Carcinoma of the esophagus ranked as the eighth most common carcinoma worldwide in 1990 and accounts for 7% of gastrointestinal (GI) malignancies.¹ Most patients in the Western world present after the age of 65 years. Approximately 13,900 people in the United States are affected annually with an overall age-adjusted incidence of 4.5 per 100,000, ranging from 2.1 per 100,000 in women to 7.7 per 100,000 in men.^2,³ Overall 5-year survival has improved in recent years to 14%, which is still low. There are significant epidemiologic differences between the two main carcinoma subtypes, and these are considered separately.

Squamous Cell Carcinoma

SCC can arise anywhere in the esophagus with an approximately equal distribution throughout (Fig. 25.1). Globally, SCC is more common than adenocarcinoma with an overall incidence of 2.5 to 5.0 per 100,000 for men and 1.5 to 2.5 per 100,000 for women.⁴ There are, however, striking geographic variations in incidence. High-risk areas include the Transkei region of South Africa and the so-called “Asian esophageal cancer belt” comprising eastern Turkey, India, northern Iran, and northern China, where the incidence is greater than 100 per 100,000 population.⁵ In the United States, African American men have the highest incidence of any ethnic group (16.8 per 100,000), and men are generally affected two to three times more often than women,⁶ although the incidence is similar in the two groups in high-risk areas of the world. The disease is most prevalent among lower socioeconomic groups.

Fig. 25.1 Endoscopy in a patient with progressive dysphagia shows crescentic stenosing squamous cell carcinoma (SCC) in the midesophagus.

Variations in incidence have been attributed to numerous etiologic factors, including environmental exposure, dietary habits, infection, radiation exposure, and associated high-risk conditions. The most important risk factors for SCC (in the Western world) are tobacco and alcohol use,^7,⁸ the risk being greatest in individuals who both smoke and drink. Many carcinogens, including nitrosamines and polycyclic hydrocarbons, exist in both tobacco smoke and alcohol, and the risk may be compounded in alcohol abusers by concomitant nutritional and immunologic deficiencies.⁵

Numerous high-risk conditions have been described. Achalasia may predispose to SCC in association with chronic stasis of food and debris in the dilated esophagus, with an incidence of SCC of up to 9% after 15 to 20 years.⁵ Lye strictures of the esophagus are associated with a 1000-fold increased risk of SCC compared with controls, with patients often presenting 40 to 50 years after lye ingestion. Up to 16% of patients with Plummer-Vinson syndrome (iron deficiency anemia, dysphagia, and postcricoid webs in elderly women) may develop pharyngeal or esophageal carcinoma.⁹ Long-standing celiac disease is rarely associated with esophageal and pharyngeal SCC in addition to enteropathy-associated T-cell lymphoma and adenocarcinoma.¹⁰ Tylosis is a rare autosomal dominant disease consisting of palmar and plantar hyperkeratosis along with thickening and fissuring of the skin. Up to 95% of patients develop esophageal SCC by age 65 years.¹¹ Patients with SCC of the head and neck have been reported to develop synchronous esophageal carcinoma in up to 8% of cases¹² with tobacco and alcohol as common risk factors for both.

Adenocarcinoma

Adenocarcinomas arise in the distal esophagus and at the esophagogastric (EG) junction (Fig. 25.2). Tumors at the EG junction and gastric cardia were previously considered as primary gastric carcinomas invading the distal esophagus. These tumors have been reclassified (Fig. 25.3) as type 1 when they arise from the distal esophagus, type 2 when the origin is the gastric cardia, and type 3 when they are subcardial.¹³ Although this classification should allow more accurate characterization of tumors at the EG junction into primary esophageal or primary gastric types, changes in terminology and classification over time must be borne in mind when interpreting data from relevant studies.

Fig. 25.2 A, Endoscopy reveals bulky polypoid distal carcinoma arising on a background of Barrett’s esophagus. B, Biopsy specimen shows intestinal metaplasia with goblet cells (open arrow) and features of adenocarcinoma (closed arrow).

Fig. 25.3 Schematic illustration of the proposed classification of carcinomas arising from the esophagogastric (EG) junction. Type 1 carcinomas are classified as esophageal in origin, as are type 2 tumors, although this is still debated. Type 3 carcinomas are classified as primary gastric in origin.

(From Siewert JR, Stein HJ: Carcinoma of the cardia: Carcinoma of the gastroesophageal junction—classification, pathology and extent of resection. Dis Esoph 9:173–182, 1996.)

Current evidence suggests that type 1 (and possibly type 2) carcinomas of the EG junction have a similar clinical course to distal esophageal tumors and should be staged as for esophageal carcinoma.¹⁴ Epidemiologic differences between esophageal adenocarcinoma and type 3 adenocarcinoma of the EG junction suggest that these diseases are separate entities,¹⁵ and type 3 tumors are usually staged according to criteria for gastric cancer.

In contrast to SCC, the incidence of esophageal adenocarcinoma has been increasing in many parts of the developed world since the 1970s, a consistent finding across the United States, Europe, and Australasia.¹⁶^–¹⁸ The most rapid increases have been reported in the United States at 10% per year,¹⁹ especially in white men, and adenocarcinoma is now more common than SCC.¹⁶ Current incidence in the developed world is approximately 4.0 per 100,000 population, varying from less than 1.0 in Eastern Europe to 5.0 to 8.7 per 100,000 in Great Britain.^3,⁴ Similar trends have not been observed to date in Asian populations.²⁰

The predominant risk factors for adenocarcinoma are gastroesophageal reflux (GER) and Barrett’s esophagus. In contrast to SCC, lower socioeconomic status and tobacco and alcohol use are not strongly associated with increased incidence,²¹ although smoking has been found to be a risk factor in some studies.^22,²³ Chronic GER predisposes to Barrett’s esophagus²⁴ but was also associated independently with the development of adenocarcinoma in a large study of Swedish patients.²⁵ In this population, the development of adenocarcinoma correlated with duration, frequency, and severity of GER. Obesity has also been implicated as an independent risk factor in the development of adenocarcinoma, perhaps because of an influence on GER. A meta-analysis of eight studies reported an odds ratio for esophageal adenocarcinoma of 1.52 (95% confidence interval 1.147 to 2.009) in patients with a body mass index of 25 to 30 kg/m², increasing to 2.78 (95% confidence interval 1.850 to 4.164) in patients whose BMI was greater than 30 kg/m².²⁶ There are wide variations in the reported relative risk of cancer development in Barrett’s esophagus, but it is estimated to be approximately 0.5% per year (i.e., 1 in 200 patient-years).^24,²⁷ There is a weak correlation between length of the Barrett’s segment and malignant potential.²⁸

Clinical Features

The esophagus lacks a serosal covering, and early tumor growth causes asymptomatic dilation of the smooth muscle. In most patients, dysphagia results only when the lumen has narrowed to 50% to 75% of its normal circumference. By this time, local or nodal spread has often occurred, and the tumor is incurable. Cancers can manifest early with dysphagia, but this is uncommon. Dysphagia may be present for several months before medical advice is sought, and subjective localization of the site of obstruction is a poor indicator of the actual site of disease in the esophagus.²⁹ Symptoms are commonly gradual in onset, with progressive difficulty swallowing solids and then liquids. In rare cases, EG junction tumors infiltrating the submucosa affect motility and result in “pseudoachalasia” with no obvious endoscopic mucosal abnormality and clinical features similar to achalasia.

Anorexia and weight loss, which often precede the onset of dysphagia, are common, and odynophagia may occur with ulcerated tumors. Persistent retrosternal pain, unrelated to swallowing, and back pain are sinister symptoms suggesting mediastinal invasion.²⁹ Cough worsened by swallowing or recurrent pneumonia suggests esophagobronchial fistulization. This complication occurs in 5% to 10% of patients and is associated with poor outcome resulting in a median survival time of 1.5 to 4 months.³⁰ Hematemesis is uncommon.³¹ Exsanguination resulting from aortoesophageal fistula is rare. Tumor involvement of the left recurrent laryngeal nerve results in hoarseness.

Physical examination may reveal evidence of weight loss and dehydration. Examination of the neck may detect cervical or supraclavicular lymphadenopathy. The oral cavity and pharynx should be carefully inspected in patients with SCC for evidence of synchronous head and neck malignancy. Signs of pneumonia may result from aspiration or fistula into airways. Hepatomegaly or jaundice from liver involvement indicates incurable disease.

Esophageal carcinoma progresses through direct extension, lymphatic spread, or hematogenous metastasis or a combination of these. Lack of a serosal covering facilitates direct extension and invasion of structures in the neck or chest. Early lymphatic spread via rich interconnecting lymphatic networks in the esophageal submucosa is common. Tumors at any site may involve nodes in the neck or the mediastinum, although proximal lesions metastasize more commonly to cervical nodes, and distal lesions metastasize to abdominal nodes.³² Depth of invasion is a major determinant of lymph node metastasis. Disease confined to the mucosa is associated with nodal involvement in less than 5% of cases,³³ whereas penetration into the submucosa is associated with a 15% to 50% risk of metastases.^34,³⁵ Hematogenous spread occurs to the lungs, liver, adrenals, kidneys, pancreas, peritoneum, bones, and brain.

Diagnosis

Esophagogastroduodenoscopy

Indications and Contraindications

Dysphagia is the cardinal symptom of esophageal carcinoma and the main indication for endoscopy in this disease. Other indications for endoscopy include persistent dyspepsia or reflux symptoms or the onset of new symptoms in patients older than 45 years. Odynophagia, retrosternal chest pain, nausea and vomiting, anorexia, and iron deficiency anemia are other indications. Screening for esophageal cancer by endoscopy is not indicated except perhaps in high-risk patient groups as described previously.

Flexible videoendoscopy with biopsy is the “gold standard” investigation for the diagnosis of esophageal carcinoma (see Figs. 25.1 and 25.2). Endoscopy is more sensitive and specific than double-contrast barium for the diagnosis of upper GI cancer,³⁶ and when biopsy and cytology are combined, the accuracy of endoscopy for diagnosis approaches 100%.³⁷ Rigid esophagoscopy is rarely necessary and is no longer recommended on the grounds of safety and cost-effectiveness.³⁸ In rare patients with pseudoachalasia and repeated negative mucosal biopsy results, endoscopic ultrasound (EUS) with or without fine needle aspiration (FNA) biopsy from within the esophageal wall may provide supportive evidence for malignancy and a tissue diagnosis.³⁹

Contrast radiography has little, if any, role in the diagnosis or staging of esophageal cancer, although radiography retains a role in the evaluation of suspected perforation or fistulization. Contrast studies may also be useful when there is complete obstruction and when tortuous, complex strictures prevent passage of the endoscope. In these situations, a radiologic “road map” can facilitate dilation and subsequent completion of endoscopy or stent insertion.

There are few contraindications to endoscopy, and these are general contraindications to upper endoscopy. Patients who are very frail and terminally ill at presentation are unlikely to benefit. Coagulopathy, sepsis, dehydration, or severe metabolic abnormalities need to be corrected before endoscopy is performed. Severe cardiorespiratory disease is a relative contraindication.

Equipment

Good-quality videoendoscopes are essential. For assessment of dysplasia or early neoplasia, high-resolution instruments with magnification and instruments with enhanced imaging techniques (e.g., autofluorescence, narrow band imaging, or confocal endomicroscopy) can provide additional useful information.⁴⁰ Biopsy forceps and cytology brushes are essential, and either balloon or Savary bougie dilators (see Chapter 17) should be available if dilation is necessary to facilitate endoscope passage and completion of the procedure.

Anatomy

Clear understanding of EG anatomy and the use of precise measurements and terminology are vital when diagnosing and reporting the location and nature of esophageal malignancies to facilitate accurate staging and treatment planning. SCCs, esophageal adenocarcinomas, and cancers of the EG junction all may require different management strategies, and the endoscopy report should be as accurate and informative as possible. Key information includes the following:

1 Tumor location and length—the proximal and distal extent of the tumor (in centimeters from the incisors) must be noted.

2 Presence and extent of any associated Barrett’s esophagus (using the Prague criteria [see Chapter 26]).

3 Presence and size of any associated hiatal hernia.

4 Position of the tumor relative to the EG junction, defined as the point where the gastric folds converge in the dilated esophagus. Tumors of the EG junction should be classified, if possible, as follows: type 1, primarily esophageal but extend down to or across the EG junction; type 2, arising at the cardia and straddling the EG junction more or less equally; type 3, primarily gastric arising in subcardia but extending up to or across the EG junction.

5 For SCC lesions, the presence of synchronous “satellite” lesions by careful inspection of the entire esophageal mucosa, including the hypopharynx, larynx, and oral cavity. The use of chromoendoscopy with Lugol’s iodine may aid detection of early lesions elsewhere in the esophagus (see Chapter 30).

6 Morphology and size of small, early lesions using the Paris classification (Fig. 25.4).

Fig. 25.4 Paris classification of early gastrointestinal (GI) neoplasia. Type 0-I lesions are elevated above the surface mucosa by more than half the height of the cups of closed biopsy forceps. Type 0-II lesions are flat but may be minimally elevated (0-IIa), flat (0-IIb), or depressed (0-IIc). Type 0-III lesions are ulcerated and depressed. Any combination of these features may coexist.

Early lesions may appear as minor irregularities of the mucosa; areas of erythema; or depressed, raised, or ulcerated areas (Figs. 25.5 and 25.6; see also Figs. 25.1 and 25.4). A high index of suspicion is required, and biopsy specimens should be obtained of any tissue with these abnormalities. A more recent study has suggested that characterization of early lesions in Barrett’s segments according to the Paris classification may offer useful information to aid decisions regarding the likelihood of submucosal invasion and the suitability for endoscopic mucosal resection (EMR) (see Figs. 25.4 and 25.6C). Elevated lesions (type 0-I) are associated with a higher prevalence of submucosal involvement, and ulcerated or depressed lesions (type 0-III) are technically unsuitable for EMR.⁴¹ This study also showed that most early cancers in Barrett’s esophagus were flat lesions that were difficult to visualize. Dye staining of the mucosa improves the detection rate and is discussed subsequently. More advanced lesions are usually obvious polypoid or ulcerating masses. Stenosis of the esophageal lumen may be present because of tumor bulk or involvement of the muscular layers. A tightly closed distal esophageal sphincter with normal mucosal appearance and resistance to the passage of the endoscope suggests pseudoachalasia.

Fig. 25.5 Early esophageal adenocarcinoma (Paris type 0-Ia). A, White light image. B, Autofluorescence shows lesion as purplish discoloration. C, Narrow band imaging reveals irregular surface crypt pattern. The lesion was resected endoscopically and staged as T1m3.

Fig. 25.6 Early esophageal squamous cell carcinoma (SCC) before (A) and after (B) staining with Lugol’s iodine. A, Before staining, the mucosa appeared reddened and irregular. C, After staining with Lugol’s iodine, the true extent of the lesion is apparent. Histology confirmed intramucosal carcinoma (T1m1).

Procedure

1 Diagnostic endoscopy is performed with the patient in the left lateral position using topical pharyngeal anesthesia or conscious sedation.

2 Intravenous sedation improves patient tolerance of prolonged procedures and allows esophageal dilation to be performed if necessary. Care must be exercised, however, to avoid oversedation and the attendant risks, especially pulmonary aspiration of food and secretions lying above a stenotic tumor.

3 The mouth, pharynx, and larynx should be carefully inspected, particularly in patients with a history of tobacco and alcohol use and patients in whom SCC may be present.

4 The entire esophagus should be visualized, and the endoscope should be retroflexed in the stomach to examine the EG junction and gastric cardia. In patients with Barrett’s esophagus, particular care should be taken in the examination of the mucosa between the 12 o’clock and the 3 o’clock position because 48% of all dysplastic and neoplastic lesions occur in this area.⁴¹

5 Any suspicious lesions should be carefully inspected and documented.

6 To complete the procedure, the remainder of the stomach and the duodenum are examined.

Chromoendoscopy

The diagnosis of early carcinoma may be difficult in view of the subtle nature of the lesion. Chromoendoscopy involves the use of agents that enhance the distinction between diseased and normal mucosa, either by filling surface crevices or by differential uptake by diseased epithelium (vital staining). Many chromoendoscopy agents have been studied in the detection of esophageal carcinoma; Lugol’s iodine and methylene blue have been most widely studied.

Lugol’s iodine reacts with glycogen in squamous epithelial cells to produce a uniform dark brown coloration. Inflamed, dysplastic, and malignant cells are glycogen-depleted and consequently appear minimally stained or unstained.^42,⁴³ Using a standard washing catheter inserted through the biopsy channel of the endoscope, 1% to 3% Lugol’s iodine is sprayed onto the mucosa. Most highly dysplastic or malignant lesions remain unstained (see Fig. 25.6), and clinical trials have shown that biopsy of these areas enhances detection of high-grade dysplasia and early carcinoma.^44,⁴⁵ The technique is simple and does not require specialized equipment or additional staff; it is described in more detail in Chapter 30.

Methylene blue is a vital stain taken up by the cytoplasm of absorptive cells. These include goblet cells present in Barrett’s epithelium, in addition to normal cells of the colon and small intestine.⁴⁶ Methylene blue staining was first shown to stain selectively areas of specialized intestinal metaplasia in Barrett’s esophagus in 1996.⁴⁷ Neoplastic change is associated with a reduction in goblet cell numbers, an increasing nuclear-to-cytoplasm ratio, and reduced absorption of methylene blue. Increasing grades of dysplasia may appear as heterogeneous or unstained areas, allowing targeted rather than random biopsy specimens to be taken.^48,⁴⁹ However, the emergence of electronic chromoendoscopy in the setting of Barrett’s esophagus has eclipsed methylene blue dye staining.

Biopsy and Cytology

Biopsy samples are obtained using forceps inserted via the biopsy channel of the endoscope. The cup volume of standard forceps is 12.4 mm³. The cup volume of the larger jumbo forceps is 30.4 mm³ allowing larger biopsy samples to be taken, but an endoscope with a 3.7-mm channel is required. A nonendoscopic balloon device for obtaining esophageal cytology has been developed in China mainly for use in screening high-risk populations.⁵⁰

Jumbo forceps may provide better tissue samples for detection of high-grade dysplasia or early carcinoma in Barrett’s esophagus.⁵¹ Biopsy specimens are taken from the edge of ulcerated lesions to avoid necrotic tissue, and at least six samples are required to confirm the diagnosis in 100% of patients.⁵² Larger biopsy specimens can also be obtained by a “turn and suction” technique, in which the forceps are inserted, opened, and withdrawn until flush with the endoscope tip. The tip is turned onto the esophageal wall or lesion while suctioning air from the lumen; this draws tissue into the forceps, which are closed and withdrawn in the usual way.⁵³

Brush cytology alone may detect malignancy and in some studies has been shown to improve the diagnostic yield when combined with standard biopsy.^38,⁵⁴ For best results, brushing should be performed before biopsy to minimize contamination with blood. Samples are obtained by passing the brush catheter into the lumen and drawing the brush across the lesion several times until minor mucosal bleeding is noted. Smears are made on slides and fixed in alcohol before staining using Papanicolaou’s technique.

Use of Esophageal Dilation

In 20% to 40% of cases, a malignant stricture prevents the passage of a standard adult endoscope.⁵⁵ This situation may prevent both a complete examination and the performance of an adequate biopsy from within the main body of the tumor, but a cytology brush passed into the stricture may be a useful adjunct to obtain the biopsy sample from the proximal end of the lesion.⁵⁶ Dilation facilitates biopsy, relieves symptoms, and enables subsequent staging with EUS. Biopsy immediately after dilation is safe⁵⁷; for dilation of malignant strictures, the complications of hemorrhage and perforation occur in 2.5% to 10% of patients.^58,⁵⁹ Dilation provides only short-term palliation of malignant dysphagia, however, with the effects lasting days or at the most a couple of weeks. The issue of dilation before EUS staging is discussed later (see also Chapter 17).

Postprocedure Care

Most patients recover quickly after diagnostic upper endoscopy. Topical anesthesia wears off after 30 to 60 minutes, and patients can eat and drink normally after this time if a supervised test of swallowing with sterile water is successful. Standard nursing care for sedated patients applies. Patients who have undergone dilation should have nothing by mouth until reviewed and can resume fluids and then a soft diet when deemed well. Patients with chest or back pain, tachycardia, vomiting, or distress after dilation should have nothing by mouth and be urgently evaluated for possible perforation by erect chest x-ray and water-soluble contrast radiography or computed tomography (CT) scan. Before leaving the endoscopy unit, patients should be told of the likely diagnosis and how and when biopsy results will be communicated. They should also be given a clear explanation of the likely next steps (e.g., staging CT scan and EUS).

Staging of Esophageal Carcinoma

Prognosis depends on tumor stage at diagnosis. Patients with early disease (T1N0M0; stage I) have 5-year survival rates greater than 90% with surgery alone, but prognosis worsens with advancing stage at diagnosis; patients with stage IV disease have 5-year survival rates of less than 5%. In patients without nodal involvement at surgery (N0), 5-year survival is approximately 40% to 60%, but 5-year survival is only 5% to 17% in patients with nodal involvement (N1). Patients undergoing surgery alone for T3N1 disease have 5-year survival rates of 8% to 10%,^60,⁶¹ underlining the reality that although these tumors may be technically resectable, they are rarely curable. Accurate staging is essential in determining prognosis and in identifying patients for whom surgery alone is likely to be curative and patients with advanced disease for whom surgery has little to offer and for whom medical therapy or palliation should be the goal of therapy.

The benefits of neoadjuvant therapy have not yet been conclusively shown.⁶²^–⁶⁴ A full discussion of the relative benefits of neoadjuvant therapy is beyond the scope of this chapter; however, given its increasing use and the considerable morbidity associated with it, it is imperative that patients undergo accurate staging to guide stage-specific therapy with the hope of improving survival. These strategies vary according to local practice and must be understood by clinicians staging such patients. In addition, to obtain clinically useful and important information from future trials of neoadjuvant therapy, it is essential that study groups are well matched, and highly accurate staging is crucial in this regard.