The incidence of esophageal cancer in the United States is approximately 13,000 cases per year. Adenocarcinoma of the esophagus (EAC) is the fastest growing solid malignancy, and it is now more frequent than esophageal squamous cell carcinoma (ESCC) in the United States. Although resection offers the best chance for cure, most patients who present with symptoms already have systemic disease and are incurable. The most important prognostic factor for esophageal cancer remains the stage of disease at the time of diagnosis. Currently, the best strategy for improving survival is early diagnosis followed by resection. Neoadjuvant chemoradiation is being used increasingly in the treatment of locally advanced disease. However, despite improvements in operative technique and postoperative care, the overall 5-year survival remains less than 15 percent, highlighting the need for novel diagnostic and treatment modalities.

Pathophysiology

Esophageal Squamous Cell Carcinoma

Nutritional deficiencies, including low levels of vitamins A, C, and riboflavin as well as minerals such as selenium, molybdenum, and zinc contribute to the pathogenesis of ESCC. High levels of nitrates and nitrites, found in pickled and preserved foods, are converted to N-nitrosamines and have been associated with ESCC. Several studies have linked alcohol and tobacco use with the development of esophageal cancer, and one study found ethanol to be associated with nearly 80 percent of esophageal cancers.¹ Other predisposing conditions include long-standing achalasia, caustic injury, tylosis, and Plummer–Vinson syndrome.

Esophageal Adenocarcinoma

Barrett metaplasia, and specifically intestinal-type columnar mucosa, is the precursor lesion to EAC. Microscopically, columnar epithelium is seen with mucosal glands that contain intestinal goblet cells (Fig. 16-1A). On endoscopy, Barrett mucosa appears as red, velvety areas between smooth, pale esophageal squamous mucosa (Fig. 16-2A). After the squamous epithelium is injured chronically by reflux, there is a metaplastic change to a columnar epithelium. With further injury and multiple genetic changes, progression occurs in a metaplasia–dysplasia–adenocarcinoma sequence.

In patients with Barrett metaplasia, the risk of EAC is increased 30 to 125 times that of the age-matched population. Barrett esophagus results from chronic inflammation due to gastroesophageal reflux. At endoscopy, Barrett mucosa is found in 12 to 18 percent of patients with reflux.² Although the esophageal mucosa is relatively resistant to acid, mixed reflux with bile acids, pepsin, and gastric acid appears to be more harmful, and up to 67 percent of patients with Barrett metaplasia have bile-stained duodenogastric reflux.

EAC is believed to have a 4- to 5-year preclinical phase, suggesting that surveillance may be effective. Cancers detected during surveillance tend to be less advanced, and the American College of Gastroenterology has suggested that patients with chronic reflux undergo upper endoscopy. Abnormal mucosa is biopsied to diagnose Barrett metaplasia and to detect the presence of dysplasia (Fig. 16-1B). Surveillance intervals are increased to every 3 years after two consecutive biopsies are negative for dysplasia.

Other risk factors for EAC include ectopic gastric mucosa, obesity, smoking, diets high in saturated fat and red meat, and medications that reduce lower esophageal sphincter pressure. Concerns have also been raised that the treatment of Helicobacter pylori, specifically the acid-suppressing effects of the Cag A+ strain, may actually increase the incidence of EAC.

Although the majority of ESCCs are located in the middle third of the esophagus, EACs (approximately 79 percent) arise in the distal esophagus. High-grade dysplasia (HGD) remains the best predictor of progression to adenocarcinoma. An extensive lymphatic network and the long interval during which esophageal tumors remain asymptomatic contribute to the high incidence of nodal disease with 30 to 58 percent of patients having lymph node metastases when the submucosa is involved.³ The extent of invasion and the presence or absence of lymph node metastases are important in determining patient prognosis. The most common sites of distant metastases include the liver, lungs, bone, brain, and adrenal glands (Table 16-1).

Clinical Features

Epidemiology

In the United States, the annual incidence of ESCC is 2.6 per 100,000. The incidence is four to five times higher in African Americans than in Caucasians. Regions with a high incidence are generally located in poorer areas of the world including parts of China, Central Asia, and Latin America. The overall 5-year survival rate is approximately 15 percent.

The incidence of EAC has increased progressively from the 1970s, and esophageal adenocarcinoma is the most rapidly increasing solid malignancy in the United States. Adenocarcinoma has surpassed ESCC as the most common cancer of the esophagus in America, and esophageal carcinoma is the seventh leading cause of cancer-related deaths. The median age at diagnosis is 68. Men are affected six to eight times more frequently than are women, and Caucasians are affected three to four times as often as African Americans. The incidence is higher in developed countries.

Clinical Presentation

Dysphagia is the most common initial symptom but generally only occurs when the tumor involves more than 50 percent of the circumference of the esophagus. Odynophagia is the next most common symptom and may be caused by an ulcerated lesion. Constant pain in the midback or midchest suggests mediastinal invasion. Hoarseness may develop with proximal tumors and indicates involvement of the recurrent laryngeal nerve. Regurgitation may occur as the growing tumor narrows the esophageal lumen, and weight loss is frequently present at presentation. Although patients often have a history of reflux symptoms, clinical features do not distinguish patients with or without Barrett, which is frequently asymptomatic. The evaluation of a suspected esophageal adenocarcinoma is outlined in Figure 16-3.

Diagnostic Modalities

Endoscopy

The management and prognosis of esophageal carcinoma depend on accurate clinical staging. Endoscopic evaluation is essential in all patients suspected of having esophageal carcinoma (Fig. 16-2B). The location of the lesion, degree of obstruction, and the length of the lesion should be determined in all patients. Any abnormal lesions should be biopsied. Other findings to be noted include the presence of Barrett mucosa or a hiatal hernia, and the fundus should be closely examined on retroflexion for any tumor involvement. Although advanced carcinoma is easily identified, early mucosal changes may be difficult to recognize. Chromoendoscopy with indigo carmine or acetic acid and narrow band imaging can highlight mucosal details and the microvasculature by using blue and green light with shorter wavelengths resulting in better penetration of superficial tissues. Lugol’s solution can be used to identify dysplastic squamous lesions. Normal epithelium, which contains glycogen, is stained by the iodine. New techniques are being developed to improve visualization including confocal endomicroscopy and fluorescent-labeled peptides designed to bind to dysplastic or cancerous lesions.⁴ Mapping biopsies with four-quadrant biopsies obtained every 1 to 2 cm can also help to delineate abnormal lesions.

Bronchoscopy is important to evaluate possible tracheal invasion by tumors in the upper or middle thirds of the esophagus (Fig. 16-2C). Patients with infracarinal bulky tumors or subcarinal lymphadenopathy on computed tomography (CT) should also undergo bronchoscopy. Findings may range from bulging of the bronchial wall and subtle mucosal changes to frank tumor invasion or the presence of a tracheoesophageal fistula. The carina may appear widened due to subcarinal lymphadenopathy. Bronchial biopsies are obtained to confirm that airway invasion is present.

Radiographic Studies

Contrast Studies.

The barium swallow is an essential diagnostic study in the evaluation of dysphagia and allows visualization of the esophageal mucosa, distensibility, and motility (Fig. 16-3). Involvement of the fundus can also be seen on the esophagram. Subtle mucosal irregularities, ulcerations, or small polypoid lesions are best seen on a double-contrast esophagram.

Computed Tomography.

Staging CT scans of the chest and upper abdomen are useful in the initial evaluation of esophageal carcinoma as well as assessing the response to neoadjuvant therapy. CT is used to determine the local extent of the tumor, the relationship to adjacent structures, lymphadenopathy, and the presence of distant metastases. CT cannot distinguish the layers of the esophageal wall and is not as useful in determining the T stage. However, loss of fat planes can be useful in determining invasion of adjacent structures. The sensitivity for detecting lymphadenopathy (>1 cm) is 30 to 60 percent in the mediastinum and 50 to 75 percent in the abdomen, whereas CT has a 70 to 80 percent sensitivity for identifying metastatic disease greater than 2 cm.⁵

Endoscopic Ultrasound.

Endoscopic ultrasound (EUS) provides the most accurate assessment of the depth of tumor invasion, or T stage, and is able to identify five distinct layers in the esophageal wall (Fig. 16-4). EUS is most useful in the staging of early carcinoma. EUS is also more sensitive in detecting regional lymphadenopathy and can evaluate the extent of periesophageal invasion. Curvilinear arrays assist in the performance of fine-needle aspiration (FNA), which is up to 98 percent sensitive and 100 percent specific. EUS has also been evaluated for assessing the response to neoadjuvant therapy but may be prone to overstaging.

Positron Emission Tomography.

Positron emission tomography (PET) improves staging by identifying distant disease not seen on CT alone. PET has a higher sensitivity than CT in detecting nodal and distant metastases, although PET cannot distinguish the primary tumor from peritumoral lymph nodes. Sensitivity ranges from 78 to 95 percent, and specificity from 95 to 100 percent. The role of PET in restaging after neoadjuvant treatment needs to be further evaluated. Although studies suggest that decreased activity seen on PET corresponds with response to chemoradiation, PET is not sensitive enough to identify complete responders.

Thoracoscopy and Laparoscopy

Thoracoscopic and laparoscopic staging offer direct visualization and the ability to obtain biopsies to determine nodal status, the extent of local invasion, and the presence of metastatic disease and can be useful in specific circumstances. Laparoscopy should be considered in patients with suspected intraperitoneal metastases to assess for tumor implants whereas thoracoscopy is useful to evaluate for small pulmonary nodules or mediastinal lymph nodes not accessible by endobronchial ultrasound (EBUS) or CT-guided biopsy. Laparoscopic ultrasound is also being investigated as a staging modality and may provide improved accuracy in T and N staging. Laparoscopic ultrasound may be more accurate in staging celiac nodes than EUS, providing closer access for the ultrasound probe as well as direct inspection.

Staging

Accurate staging is essential for treatment selection, and the stage at diagnosis is the most important prognostic factor. The evaluation of patients with suspected esophageal cancer should include appropriate diagnostic studies as described above as well as biopsies of any suspected metastatic lesions (Fig. 16-5). Although patients with stage I tumors have a 65 percent 5-year survival, those with biopsy-proven distant metastatic disease have a mean survival of only 6 months and are considered unresectable. Both esophageal squamous cell and adenocarcinoma are staged according to the American Joint Committee for Cancer TNM system. Significant changes in the 7th edition take into account the histology, grade, and number of regional lymph nodes involved.

Medical Therapy

Radiation Therapy

Results of a large review published by Earlam and Cunha-Melo with more than 8000 inoperable patients due to prohibitive surgical risk or unresectable esophageal carcinoma showed 1-, 2-, and 5-year survival rates of 18, 8, and 6 percent after definitive radiotherapy.⁶ Postoperative radiotherapy has been shown to decrease local recurrence but has not improved survival rates. Several trials of neoadjuvant radiotherapy have also failed to show increased resection rates or improved survival compared with surgery alone.

Chemotherapy

Law et al. showed that neoadjuvant chemotherapy resulted in significant downstaging of disease in nearly 50 percent of patients, but a pathologic complete response was seen in less than 10 percent.⁷ A marginal survival benefit was noted in this subgroup of patients. Kelsen et al. reported a large multicenter study of neoadjuvant chemotherapy versus surgery alone, which included 440 patients. At 2-year follow-up, no significant survival benefit was seen.⁸

Chemoradiotherapy

The Radiation Therapy Oncology Group (RTOG) randomized trial reported by Al-Sarraf et al. provided convincing evidence of the superiority of chemoradiation over radiation alone.⁹ The 2- and 5-year survival rates were 36 and 27 percent in the chemoradiation group compared with 10 and 0 percent in the group treated with radiation alone. There was also a reduction in both local recurrence and distant disease. However, the toxicity of the treatments was significant. Many surgeons advocate neoadjuvant therapy for patients with esophageal carcinoma, except in patients with early disease, due to the poor survival rates following resection alone. Neoadjuvant chemoradiotherapy is routine at the University of Michigan in patients with tumors staged as T2 or greater or patients with positive nodal disease (Fig. 16-5). Neoadjuvant therapy is limited to patients younger than 75 years due to the significant toxicity and the decrease in patients able to complete trimodality therapy with increasing age.

The combination of chemoradiation with surgery has resulted in significant downstaging of disease, but a survival advantage has not been consistently demonstrated in randomized trials. Most regimens are cisplatin-based and commonly combined with 5-fluorouracil. Chemoradiation is followed by resection 5 to 6 weeks after completion of therapy. Walsh et al. reported a randomized trial of 113 patients receiving neoadjuvant therapy or surgery alone and showed significantly improved survival after neoadjuvant treatment of 17 months versus 12 months.¹⁰ However, the survival in the surgery arm was lower than most published series. Urba et al. performed a randomized trial of 100 patients who underwent either transhiatal esophagectomy following neoadjuvant chemoradiation therapy or surgery alone.¹¹ Seventy-five percent of patients had adenocarcinoma. Twenty-eight percent had a complete pathologic response. Survival at 3 years was 30 percent after neoadjuvant therapy versus 16 percent after surgery alone although this was not statistically significant. A meta-analysis of randomized trials comparing trimodality therapy with surgery alone showed a slight increase in overall survival with a complete pathologic response associated with the best survival.¹² Gebski et al. performed a meta-analysis including 1200 patients undergoing neoadjuvant chemoradiation and found a hazard ratio (HR) of 0.81 (95 percent CI 0.70–0.93; p = 0.002).¹³