Clinical Presentation

Symptoms of esophageal cancer often start 3 to 4 months before diagnosis. Location of the primary tumor in the esophagus may influence presenting symptoms. Dysphagia is seen in >90% of patients regardless of location. Odynophagia is present in up to 50% of patients.⁵⁰ Weight loss is common, with 40% to 70% of patients reporting a loss of >5% of total body weight. This extent of weight loss has been associated with a worse prognosis. Less frequent symptoms may include vague chest pain, hoarseness, cough, and glossopharyngeal neuralgia.⁵¹

Advanced lesions can produce signs and symptoms from tumor invasion into local structures. Hematemesis, hemoptysis, melena, dyspnea, and persistent cough secondary to tracheoesophageal or bronchoesophageal fistula may occur. Compression or invasion of the left recurrent laryngeal nerve or the phrenic nerves can cause dysphonia or hemidiaphragm paralysis. Superior vena cava syndrome and Horner's syndrome can also occur for very advanced lesions. Pleural effusion and exsanguination resulting from aortic communication may also be seen.⁵⁰ Abdominal and back pain may occur with celiac axis nodal involvement with lower esophageal tumors.

Diagnostic Workup

After a thorough history and physical examination, all patients with suspected esophageal cancer should have a workup similar to that outlined in Table 53.4. Attention should be paid to cervical and supraclavicular lymph nodes. Basic blood counts and a metabolic panel with liver function tests should be obtained.

TABLE 53.4. Diagnostic Workup for Esophageal Cancer

Although the esophagogram may be used to define lesion extent, endoscopy is the best tool to diagnose and define the extent of the lesion. During flexible endoscopy, biopsies and brushings should be taken of the primary site and suspicious areas harboring satellites or submucosal spread. In addition, accurate endoscopic measurement and characterization of tumor and gastroesophageal junction in relation to the incisors facilitates radiation treatment planning. Examination with panendoscopy of the oral cavity, pharynx, larynx, and tracheobronchial tree may also be performed at the time of esophagoscopy in patients with squamous cell carcinomas, given the high incidence of second tumors in the head and neck and upper airway.² In addition, bronchoscopy should generally be performed in patients with proximal malignancies to evaluate for the presence of tracheal or carinal invasion, particularly for patients with tumors abutting these structures on computed tomography (CT). CT of the thorax and abdomen is critical to identify metastases to the liver, upper abdominal nodes, or adrenals. However, CT may not adequately assess periesophageal lymph node involvement or accurately define the true extent of the primary tumor.^52,53 Conventional CT scan can accurately determine resectability in only 65% to 85% of cases. Furthermore, CT accurately predicts T stage in approximately 70% of cases and nodal involvement in only 50% to 70% of cases.^54–56

To more accurately assess periesophageal and celiac lymph node involvement and transmural extent of disease, endoscopic ultrasonography (EUS) should be performed. EUS provides accuracy rates of 85% to 90% for tumor invasion (T stage) and 75% to 80% for lymph node metastases when matched to surgical pathology.^57–60 However, the accuracy of endoscopic ultrasound following neoadjuvant therapy is significantly less, ranging from 27% to 48% for T staging and 38% to 71% for N staging. This is possibly due to the failure to discriminate tumor from postradiation inflammation and fibrosis.^61–63

Surgical staging procedures, including thoracoscopy, mediastinoscopy, and laparoscopy, may provide additional staging information and are considered in selected patients at some institutions.⁶⁴ Laparoscopy would primarily be used for tumors at the gastroesophageal junction.

Patients with significant obstruction with inability to maintain their weight may require placement of a feeding tube. If surgery is planned, gastric tube placement is generally avoided, given that the stomach will ultimately serve as the “neoesophagus” following resection.

More recently, positron emission tomography (PET) has proven to be a valuable staging tool in esophageal cancer patients. The addition of PET to standard staging studies such as CT can improve the accuracy of detecting stage III and stage IV disease by 23% and 18%, respectively.^65,66 Overall, it is estimated that PET will detect distant metastatic disease in approximately 20% of patients who are considered to have local regional disease only by CT. However, PET also appears to have a lower accuracy in detecting local nodal disease compared to CT alone or in combination with endoscopic ultrasound. Of importance, emerging data suggest that PET can be used to predict response to therapy, with “PET responders” experiencing significantly improved outcomes compared to “nonresponders.”⁶⁷ In addition, PET has been used to predict response to treatment early during the treatment course. This has led to ongoing investigation of early treatment response as measured by PET as a surrogate for therapeutic efficacy and clinical outcomes.⁶⁸

Staging Systems

Esophageal staging can be based on pathologic or clinical criteria. Pathologic staging is performed after invasive procedures, including esophagectomy, mediastinotomy, or thoracotomy. Clinical staging is often employed with “definitive” and neoadjuvant chemoradiation approaches and is less accurate. With the combination of CT, PET, and EUS, clinical staging closely correlates with pathologic stage. Note that the most recent AJCC staging system takes into consideration tumor type and grade, as well as involved number of lymph nodes (Table 53.5).

TABLE 53.5. American Joint Committee on Cancer 2010 Esophageal Cancer Staging System

Pathologic Classification

Squamous cell carcinoma and adenocarcinoma comprise 95% of all esophageal tumors, although other rare histologic subtypes are occasionally seen (Table 53.6).⁶⁹

TABLE 53.6. Pathologic Classification of Malignant Esophageal Tumors

Given that there has been a rise in adenocarcinoma compared to squamous cell carcinoma, examinations of outcomes by histology have been performed. Some series have reported that patients with squamous cell carcinomas have improved survival,⁷⁰ whereas others have suggested that patients with adenocarcinoma have an improved survival⁷¹ and others report no survival differences. Overall there can be no direct comparison until randomized studies are done with stratification based on histology.

Pseudosarcoma is a variant of a poorly differentiated squamous cell carcinoma with spindle-shaped cells in the stroma resembling fibroblasts. Verrucous carcinoma is a well-differentiated, papillary variant of squamous cell carcinoma.² Squamous cell carcinoma in situ is rarely seen in the United States and should be distinguished from dysplasia.^72–74

Adenocarcinoma may arise from foci of ectopic gastric mucosa or intrinsic esophageal glands. However, as described previously, it is believed the vast majority arise from Barrett's esophagus. If a focus of squamous cell metaplasia is found in an adenocarcinoma, the tumor may be referred to as an adenoacanthoma.⁷⁵

Adenoid cystic carcinomas are rare, with an incidence of 0.75%. Patients with this malignancy present around the sixth decade of life and have a poor median survival.⁷⁶ Mucoepidermoid tumors (adenosquamous carcinomas) are more aggressive and carry a poor prognosis.⁷⁷ The incidence of small-cell carcinoma is approximately 2%. Patients with these malignancies often present in the sixth to eighth decades of life, and the lesion is usually located in the middle to lower esophagus in males.^78,79 These are believed to originate in the argyrophilic cells in the esophagus and may produce paraneoplastic syndromes, such as antidiuretic hormone secretion and hypercalcemia.⁸⁰ The clinical course of small-cell carcinoma is similar to that of small-cell carcinoma of the lung and may be responsive to chemotherapy and radiation therapy.^77,79

Nonepithelial tumors of the esophagus are rare. Among these, leiomyosarcomas are the most common. Twenty-five percent of patients with this tumor present with metastases.^81–83 Histologically, these tumors have interlacing bundles of spindle-shaped cells. Less aggressive forms have fewer mitotic figures and less anaplasia. Prognosis has been reported to be more favorable than that of squamous cell carcinoma.⁷⁷ In patients with Kaposi's sarcoma, gastrointestinal involvement of the esophagus can be seen.⁸⁴

Malignant melanoma is rare and can occur as a primary esophageal tumor or as a metastasis. These lesions are usually large and often covered by intact squamous mucosa with focal areas of ulceration. Spread is usually submucosal. Mean survival is approximately 7 months.^85,86 Lymphoma comprises approximately 1% of esophageal malignancies. It is usually associated with direct extension from other organs, although primary esophageal lymphoma has been reported.⁸⁷

Prognostic Factors

According to the Union Internationale Contre le Cancer/American Joint Cancer Committee seventh-edition staging system, R-status, age, and histologic subtype were independent prognostic factors of survival, whereas tumor grade and site were not.⁸⁸ It should be recalled that these data consider patients treated with surgery alone and as such do not apply to patients receiving chemotherapy or radiotherapy. A study published by Nomura et al.⁸⁹ evaluated 301 patients treated with chemoradiotherapy showed that T stage, M stage, and gender were prognostic factors in multivariate analysis.

In addition to stage, other factors portend outcome. Tumor length/size may also impact outcome. In a study of 582 patients undergoing surgical resection as primary treatment, tumoral length adversely affected survival, with 5-year survival rates of 77%, 48%, 38%, and 23% for tumor lengths of 1, 2, 3, or >3 cm, respectively (p < .001).⁹⁰ Of note, length was not prognostic if patients were N+ or M+. Similarly, in adenocarcinoma patients, 5-year survival rates have been shown to be significantly higher for patients with tumors ≤2 cm compared to those >2 cm.⁹¹

In another large study from the Mayo Clinic, clinicopathologic factors that affected prognosis included T and N status, tumor grade, age >76 years, extracapsular lymph node extension, and the absence of chemotherapy or radiotherapy; anatomic location did not influence survival.⁹² In addition, weight loss and low overall performance status also indicate poor prognosis.⁹³ Deep ulceration of the tumor, sinus tract formation, and fistula formation are other poor prognostic factors.⁵⁰

Obtaining uninvolved pathologic margins at resection is of significant importance with regard to long-term outcome. An Intergroup study (discussed later) evaluating chemotherapy preceding and following esophagectomy showed that outcomes were similar in patients undergoing R1 resection (positive microscopic margins) or R2 resection (gross residual disease) or patients not undergoing resection at all. Only patients undergoing R0 resection (uninvolved margins) had a substantial chance of long-term disease-free survival.⁴⁷ A patterns-of-care survey examined the outcomes of patients with adenocarcinoma and squamous cell carcinoma of the esophagus between 1996 and 1999. Patients were treated with radiation therapy across 59 institutions. On multivariate analysis, significant improvements in survival were seen in patients treated at centers with ≥500 new cancer patients per year compared to centers seeing <500 (hazard ratio 1.32; p = 0.03).⁹⁴