Esophageal cancer carries a poor prognosis among gastrointestinal malignancies. Although esophageal squamous cell carcinoma predominates worldwide, Western nations have seen a marked rise in the incidence of esophageal adenocarcinoma that parallels the obesity epidemic. Efforts directed toward early detection have been difficult, given that dysplasia and early cancer are generally asymptomatic. However, significant advances have been made in the past 10 to 15 years that allow for endoscopic management and often cure in early stage esophageal malignancy. New diagnostic imaging technologies may provide a means by which cost-effective, early diagnosis of dysplasia allows for definitive therapy and ultimately improves the overall survival among patients.
Key points
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Esophageal cancer is particularly deadly, with a 5-year survival in developed nations of 18%.
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Esophageal squamous cell carcinoma predominates in the developing world and worldwide, whereas esophageal adenocarcinoma (EAC) predominates in Western nations.
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Esophageal adenocarcinoma is commonly associated with GERD and obesity.
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Barrett’s esophagus is a precursor of EAC; however, screening and surveillance remain controversial.
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Introduction
Esophageal malignancy ranks sixth among cancer deaths worldwide. It is estimated that just over 450,000 new cases of esophageal cancer were diagnosed in 2012, with around 400,000 deaths attributable to this condition in the same year. Malignancies of the esophagus have a particularly poor prognosis because they typically cause no symptoms and thus are diagnosed late in their course. At this stage, resection and definitive cure are usually not an option. More than half present with distant metastases or unresectable disease. This leads to a dismal 5-year survival that, although it has been increasing over time, remains a mere 18%. There is a significant difference between developed and developing nations with respect to esophageal cancer incidence: it ranks 13th among all malignancies in the United States compared with 8th worldwide. Histology also differs, and although esophageal squamous cell carcinoma (ESCC) is more common throughout the world, esophageal adenocarcinoma (EAC) predominates in the United States.
Screening and surveillance for esophageal cancer have proven to be a difficult undertaking, given that esophageal symptoms (eg, gastroesophageal reflux disease [GERD]) correlate poorly with esophageal cancer and its precursor lesions. In fact, most patients diagnosed with early esophageal cancer lack any symptoms before the onset of dysphagia and weight loss that can signal an advanced-stage tumor. In cases where early esophageal cancer is detected, evolving therapies have not only improved the cure rate but have decreased the morbidity associated with treatment.
Introduction
Esophageal malignancy ranks sixth among cancer deaths worldwide. It is estimated that just over 450,000 new cases of esophageal cancer were diagnosed in 2012, with around 400,000 deaths attributable to this condition in the same year. Malignancies of the esophagus have a particularly poor prognosis because they typically cause no symptoms and thus are diagnosed late in their course. At this stage, resection and definitive cure are usually not an option. More than half present with distant metastases or unresectable disease. This leads to a dismal 5-year survival that, although it has been increasing over time, remains a mere 18%. There is a significant difference between developed and developing nations with respect to esophageal cancer incidence: it ranks 13th among all malignancies in the United States compared with 8th worldwide. Histology also differs, and although esophageal squamous cell carcinoma (ESCC) is more common throughout the world, esophageal adenocarcinoma (EAC) predominates in the United States.
Screening and surveillance for esophageal cancer have proven to be a difficult undertaking, given that esophageal symptoms (eg, gastroesophageal reflux disease [GERD]) correlate poorly with esophageal cancer and its precursor lesions. In fact, most patients diagnosed with early esophageal cancer lack any symptoms before the onset of dysphagia and weight loss that can signal an advanced-stage tumor. In cases where early esophageal cancer is detected, evolving therapies have not only improved the cure rate but have decreased the morbidity associated with treatment.
Squamous cell carcinoma of the esophagus
Demographics
Before 1990, ESCC was the predominant histologic subtype of esophageal cancer in the United States. Since that time, however, there has been a decline of around 4% per year in the proportion of these cancers. This is thought to be related to two main factors. First, the incidence of EAC is on the rise (see later). Second, there has been a steady decrease in the rates of tobacco and alcohol abuse, which are major contributors to ESCC, over that same time period. Although most ESCCs diagnosed in the United States are still found in white persons (including Hispanics), African Americans are disproportionately affected and account for 26% of cases.
Risk Factors
The risk factors for ESCC vary between developed and developing nations. In developing parts of the world, nutritional deficiencies and the subsequent lack of antioxidants that comes with a consistent diet of fruits and vegetables plays a role. Specifically, deficiencies in vitamins A, C, and E, and zinc, folate, and selenium contribute. In industrialized countries, alcohol (>140 g/week) and tobacco use are known risk factors, with a synergistic effect in patients who abuse both. Achalasia is associated with ESCC, likely caused by the effects of chronic stasis and inflammation in the esophagus. In fact, patients with achalasia are 28 times more likely to develop esophageal cancer than their unaffected counterparts. Despite this fact, given the low absolute risk, screening/surveillance strategies have failed to demonstrate a survival benefit and are not routinely recommended in these patients.
Caustic ingestion, usually accidental in children and intentional in adolescents and adults, has been linked to ESCC. The incidence has been reported as somewhere between 2% and 30%, with an occurrence rate 1000 times that of age-matched individuals. As with achalasia, the pathophysiology seems to be related to the chronic inflammation/regeneration of the squamous mucosa of the esophagus. In most patients, the development of dysplasia occurs over several decades; however, ESCC can develop in those whose ingestion occurred as recently as 1 year prior.
Tylosis is an autosomal-dominant inherited condition known to predispose to ESCC, with patients typically also demonstrating hyperkeratosis of the hands and feet. This susceptibility is traced to a gene mutation on 17q25.1 that encodes for a protein central to EGFR signaling. In the presence of this mutation, affected patients have between 50% and 100% chance of development of ESCC. The American Society for Gastrointestinal Endoscopy recommends screening endoscopy every 1 to 3 years in individuals with the identified mutation.
Adenocarcinoma of the esophagus
Demographics
EAC is on the rise in the Western world. A recent analysis of the trends in esophageal cancer diagnosis from the Surveillance, Epidemiology, and End Results database demonstrated that over the past 30 years, the proportion of patients with EAC nearly doubled, from 35% to 61%. This change is attributed not only to the declining incidence of ESCC noted previously, but also the rise in obesity and related conditions over the same time period.
Risk Factors
There is a clear link between GERD and EAC, and chronic exposure of the distal esophagus to acid is thought to be a critical aspect of the pathophysiology of this malignant transformation. It is thought that through the process of healing erosive esophagitis, metaplasia occurs and leads to formation of a premalignant columnar lining of the esophagus. As a result, conditions that increase esophageal acid exposure are risk factors for EAC. Obesity, in particular, has been thought to contribute to the rising incidence of EAC in developed nations. Beyond the mechanical implications of the obese body habitus (eg, formation of hiatal hernia) and the net effect of increased acid exposure in the distal esophagus, there is increasing evidence to suggest a link between the rise in serum adipokines in obese patients and the risk of EAC. Finally, cigarette smoking is a risk factor for EAC, just as it is in many cancers. Unlike ESCC, however, the link between EAC and alcohol use is not well-established.
Barrett’s esophagus
Although the presence of columnar-lined epithelium in the distal esophagus was first described in 1906 by Tileston, it was Barrett’s subsequent article that led to the eponymous term “Barrett’s esophagus.” Barrett’s esophagus is defined as a change in the normally squamous epithelium of the distal esophagus to a columnar type. This gives the classic endoscopic appearance of salmon-colored mucosa, which also demonstrates the presence of goblet cells when examined under the microscope ( Fig. 1 A ). This specialized intestinal metaplasia, or nondysplastic Barrett’s esophagus, is thought to occur as a response to chronic inflammation and has an increased risk of further development into EAC. Patients diagnosed with Barrett’s esophagus are more than 11 times more likely to develop esophageal cancer when compared with those without. This represents a yearly incidence of EAC between 0.12% and 0.36% in those affected. Furthermore, the length of a Barrett’s segment correlates positively with the risk of progression to high-grade dysplasia and EAC. It should be noted, however, that although the relative risk of esophageal cancer is high in these patients, the absolute risk remains low; Barrett’s esophagus can be found in 5% to 6% of the US population.
Screening for Barrett’s esophagus is a controversial undertaking. One particular difficulty with a screening program for esophageal malignancy is the selection of individuals who should undergo endoscopy. Based on its decreased relative prevalence when compared with colon cancer (4.4 vs 43.7/100,000 ), for example, a population-wide screening effort similar to colonoscopy would be cost-prohibitive. Furthermore, Barrett’s esophagus itself is an asymptomatic condition; most patients have chronic GERD symptoms reflective of the underlying disorder. Among all patients with GERD, only 5% to 15% are found to have Barrett’s esophagus. However, screening and surveillance continue to be recommended by various gastrointestinal societies in patients with multiple risk factors for EAC.
On identification of Barrett’s esophagus, patients are usually enrolled in a surveillance protocol. In patients with nondysplastic Barrett’s esophagus, it is generally accepted that surveillance esophagogastroduodenoscopy in these patients should be performed every 3 to 5 years, with methodical documentation of the Barrett’s extent and standardized sampling of the affected areas. This continues as long as there is no evidence of dysplastic progression.
A diagnosis of low-grade dysplasia carries a risk of progression between 0.3% and 0.8% per year. It also poses a unique challenge because of only slight interobserver agreement in its characterization among pathologists (kappa = 0.14; overall 55.6%). This is reflected in the guidelines for management of low-grade dysplasia in the setting of Barrett’s esophagus. It is first recommended that two expert pathologists confirm the diagnosis. Once confirmed, it should be followed with endoscopy every 6 months for the first year, then yearly thereafter unless there is development of further dysplastic progression.
When a high-grade dysplastic lesion is identified within a Barrett’s segment ( Fig. 1 B), the endoscopist and patient must decide whether to remove the lesion (endoscopic mucosal resection [EMR]) or pursue surgical resection. The risk of progression to adenocarcinoma in the setting of high-grade dysplasia is 6% per year. It is recommended that any nodules found within a segment of Barrett’s mucosa be removed, typically via EMR, because this allows for histologic evaluation and definitive staging of the lesion. After resection of the dysplastic segment, the remaining metaplastic epithelium should be removed until the distal esophagus once again is covered entirely by squamous (now termed neosquamous) epithelium (see the section on treatment). Surveillance endoscopy then continues, with systematic biopsies obtained over the extent of the previously columnar mucosa. Although rare, there have been reports of “buried” dysplasia and adenocarcinoma beneath the neosquamous epithelium following ablation of a Barrett’s segment.
Diagnosis
The diagnosis of esophageal cancer is most often preceded by symptoms of progressive dysphagia and, in many cases, weight loss. Chest pain occurs less often but may signal invasion of tumor into the mediastinum. Odynophagia may be present if there is significant ulceration of an esophageal lesion or severe esophagitis proximal to the obstruction. Asymptomatic patients may present with more insidious findings, such as anemia, mediastinal lymphadenopathy, or even hoarseness caused by recurrent laryngeal nerve encasement.
Occasionally, patients are first evaluated with a barium esophagram; this study would demonstrate narrowing of the lumen and dilation proximal to the level of the tumor. The gold standard for evaluation of worrisome esophageal symptoms is upper endoscopy, which allows not only visualization of a tumor but also tissue sampling for pathologic confirmation. Esophageal malignancy can present as a flat, subtle area or a lumen-obscuring mass ( Fig. 1 C). Persistent ulceration and refractory strictures of the esophagus should raise suspicion for malignancy. Given the wide range of presentations of this malignancy, the endoscopist must carefully evaluate the entire esophagus during an upper endoscopy. Because of implications for treatment (surgical planning, the need for stent placement, and posttreatment evaluation), it is imperative that the size, morphology, and proximal and distal extent of the tumor are carefully described in the endoscopy report. It is generally recommended that at least 7 biopsies be obtained to ensure adequacy of sample. Brushings alone are inadequate, but if added to biopsy samples this brings the sensitivity to near 100%.
Staging
Staging of esophageal cancer is described using the American Joint Committee on Cancer’s TNM system ( Table 1 ). This method allows for a description of the degree of tumor invasion (T), the number of regional lymph nodes involved (N), and any distant metastases (M). There is a clinically significant division between esophageal tumors that involve the submucosa (T1b) and beyond, from those that are limited to the mucosal layer (T1a, T0). Fig. 2 demonstrates the principles of T-staging for tumors of the esophagus.
| Esophageal Adenocarcinoma Clinical Staging | ||||
|---|---|---|---|---|
| Stage | T | N | M | Grade |
| 0 | Tis (high-grade dysplasia) | N0 | M0 | 1, X |
| IA | T1 | N0 | M0 | 1–2, X |
| IB | T1 | N0 | M0 | 3 |
| T2 | N0 | M0 | 1–2, X | |
| IIA | T2 | N0 | M0 | 3 |
| IIB | T3 | N0 | M0 | Any |
| T1–2 | N1 | M0 | Any | |
| IIIA | T1–2 | N2 | M0 | Any |
| T3 | N1 | M0 | Any | |
| T4a | N0 | M0 | Any | |
| IIIB | T3 | N2 | M0 | Any |
| IIIC | T4a | N1–2 | M0 | Any |
| T4b | Any | M0 | Any | |
| Any | N3 | M0 | Any | |
| IV | Any | Any | M1 | Any |
| Esophageal Squamous Cell Carcinoma Clinical Staging | |||||
|---|---|---|---|---|---|
| Stage | T | N | M | Grade | Tumor Location |
| 0 | Tis (high-grade dysplasia) | N0 | M0 | 1, X | Any |
| IA | T1 | N0 | M0 | 1, X | Any |
| IB | T1 | N0 | M0 | 2–3 | Any |
| T2–3 | N0 | M0 | 1, X | Lower, X | |
| IIA | T2–3 | N0 | M0 | 1, X | Upper, middle |
| T2–3 | N0 | M0 | 2–3 | Lower, X | |
| IIB | T2–3 | N0 | M0 | 2–3 | Upper, middle |
| T1–2 | N1 | M0 | Any | Any | |
| IIIA | T1–2 | N2 | M0 | Any | Any |
| T3 | N1 | M0 | Any | Any | |
| T4a | N0 | M0 | Any | Any | |
| IIIB | T3 | N2 | M0 | Any | Any |
| IIIC | T4a | N1–2 | M0 | Any | Any |
| T4b | Any | M0 | Any | Any | |
| Any | N3 | M0 | Any | Any | |
| IV | Any | Any | M1 | Any | Any |
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