The upper thoracic esophagus is bordered superiorly by the thoracic inlet and inferiorly by the lower border of the azygos vein, extending from approximately 20 to 25 cm. Radiographically, tumors in this location would be located between the sternal notch and azygos vein. The middle thoracic esophagus extends from the lower border of the azygos vein to the inferior pulmonary veins, extending from approximately 25 to 30 cm. The lower thoracic esophagus extends from the inferior pulmonary veins and to the stomach and is inclusive of the gastroesophageal junction, typically extending from approximately 30 to 40 cm. Endoscopically, the gastroesophageal (GE) junction is often defined as the point where the first gastric fold is encountered, although this may be a “theoretical” landmark. The location of the GE junction can be accurately defined histologically as the squamocolumnar junction. In the most recent AJCC staging system, cancers with an epicenter in the lower thoracic esophagus, gastroesophageal junction, or within the proximal 5 cm of the stomach (i.e., cardia) and extending up to the GE junction or esophagus are staged as an adenocarcinoma of the esophagus. If the epicenter is >5 cm distal to the gastroesophageal junction or within 5 cm of the gastroesophageal junction but does not extend to the junction/esophagus, tumors are classified as stomach cancers. Useful landmarks in reference to endoscopy include the carina (~25 cm from the incisors) and gastroesophageal junction (~40 cm from the incisors).
Note the lengths of various segments of the esophagus as measured from the upper central incisors.
Siewert et al.3,4 characterized cancer involving the gastroesophageal junction according to the location of the tumor (Fig. 53.3). If the tumor center is located from >1 cm up to 5 cm above the gastroesophageal junction (Z-line), the tumor is classified as a type I adenocarcinoma of the distal esophagus. If the tumor center is located within 1 cm cephalad to 2 cm caudad to the gastroesophageal junction, it is classified as type II. If the tumor center is located >2 cm below the gastroesophageal junction, the tumor is classified as type III. However, locally advanced/bulky tumors can make it difficult to accurately distinguish where tumors originated in relationship to the GE junction.
Lymphatic Drainage
The esophagus has an extensive, longitudinal interconnecting system of lymphatics. The esophageal lymphatic network is primarily located within the submucosa; however, channels are also present within the lamina propria, facilitating spread of even superficial cancers of the esophagus involving the mucosa. In addition to these longitudinal lymphatics, intramural lymphatics may traverse the muscularis propria, facilitating tumor spread to regional lymphatic channels and paraesophageal nodes. Supporting this, autopsy series have demonstrated a relatively high incidence of directly draining channels extending from the submucosa lymphatics into the thoracic duct (Fig. 53.1), facilitating systemic spread. Lymph can travel the entire length of the esophagus before draining into lymph nodes,2 and thus the entire esophagus is at potential risk for lymphatic involvement. Up to 8 cm or more of ‘normal’ tissue can exist between gross tumor and micrometastases “skip areas” secondary to this extensive lymphatic network.5 In addition, as many as 71% of frozen tissue sections scored as margin negative by conventional histopathology show involvement by lymphatic micrometastases with immunohistochemistry.6 Lymphatics of the esophagus drain into nodes that usually follow arteries, including the inferior thyroid artery, the bronchial and esophageal arteries, and the left gastric artery (celiac axis).7
Epidemiology and Risk Factors
Esophageal carcinoma accounts for approximately 6% of all gastrointestinal malignancies. In 2012, there will be an estimated 17,460 new patients diagnosed with esophageal cancer in the United States and 15,070 deaths. Most cases occur in males, at a rate of 4:1 relative to females.8,9
The incidence of esophageal carcinoma varies according to geography. The highest incidence occurs in Linxian, China, Russia, and the Caspian region of Iran. The incidence there is 100/100,000 persons. In addition, there are many differences within regions within those countries. In areas such as northern France, Kazakhstan, and South Africa incidence can be as high as 50 to 99/100,000. Although the reasons for the geographic discrepancy are unknown, some reports have linked the arid climate and alkaline soil with these high-risk areas, as well as the ingestion of nitrosamines, and inversely to the consumption of riboflavin, nicotinic acid, magnesium, and zinc.10,11 In the United States, the incidence rate among males is <5/100,000. Over the last 20 years, there has been an increase in the incidence of adenocarcinoma at a rate of 5% to 10% per year. This is a more rapid increase than that for any other cancer.12 In 1987, adenocarcinoma was reported to represent 34% and 12% of esophageal cancers in White men and women versus 3% and 1% for African American men and women, respectively.12 As of 1998, esophageal adenocarcinoma accounted for almost 55% of all diagnosed cases in White men. African American men are more frequently diagnosed with squamous cell carcinoma.12–14
In North America and Western Europe, alcohol and tobacco use are the major risk factors for squamous cell carcinoma, accounting for 80% to 90% of cases.15 Reports have described the relative risk of esophageal cancer by the amount of alcohol and tobacco consumed, including a relative risk of 155:1 when consuming >30 g/day of tobacco along with 121 g/day of alcohol.16
Diets of scant amounts of fruits, vegetables, and animal products are associated with increases in squamous cell carcinoma.17 Patients with Plummer-Vinson (Paterson-Kelly) syndrome, a condition characterized by iron-deficiency anemia and low riboflavin levels, are at an increased risk for oral cavity, hypopharyngeal, and esophageal cancer. In addition, dietary intake of nitrosamines, nitrosamides, and N-nitroso compounds has been implicated in esophageal carcinoma. Examples of nitrate-rich foods include pickled vegetables, alcoholic beverages, cured meats, and fish.18,19
Other risk factors associated with esophageal carcinoma include achalasia and tylosis. Achalasia of long duration (25 years) is associated with a 5% incidence of squamous cell carcinoma.20,21 Patients with tylosis (hyperkeratosis of the palms and soles and papilloma of the esophagus) have a reported 38% risk in developing esophageal cancer at a mean age of 45 years.22 In addition, carcinoma of the esophagus occurs in 2% to 4% of patients with head and neck cancer.
Risk factors leading to the development of adenocarcinoma of the esophagus are being increasingly understood. Most esophageal adenocarcinomas tend to arise from the metaplastic columnar-lined epithelium known as Barrett's esophagus.23 Severe and long-standing gastroesophageal reflux disease has clearly been shown to be a significant risk factor for Barrett's esophagus, which may lead to adenocarcinoma. It has been estimated that patients with long-standing severe reflux have a 44-fold risk of developing adenocarcinoma.24Tobacco use is a more moderate risk factor for adenocarcinoma development. Smokers appear to have a twofold to threefold greater risk for developing esophageal adenocarcinoma than nonsmokers.25,26 The relative risk of esophageal adenocarcinoma persists to three decades following smoking cessation, in contrast to a significant decline in similar patients with squamous cell carcinoma.27 Obesity has also been linked to a threefold to fourfold risk of adenocarcinoma, possibly due to an increased risk of reflux.28 It has been estimated that a middle-aged patient with Barrett's esophagus has a 10% to 15% risk of developing esophageal adenocarcinoma during his or her lifetime.29
Although many risk factors are associated with esophageal carcinoma, few studies have demonstrated a causal relationship leading to pathogenesis. Motesano et al.30 reported possible genetic abnormalities involved in the genesis of esophageal cancer. In addition, possible differences in mechanisms of pathogenesis for squamous cell carcinoma and adenocarcinoma were described. Genetic abnormalities in squamous cell carcinoma include p53 mutations and multiple allelic losses at 3p and 9q, with amplification of cyclin D1 and epidermal growth factor receptor (EGFR). These mutations lead to cell hyperplasia, low- and high-grade dysplasia, and, ultimately, squamous cell carcinoma. In contrast, genetic abnormalities in adenocarcinoma include overexpression of p53, multiple allelic losses at 17p, 5q, and 13q, and amplification and overexpression of EGFR and human epidermal growth factor receptor 2 (HER-2). These abnormalities may be involved in the stepwise development of Barrett's esophagus, dysplasia, and, ultimately, adenocarcinoma. These differences suggest that squamous cell carcinoma and adenocarcinoma have different series of genetic mutations as etiologies, but these abnormalities occur in 23% to 94% of tumors studied.
Natural History and Patterns of Spread
Squamous cell carcinoma is characterized by extensive local growth and proclivity to lymph node metastases. Because the esophagus has no covering serosa, direct invasion of contiguous structures may occur early. Lesions in the upper esophagus can impinge on or invade the recurrent laryngeal nerves, carotid arteries, and trachea. If extraesophageal extension occurs in the mediastinum, tracheoesophageal or bronchoesophageal fistula may occur. Tumors in the lower one-third of the esophagus can invade the aorta or pericardium, resulting in mediastinitis, massive hemorrhage, or empyema.
A review correlating the incidence of lymph node metastases with depth of penetration revealed that 18% of patients with spread to the submucosa had lymph node involvement.31 For T1 lesions, the reported incidence of nodal spread is 14% to 21%; for T2 lesions, this rises to 38% to 60%.32,33 The location of involved lymph nodes is influenced by the origin of the primary tumor. At autopsy, lymph node metastases are found in approximately 70% of patients.34,35–36 In patients with cervical lesions, lymph node metastases to the abdominal lymph nodes are rare. Distant metastasis can occur at almost any site (Table 53.1).37
A review of 1,077 patients with squamous cell carcinoma of the thoracic esophagus undergoing esophagectomy further characterized patterns of nodal spread. Primary disease was located in the upper (5%), middle (63%), and lower (32%) thoracic esophagus. In total, 47% of patients had lymph node metastases. On multivariate analysis, T stage, tumoral length, and degree of differentiation significantly correlated with incidence of lymph node metastases. In approximately 6% of cases, skip metastasis (distant lymph node metastases without regional lymph node metastasis) occurred, usually in patients with poorly differentiated, large and deeply invasive tumors. Of involved nodes, 37% were macroscopically involved versus 63% microscopically involved, indicating that most lymph node metastases would be below the resolution of detection using contemporary imaging tools. Lymph node involvement was grouped into five categories; cervical, thoracic upper mediastinum, thoracic middle mediastinum, thoracic lower mediastinum, and abdominal lymph nodes. Figure 53.4 shows the incidence of nodal metastases based on primary tumor location.38
For lower esophageal and gastroesophageal junctional adenocarcinomas, approximately 70% of patients will have nodal metastases at presentation. This is influenced by tumoral depth of penetration, with nearly all T3 and T4 lesions exhibiting metastases in surgical series. Pathologic resection data demonstrated rates of lymphatic involvement for lower esophageal and GE junctional tumors of 45%, 85%, and 100% for T2, T3, and T4 tumors, respectively (Fig. 53.5).33 In patients with lower esophageal cancer, involvement of both mediastinal and abdominal lymph nodes is common (Fig. 53.6).33 The primary direction for lymphatic flow for the lower esophagus is toward the abdomen. According to the classification by Siewert, nodal metastases are often seen in the mediastinum and abdomen for type I tumors, whereas type III tumors metastasize almost exclusively inferiorly, toward the celiac axis. Type II tumors are intermediate, preferentially spreading inferiorly and less frequently into the mediastinum. The primary value in the Siewert classification is to the guidance of appropriate type surgery (i.e., type I tumors are generally treated with esophagectomy and mediastinal lymph node resection, with types II and III approached through the abdomen), although it may be useful in radiation field design as well.3 Generally speaking, the incidence of abdominal nodal involvement increases as one proceeds distally in the esophagus to the gastroesophageal junction. For patients with tumors arising from the gastroesophageal junction, mediastinal involvement is less common. Nodal metastases above the level of the carina are rare in lower esophageal and junctional tumors.39 In addition, histologic analyses of lower esophagus and gastroesophageal junction adenocarcinoma specimens suggest that many patients without nodal involvement on conventional histopathology actually have involvement when assessed by immunohistochemistry.40
Extensive nodal mapping has been performed by Japanese investigators, who have devised the Japanese Gastric Cancer Association Classification (Fig. 53.7).41 Using this system of nodal classification, investigators from Erlangen evaluated 326 patients with esophagogastric junction carcinoma undergoing primary resection. Tumors were stratified as AEG type I (distal esophagus), II (gastric cardia), and III (subcardia). Note there was significant overlap in the majority of tumors for all stages, with an overall incidence of lymph node metastasis of 71%. In T1 patients, only 17% exhibited lymph node metastasis, whereas 78%, 86%, and 90% of T2, T3, and T4, respectively, had involved nodes. Figure 53.8 shows varying patterns of nodal spread based on T stage as well as AEG location. Additional generalizations from this study include the following: (a) lymph vascular invasion was highly predictive of nodal spread and (b) proximal extension of type II and III tumors into the distal esophagus (particularly beyond the Z-line) predicted an increasing incidence of paraesophageal lymph node involvement.42
A: Frequency of nodal involvement for T2 tumors. B: Frequency of nodal involvement for T3-4 tumors. C: Frequency of involvement for AEG type I tumors. D: Frequency of nodal involvement for AEG type II/III tumors.
Local Failure
Aisner et al.43 and LePrise et al.44 reviewed the patterns of failure in esophageal cancer after radical irradiation, radical surgery, or a combination of both (Table 53.2). These data suggest that high rates of local recurrence occur when either radiation therapy or surgery alone is used. In a series at the University of Pennsylvania and Fox Chase Cancer Center of patients with adenocarcinoma of the esophagus and gastroesophageal junction treated with surgery alone, the local-regional recurrence rate was 77%.45 In contemporary randomized trials, local failure rates with surgery alone range from 32% to 45%.46–49 Similarly, data from recent randomized trials of esophageal cancer using “definitive” chemoradiation also indicates that local failure is a major cause of failure, with approximately 50% of patients failing locally (Table 53.3). In many trials, patterns of failure are reported as first site of recurrence. This fact, along with infrequent posttherapy imaging and inability to detect subclinical recurrences, likely leads to underestimates of local recurrence rates. These data clearly emphasize the need for improvements in local treatment modalities.
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