Esophageal cancer is the eighth most frequent cancer worldwide. It is the sixth most common cause of cancer death, accounting for 5.4% of all cancer deaths.¹ Although the annual incidence of esophageal cancer in the United States is 4.5 per 100,000, some of the highest incidences are found in Asia, with roughly 100 per 100,000 individuals affected in the Linxian Province of central China.^2,3 Esophageal cancer remains one of the most lethal of all malignancies, with incidence and mortality rates roughly equal. Once a diagnosis is established, the prognosis is dismal, with a 5-year survival rate of 17%.⁴ The results of single-modality treatment have been poor, with the exception of surgery for early esophageal cancer. More recently, neoadjuvant chemotherapy, radiotherapy, and combined chemoradiation therapy have been added as treatment modalities to enhance local control, increase resectability rates, and improve disease-free survival.⁵ The initial results of these multimodality treatments have been encouraging. Since management of esophageal cancer and survival of patients is stage dependent, accuracy of clinical staging is vital. An array of technologies such as CT, MRI, and PET of the esophagus, as well as endoscopic ultrasound (EUS) and minimally invasive thoracoscopic/laparoscopic staging (Ts/Ls), offer more reliable preoperative diagnosis and staging of patients with esophageal cancer. This may result in allocation of patients to stage-specific regimens with resulting improved cure rates.

The boundaries of the esophagus are the inferior cricopharyngeal constrictor proximally and the esophagogastric junction distally. The esophagus is composed of four layers: mucosa, submucosa or lamina propria, muscularis propria, and adventitia (Fig. 10-1). The esophagus has no serosa, providing a teleologic explanation for the ease of spread of esophageal cancer. Familiarity with the histology of the esophageal wall is critical to understanding the staging system of esophageal cancer (see also Chapters 11 and 12).

Anatomically, the normal adult esophagus is approximately 35 cm in length and 2.5 cm in diameter, although it is not uniform throughout its course. The course of the esophagus begins in the midline in the upper neck at the level of the sixth cervical vertebra, which corresponds roughly to the level of the cricoid cartilage, and then deviates to the left in the lower neck and upper thorax. At the level of the tracheal bifurcation (24 cm from the incisors by endoscopic measurement), the esophagus again returns to the midline only to deviate to the left once again in the lower thorax, where it enters the abdomen through the diaphragmatic hiatus (40 cm from the incisors). Clinically, the esophagus is divided into three segments, the cervical, middle, and distal segments. The cervical segment ranges from the cricoid cartilage to the thoracic inlet (10–18 cm from the incisors). The middle esophageal segment ranges from the thoracic inlet to the midpoint between the tracheal bifurcation and the esophagogastric junction (19–34 cm). The distal esophageal segment extends from the midpoint between the tracheal bifurcation and the esophagogastric junction (35–44 cm). Three distinct narrowings are present in the esophagus. The first narrowing is formed by the cricopharyngeus muscle and is the narrowest segment of the gastrointestinal tract, located 12 to 15 cm from the incisors in the adult. The second narrowing is caused by the tracheal bifurcation and aortic arch at approximately 24 to 26 cm from the incisors. The last narrowing is located at the lower esophageal sphincter, approximately 40 to 44 cm from the incisors.⁶

The arterial blood supply of the esophagus is segmental (Fig. 10-2). The upper esophagus is supplied by branches from the inferior thyroid and subclavian arteries. The midesophagus receives blood from the bronchial arteries and direct branches from the thoracic aorta. The lower esophagus is supplied by branches of the inferior phrenic and gastric vessels. Venous drainage of the esophagus is segmental as well. The upper esophagus drains via the inferior thyroid veins. The midesophagus drains into the bronchial and azygos or hemiazygos veins. The lower esophagus drains into the coronary vein. As with the arterial network, the rich plexus of veins in the submucosa makes venous congestion unlikely.

Lymphatic drainage of the esophagus consists of two longitudinal interconnecting networks, the lymph channels and the lymph nodes. The intraesophageal or mucosal network of lymph channels is connected to the submucosa through transverse interconnections (Fig. 10-3). These collecting lymph channels merge, forming larger channels that feed into the extraesophageal lymph nodes (Fig. 10-4). It is estimated that the longitudinal flow is significant, which also may explain the frequency of spread of tumor along lymphatics. Flow proceeds in either direction freely and can be influenced by intrathoracic pressure differences and/or obstruction of lymphatic channels. The typical drainage pattern, however, is as follows: Cervical lymphatics drain into the internal jugular and supraclavicular nodes, the midesophagus drains into the paraesophageal and periesophageal nodes in the mediastinum, and the inferior esophagus drains below the diaphragm to the region of the cardia, left gastric vessels, lesser curve of the stomach, and celiac axis.^7,8

Esophageal cancer is a disease primarily of men (male:female ratio, 3:1) that occurs in the sixth and seventh decades of life with a median age of 67 years. In the United States, the incidence is 4.5 per 100,000 population, whereas in China it may be as high as 140 per 100,000 population. In addition, Russia, Japan, Scotland, and the Scandinavian countries have a higher incidence than the United States or Western Europe. In the United States, the incidence of adenocarcinoma of the esophagus is increasing dramatically across all socioeconomic boundaries. The incidence of adenocarcinoma in White men is roughly three times that in Black men, whereas the incidence of squamous cell carcinoma of the esophagus is six times higher in Blacks. Esophageal cancer rates have been declining in African Americans, a consequence of a decreasing incidence of squamous cell carcinoma. Incidence of esophageal adenocarcinoma has been increasing by an alarming rate of just under 2% per year.⁹ The reason for this is largely unknown, although the worsening obesity epidemic may be partially responsible.¹⁰ Several environmental factors have been implicated in the etiology of this disease, but none has been proved scientifically. Tobacco has been shown to increase the risk of esophageal cancer approximately 10-fold, whereas alcohol abuse increases the risk from 20- to 50-fold. Furthermore, the combination of tobacco and alcohol use may increase the risk 100-fold. Adenocarcinoma has a stronger association with tobacco use, whereas squamous cell carcinoma is more closely linked to alcohol use. In addition, diets high in nitrosamines and foods contaminated with molds (Fusarium) and fungus (Geotrichum candidum) also have been implicated, as well as diets in which hot liquids are consumed. Nutritional deficiencies also have been implicated. Diets low in beta carotene, vitamins B and C, magnesium, and zinc all have been implicated. Environmental exposure to asbestos, perchloroethylene, and radiation also has been shown to contribute to increased incidence.¹¹

Several premalignant conditions have been shown to predispose to esophageal carcinoma. Achalasia causes esophageal irritation and is associated with a 5% to 10% incidence in squamous cell carcinoma over 15 to 25 years. This tumor tends to occur in younger individuals and carries a poor prognosis. Gastroesophageal reflux disease causing distal esophageal metaplasia (Barrett esophagus) appears to be related to the increased incidence of adenocarcinoma in White males. Patients with Barrett esophagus have an 11-fold risk of developing esophageal adenocarcinoma, with an annualized risk of 0.12%.¹² It is noteworthy that these patients also have a high incidence of hiatal hernia and duodenal ulcer disease. Finally, obesity now has been shown to increase the incidence of adenocarcinoma dramatically.¹⁰

The majority of esophageal carcinomas are either squamous cell carcinomas or adenocarcinomas. Squamous cell carcinoma most commonly arises in the midportion of the esophagus, whereas adenocarcinoma usually arises in the lower third, close to the esophagogastric junction. Although squamous cell carcinoma remains the dominant histology worldwide, the incidence of adenocarcinoma is rising dramatically in the West. There is a geographic heterogeneity in the distribution of these two histologic entities. In the United States, squamous cell carcinoma accounted for roughly 90% of esophageal cancers in the 1960s. However, recent data from the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) database indicate that the incidence of adenocarcinoma actually has surpassed that of squamous cell carcinoma. Based on correlative data, this is unlikely to be the result of the reclassification of squamous cell carcinoma or adjacent gastric adenocarcinoma or as an overdiagnosis of adenocarcinoma. The importance of tumor histology and tumor grade is apparent with the advent of the new AJCC staging system (see Chapters 11 and 12).

Esophageal cancer often presents in an insidious and nonspecific manner, with indigestion, retrosternal discomfort, and transient dysphagia comprising the leading complaints. Often patients may present late because they have been able to compensate subconsciously for symptoms of dysphagia by eating softer foods or chewing their food more thoroughly. Dysphagia is the most commonly presenting symptom of esophageal carcinoma. It can progress to odynophagia and eventually to complete obstruction. Pain may be transient, associated with swallowing, or constant. It may be retrosternal or epigastric in location. Weight loss may be due to dietary changes, starvation, or tumor anorexia. Patients may experience regurgitation of undigested food, that is, food that has not been tainted with acidic gastric secretions. Patients also may develop respiratory sequelae primarily from aspiration but also from other causes such as direct invasion of tumor into the tracheobronchial tree or even a tracheoesophageal fistula, usually involving the left mainstem bronchus. Symptoms may include cough, dyspnea, and pleuritic pain. Hoarseness can result from direct involvement of the recurrent laryngeal nerve, a poor prognostic sign. Also, in advanced cases of near-complete or complete esophageal obstruction, patients may become severely dehydrated, even hypokalemic, because of their inability to swallow potassium-rich saliva.

The most commonly used diagnostic and staging modalities are the barium swallow study, chest radiography, esophagoscopy, bronchoscopy, CT, MRI, and EUS with fine-needle aspiration (FNA). Additional adjuncts include thoracoscopic and laparoscopic staging, and PET scan. Usually, the first diagnostic method is a barium swallow, followed by endoscopy with biopsy. After a histologic diagnosis of carcinoma is confirmed, a CT scan of the thorax and abdomen should be obtained for the purpose of staging, paying particular attention to tumor extension, lymphadenopathy, and distant metastases. In some countries, abdominal ultrasound is often performed instead of CT to diagnose liver or celiac lymphatic metastasis.

Chest radiography has a minimal role in the modern diagnosis and staging of esophageal cancer, although it can reveal an abnormal finding in almost half of the patients with esophageal cancer. However, in some countries it is still used routinely to identify hilar or mediastinal adenopathy, evidence of pulmonary metastases, secondary pulmonary infiltrates caused by aspiration, elevation of the bronchus by midesophageal tumors and pleural effusion.¹³ Bronchoscopy is often necessary to determine involvement of the tracheobronchial tree for patients with middle- and upper-third disease.^14,15 Gallium scanning can be useful for the detection of bony metastases but generally has been replaced by PET scan in the United States. Endoscopy remains the method of choice for the confirmation of esophageal cancer.¹⁶ Its ability to detect early lesions can be improved with the use of staining techniques and, more recently, narrow-band imaging.¹⁷

Although the role of CT in evaluating esophageal cancer has been studied thoroughly, questions regarding its utility still remain. Although CT is highly effective in the assessment of mediastinal esophageal carcinomas, it is less helpful in the staging of cervical or gastroesophageal junction carcinomas. It plays a key role in assessing initial tumor bulk for radiation therapy planning and is also useful in monitoring tumor response to the cytoreductive therapy. CT is also helpful in depicting extraesophageal tumor spread to contiguous structures and distant metastases. CT evaluation is performed from the thoracic inlet through the liver to include the upper abdominal lymph node groups. Either thin barium or water-soluble oral contrast agents are administered routinely. Adequate distention of the esophagogastric junction is essential to exclude tumor involvement of this anatomic segment. Intravenous contrast material should be administered by the dynamic bolus technique to ensure optimal opacification of the heart, mediastinal vessels, and liver. Measurements of esophageal wall thickness greater than 5 mm are abnormal regardless of the degree of distention. Intraluminal air is seen in 60% of normal patients. CT staging of esophageal cancer includes assessment of (1) the extent of involvement of the esophageal wall by tumor, (2) tumor invasion of the periesophageal fat and adjacent structures, and (3) metastases to regional lymph nodes or distant organs.

The two key prognostic features of esophageal cancer are (1) the depth of tumor infiltration into or through the esophageal wall and (2) the presence or absence of visceral metastasis. Although the thickness of the esophageal wall often can be determined by CT, the individual layers of the esophageal wall cannot.¹⁸ T1 and T2 lesions generally show an esophageal mass thickness between 5 and 15 mm, and T3 lesions show a thickness greater than 15 mm. T4 lesions show invasion of contiguous structures on CT. Specific findings of tracheobronchial invasion include demonstration of a tracheobronchial fistula or extension of tumor into the airway lumen. If an esophageal tumor indents or displaces the adjacent airway, luminal invasion is likely. Thickening of the wall of the tracheobronchial tree also suggests invasion. Generally, direct visualization with bronchoscopy is necessary to rule out airway invasion (usually distal trachea or left mainstem bronchus) for upper- and middle-third tumors. Although CT is useful in determining the extent of local disease, it is not as accurate in the staging of lymph node involvement; it is limited in differentiating between small normal nodes and nodes invaded by tumor but small in size. It has been suggested that mediastinal nodes greater than 10 mm in diameter in the short axis should be classified as pathologic and that subdiaphragmatic nodes greater than 8 mm in diameter should be considered abnormal. The accuracy of CT in predicting lymph node involvement ranges from 83% to 87% for abdominal lymph nodes but only 51% to 70% for mediastinal nodes.

MRI offers an alternative to CT for the evaluation of esophageal cancer. Its application in esophageal carcinoma has received scant attention. Like CT, MRI is highly accurate for detecting distant metastases of esophageal cancer, especially to the liver, and for determining advanced local spread (T4). However, it is less reliable in defining early infiltration (T1–3). MRI appears to be as sensitive as CT in predicting mediastinal invasion. One advantage of MRI is the loss of signal in the vessels and the air-filled trachea and bronchi, which may provide a clear delineation between the tumor and the aorta and the tracheobronchial tree. Like CT, MRI is poor at detecting tumors restricted to mucosa or submucosa and also tends to understage the regional lymph nodes.¹⁹ MRI is not customarily used in the evaluation of esophageal cancer, as alternative modalities are often more reliable for determining local invasion and distant disease.

EUS has now become routine for the staging of esophageal cancer. EUS combines the technologies of flexible endoscopy and ultrasonic imaging. Tio et al.²⁰ found that the accuracy of EUS for T1a and T1b cancer was 85% versus 12% for CT. Luminal stenosis is a definite limiting factor for EUS, as it is occasionally not possible to traverse the tumor with the endoscope. Lymph nodes at a distance of more than 2 cm from the esophageal lumen cannot be imaged because of the very limited penetration depth of ultrasound. For patients with severe stenosis, a nonoptical, wire-guided echoendoscope can markedly reduce the occurrence of incomplete esophageal cancer staging and improve the detection of metastatic disease. EUS is also of help in the assessment of unresectability. The most important findings of unresectability are tumor invasion into the left atrium (with loss of smooth, flexible movement of the pericardium on real-time EUS), the wall of the descending aorta, the spinal body, the pulmonary vein or artery, or the tracheobronchial system. The latter should be confirmed with bronchoscopy with transbronchial FNA. EUS appears most helpful in predicting the superficial T1 tumors as well as the T3/4 tumors with greater depth of penetration. The positive predictive value of EUS for T2 tumors, however, is only 23%, with most tumors overstaged.²¹ Clinically, T1N0 and T2N0 tumors are found to have unanticipated nodal disease 24% and 39% of the time, respectively.²² Furthermore, for clinically T2 tumors, EUS understages nodal disease roughly two-thirds of the time.²³ It is possible to enhance specificity with ultrasound-guided needle biopsies through the EUS endoscope. The use of EUS-guided FNA was first reported in the diagnosis of esophageal cancer recurrence after distal esophageal resection in 1989.²⁴ One must use caution to avoid traversing the primary tumor with a needle resulting in a false-positive lymph node biopsy. At this time, EUS, especially when combined with FNA, is the most accurate imaging modality for locoregional staging of esophageal cancer.

Since multimodal neoadjuvant treatment for esophageal cancer has been used with increased frequency, tumor restaging remains fundamental in evaluating the response to therapy and in planning an operation. Many studies have evaluated the role of EUS in this setting. Although EUS is extremely accurate for staging untreated esophageal cancer, its accuracy in staging tumors after neoadjuvant chemoradiotherapy is relatively poor, with most errors caused by overstaging.²⁵ Although EUS is close to 90% accurate in predicting initial T stage, after neoadjuvant therapy, accuracy ranges from 27% to 82%. N stage is from 38% to 73% accurate after neoadjuvant therapy, whereas FNA can be expected to increase the accuracy further. Errors in posttherapy staging are likely due to the similar echogenic appearance of fibrosis and residual tumor. Residual nodal disease is an ominous finding. EUS, when combined with FNA, is very useful in detecting residual cancer within the lymph nodes. Others have found that ultrasound evidence of tumor regression is predictive of pathologic response to neoadjuvant therapy.

Recent evidence regarding the use of endoscopic mucosal resection (EMR) (see Chapter 173) particularly for early-stage tumors has emphasized the importance of this technology in determining the correct stage and differentiating T1a from T1b tumors when a superficial carcinoma is suspected.²⁶

As with many other malignancies, [¹⁸F]fluoro-2-deoxy-d-glucose (FDG)-PET is becoming a useful adjunct to conventional radiographic staging. PET improves staging and facilitates selection of patients for operation by detecting distant disease not identified by CT scanning alone. PET and CT are effective in showing the primary tumor and are equally sensitive in the demonstration of periesophageal nodes. The American College of Surgeons Oncology Group embarked on a prospective trial (Z0060) investigating the utility of PET scanning in the initial staging of esophageal cancer.²⁷ With 189 patients evaluated, roughly 5% of patients had a biopsy-confirmed distant metastasis detected with PET over CT alone. However, an additional 9.5% of patients had unconfirmed PET findings accepted by the treating surgeon as sufficient evidence to preclude resection. This particular study did not utilize PET/CT composite technology, which may have hampered the results. PET/CT is now accepted to have a routine role in esophageal cancer staging, with additional studies reporting the ability to detect distant metastatic disease in a significant number of patients.^28–30 Recent evidence suggests that PET scanning also may be used to measure the biologic activity of a tumor and thereby assess response to neoadjuvant therapy, stratifying survival after resection.³¹ Maximal standard uptake values (SUVmax) have been shown to be independent predictors of prognosis.³² The clinical relevance of this finding is most powerful in those patients with early-stage disease and high SUVmax who may be predicted to benefit from induction therapy.

Brain metastases are very rare in patients presenting with esophageal carcinoma. Autopsy studies reveal the prevalence of brain metastases in patients who died from esophageal cancer to be 0% to 1.8%. They tend to occur in patients with large tumors or aggressive nodal disease. Brain imaging is not generally performed during the evaluation of an esophageal cancer patient in the absence of neurologic symptoms.^33,34

The treatment of esophageal cancer is rigorously stage-driven. Patients with early-stage esophageal cancer may have a 5-year survival of over 75%, yet with more advanced disease, survival drops precipitously. The ability to recommend effective treatment algorithms and predict prognosis relies on the determination of a clinical stage for each patient with current technology.

The sixth edition of the AJCC staging system for esophageal cancer was introduced in 2002, and was not significantly different from an earlier version from 1987 because of lack of convincing survival data. Our cancer staging systems need to evolve as newer diagnostic modalities and treatments emerge, and as knowledge of the disease accumulates. As such, the staging system for esophageal carcinoma was recently revised with the introduction of the 7th edition of the AJCC staging manual (see Chapter 12) (Tables 10-1, 10-2A, and 10-2B).³⁵ Data used to generate the new staging system were assembled by a worldwide esophageal cancer collaboration, which included over 4600 patients.³⁶ Although the previous system was logical, straightforward, and simple, modifications were necessary as limitations became apparent (Table 10-3). The most important change pertains to the N descriptor. In the previous edition, the N descriptor was binary—N0 indicated no known nodal metastasis and N1 indicated any metastasis, regardless of tumor burden. The distinction was somewhat arbitrary an N1 node versus a distant M1a nodal metastasis which was not supported by recent data. The N descriptor in the new system now ranks lymph node burden with gradations from N0 through N3.