Esophageal Cancer

esophageal cancer

Published November 16, 2005

Ahmed Absi, MD

Department of Hematology & Medical Oncology

David J.
Adelstein, MD

Department of Hematology & Medical Oncology

National Guidelines

ACG Updated Guidelines for the Diagnosis, Surveillance, and Therapy of Barrett’s Esophagus

NCCN Guidelines for the Diagnosis and Treatment of Esophageal Cancer

INTRODUCTION

Esophageal cancer has long been considered one of the deadliest malignancies, and considerable controversy has surrounded its management. Mortality is high because most patients present with advanced disease for which current therapies are relatively ineffective. However, even for those patients with earlier-stage disease, treatment options are morbid, and results are suboptimal.

DEFINITION

The most common histologic types are squamous cell carcinoma and adenocarcinoma; which together constitute more than 90% of esophageal malignancies. Rarely, melanoma, sarcoma, small-cell carcinoma, or lymphoma may arise in the esophagus.¹ Although squamous cell carcinomas are more evenly distributed throughout the length of the esophagus, adenocarcinomas are predominantly a disease of the distal esophagus and gastroesophageal junction, and are rarely found in the cervical esophagus.

The esophagus itself has several unique properties that distinguish the behavior of cancer in this organ from that of other gastrointestinal malignancies. In contrast to the rest of the gastrointestinal tract, the esophagus has no serosa, thus reducing the resistance against local spread of invasive cancer cells. Furthermore, the esophagus has an extensive network of lymphatics, allowing for early regional tumor advancement. Staging, the most important step for choosing appropriate therapy, is hindered by the anatomic location of the esophagus and the inaccessibility of the regional lymph nodes to clinical evaluation. In this short overview, we will cover the most important aspects of the disease for the practicing internist.

PREVALENCE

Cancers arising from the esophagus and gastroesophageal junction are relatively uncommon in the United States, with 14,520 new cases and 13,570 deaths anticipated in 2005.² Worldwide, however, esophageal cancer is the eighth most common malignancy and the sixth most common cause of cancer-related death. The epidemiology of esophageal cancer changed dramatically during the latter half of the 20th century. Although 40 years ago squamous cell carcinoma accounted for more than 90% of all esophageal tumors in the United States, diagnoses of esophageal adenocarcinomas have significantly increased and now represent 80% of cases in the United States. Worldwide, however, squamous cell carcinoma remains most common. The mean age at diagnosis is 67 years, and men are affected more frequently than women, particularly among patients with adenocarcinoma.

There are considerable geographic and racial variations in the incidence of this cancer. The highest incidence rates are found in Asia (particularly China and Singapore), Africa, and Iran. Geographic variation has also been reported within an individual country. Differences in local exposure to environmental risk factors have been implicated as explanations for this variation. The relation between esophageal cancer and race depends on tumor type. Whereas squamous cell carcinoma is six times more common among African American men than among white men, adenocarcinoma is at least four times more common among whites.³ The reasons for this are not understood, and are not solely accounted for by the differences in other risk factors, suggesting that genetic susceptibility may play at least a partial role.

PATHOPHYSIOLOGY

The recent shift in the histology of esophageal cancer and the wide geographic variation in incidence have provided insights into the pathophysiology and risk factors associated with the disease. The relative public health importance of these different risk factors may be substantially different in different parts of the world.

Smoking increases the risk of both squamous cell carcinoma and adenocarcinoma of the esophagus, although the risk is more established for squamous cell carcinoma. When compared with nonsmokers, male smokers have at least a fourfold increase in risk of this disease. The risk correlates directly with the amount and duration of smoking. When smokers quit, their risk continues to exceed that of nonsmokers for several years after smoking cessation.

In the Western Hemisphere, alcohol is also a major risk factor for the development of esophageal squamous cell carcinoma. Heavy alcohol consumption increases the risk by a factor of 10 to 25, depending on the type and quantity of alcoholic beverages consumed, although it appears that the amount of alcohol rather than the type is of greatest importance.³ Smoking has a synergistic effect with heavy alcohol consumption, and heavy exposure to both increases the risk of squamous cell carcinoma by a factor of more than 100. This is further complicated by the increased risk of other aerodigestive tract cancers in a person who smokes and drinks alcohol.

In general, any cause of chronic irritation and inflammation of the esophageal mucosa appears to increase the incidence of squamous cell carcinoma. For instance, in certain endemic regions such as Iran, Russia, and South Africa, the ingestion of very warm foods and beverages (such as tea) has been associated with esophageal squamous cell carcinoma. In the endemic areas of China, food products rich in known carcinogens, such as N-nitroso compounds or fungi that can reduce nitrate to nitrite, have been blamed for the high incidence of esophageal squamous cell carcinoma.^{4 5} Other mechanical factors that cause chronic esophageal irritation and increase the risk of esophageal squamous cell carcinoma include achalasia and esophageal diverticuli. It is postulated that in those situations, retained food is decomposed by bacteria, releasing potential chemical irritants. Similarly, victims of lye ingestion should be monitored closely for the development of this cancer. Deficiency syndromes associated with this cancer, such as the Plummer-Vinson syndrome (the triad of dysphagia, iron deficiency anemia, and esophageal webs), are becoming increasingly rare in the developed world as overall nutrition improves.

Few genetic factors have been identified as being important in the development of esophageal squamous cell cancer. One exception is tylosis, a rare syndrome associated with hyperkeratosis of palms and soles and a high rate of esophageal squamous cell carcinoma. The disease has an autosomal dominant mode of inheritance. A gene locus has been mapped to chromosome 17q25.1, which may contain a tumor suppressor gene. Deletions in this gene have also been implicated in sporadic forms of esophageal squamous cell carcinoma, and have been identified in 70% of patients with esophageal squamous cell carcinoma in one series.⁶

Infectious agents have also been implicated in the pathogenesis of esophageal squamous cell cancer. Human papillomavirus has received the most attention. It is thought that the infection results in loss of function of the tumor suppressor genes p53 and Rb. In a series from China, human papillomavirus DNA sequences were detected in 17% of 700 patients who underwent esophageal resection for squamous cell carcinoma.⁷

The risk factors for adenocarcinoma of the esophagus are quite different. Chronic gastroesophageal reflux is the most important risk factor, with severe, long-standing reflux symptoms increasing the risk of cancer by a factor of 40. Chronic gastroesophageal reflux disease is associated with Barrett’s metaplasia (Barrett's esophagus), a condition in which an abnormal columnar epithelium replaces the stratified squamous epithelium that normally lines the distal esophagus. Most esophageal adenocarcinoma is thought to arise from Barrett's esophagus. Although this mucosal change appears to be a favorable adaptation to chronic reflux (columnar epithelium appears to be more resistant to reflux-induced injury than the native squamous cells), this specialized intestinal metaplasia may become dysplastic and ultimately malignant, with genetic alterations that either activate protooncogenes, disable tumor suppressor genes, or both.^{8 9} Factors that increase the risk for gastroesophageal reflux, such as obesity, or medications that lower the lower esophageal sphincter tone, may result in an increased risk for esophageal adenocarcinoma.

An infectious etiology for this disease has not been identified, and unlike adenocarcinoma of the gastric cardia, the role of Helicobacter pylori colonization is unknown. The genetic and molecular changes underlying the development of esophageal adenocarcinoma also remain poorly understood, although allelic losses at chromosomes 4q, 5q, 9p, 9q, and 18q, and abnormalities of p53, Rb, cyclin D1, and c-myc have been implicated.

SIGNS & SYMPTOMS

The clinical presentation of patients with esophageal cancer can be attributed to the direct effects of the local tumor, the regional or distant complications of the disease, or paraneoplastic syndromes. Adenocarcinoma and squamous cell carcinoma have similar clinical presentations, which usually reflect the extent of local esophageal involvement. Dysphagia, the most common presenting symptom, usually develops in response to dense, solid food, and progresses gradually to interfere with the intake of softer foods and, finally, liquids. This can sometimes be accompanied by vomiting or regurgitation of saliva or food uncontaminated by gastric secretions, particularly in patients with advanced local disease. Pain is frequent and can occur in the absence of dysphagia. It can be related to swallowing itself (odynophagia), or to the local extension of the tumor into adjacent structures, such as the pleura, mediastinum, or vertebral bodies. Weight loss is common and correlates with dysphagia, dietary changes, and tumor-related anorexia. Weight loss is noted in more than 70% of cases, and if present carries a worse prognosis.

Other presenting signs and symptoms reflect complications from disease spread, such as cough or fever from a respiratory tract fistula, upper or lower gastrointestinal bleeding, hoarseness from recurrent laryngeal nerve involvement, and hiccups from phrenic nerve involvement.
Symptoms related to distant metastasis in lungs, bone, liver, and central nervous system, particularly in the case of adenocarcinoma, can also be found at initial clinical presentation. Hypercalcemia is the most common paraneoplastic syndrome. In the absence of bone metastases, it is most common in patients with squamous cell carcinoma and is thought to be due to the production of a parathyroid hormone-related protein. The physical examination is often unremarkable, but should be directed toward finding evidence of metastatic disease including supraclavicular lymphadenopathy, hepatosplenomegaly, or pleural effusion.

More recently, there has been an effort to discover early, asymptomatic esophageal adenocarcinoma by screening patients with Barrett's esophagus. The identification of high-grade dysplasia (ie, carcinoma in situ) is considered to be an indication for esophagectomy because occult invasive cancer is frequently identified at the time of resection, and because invasive cancer will develop in almost 50% of patients with high-grade dysplasia who do not undergo esophagectomy.¹⁰

DIAGNOSIS

Dysphagia is an alarming symptom, and mandates the need for an immediate evaluation to define its exact cause and to initiate appropriate therapy. Dysphagia in older adults should not be attributed to normal aging. Aging alone causes mild esophageal motility abnormalities, but these are rarely symptomatic. Evaluation of dysphagia starts with either a barium-swallow examination or an upper endoscopy. Endoscopy will allow the direct visualization of any tumor mass and histologic confirmation with either a biopsy or brushing cytology. Combining these techniques yields an overall diagnostic accuracy of 98%.

After establishing a diagnosis of esophageal cancer, adequate staging is required. The current staging of esophageal cancer is based on the pathologic extent of disease (Table 1). More than 50% of patients have unresectable or metastatic disease at the time of presentation, and survival is closely related to the stage of the disease. However, the extent of pathologic disease cannot truly be determined without an esophagectomy. Informed recommendations about therapy and appropriate information regarding prognosis depend on our clinical staging tools, and these can only approximate the disease stage.¹¹

Optimal clinical staging for this disease should include at least computed tomography (CT) of the chest and abdomen, endoscopic ultrasonography, and, if appropriate, a positron emission tomographic (PET) scan.^{12 13}

The importance of CT stems from its ability to assess for the presence of metastatic disease (M; Table 1) and the extent of direct invasion of local structures such as the aorta or major airways, any of which precludes surgical intervention. The technique should use both oral and intravenous contrast, and should include cuts from the thoracic inlet down to the midabdomen. It must be noted, however, that CT is not very accurate in assessing the histologic depth of the tumor (T), nor is it sensitive in assigning lymph node status (N). In fact, the overall accuracy of CT in nodal detection is less than 60%.¹⁴

PET scan with 18-fluorodeoxyglucose has been recently incorporated into the staging evaluation of esophageal cancer. This noninvasive test is more sensitive than CT for detecting distant metastases. Recent studies have suggested that PET scanning can detect metastatic disease in 15% of patients who were thought, on the basis of conventional diagnostic techniques, to have localized esophageal cancer.¹⁵ The superimposition of CT and PET scans is even more sensitive in identifying patients with occult metastases.

Endoscopic ultrasonography has proven very useful in assessing the local depth of the tumor (T), lymph node involvement (N), and, with increased clinical experience, involvement of nonregional (M1a) lymph nodes. The overall accuracy of endoscopic ultrasonography in tumor depth assignment is about 80% and improves with more advanced stages of disease. With stringent criteria, the accuracy of detecting lymph node involvement approaches almost 75%. This accuracy can be improved further by endoscopic fine-needle aspiration of suspicious lymph nodes, which allows pathologic confirmation of involvement.¹⁶

After the clinical disease stage is established, it also becomes important to assess the cardiopulmonary fitness and medical suitability of patients before surgical resection can be undertaken.

THERAPY OUTCOMES

Historically, esophageal cancer has carried a very dismal prognosis. This has been attributed to the late presentation of patients with this disease and the technical difficulty of an adequate surgical resection in the presence of advanced local and regional involvement. Furthermore, high-dose, definitive, radiation therapy, as an alternative to surgical resection, is challenging because of the anatomic location of the esophagus. Any radiation therapy portal encompassing the esophagus will also include other vital structures, such as major blood vessels, major airways, heart, and lungs. Although modern radiation techniques have fewer adverse side effects, toxicity is still common with the radiation doses required. The frequent medical comorbidities and the high incidence of second malignancies in these patients also affect the overall treatment success. Two historical reviews of the outcomes after esophageal cancer treatment, published in 1980, demonstrated this very clearly. The overall 5-year survival was 4% after surgical resection, with an unacceptable surgical mortality rate of almost 30%. The overall 5-year survival was only 6% after radiation therapy.^{17 18}

Surgical results have improved significantly over recent years, however. Multiple surgical series from major medical centers now report that patients undergoing surgery alone have a median survival between 13 and 19 months, 2-year survival rates between 35% and 42%, and 5-year survival rates of 15% to 24%.¹⁹ Although these numbers are certainly more promising, they can hardly be characterized as a medical success story, especially when we keep in mind that much of this improvement is due to better clinical staging and better patient selection.

The goal of oncologic surgery for this disease is the resection of the primary tumor and draining lymph nodes. Given the propensity for submucosal skip lesions in the esophagus, this usually requires a subtotal esophagectomy, using either a transthoracic or a transhiatal approach. The transhiatal approach requires a laparotomy, blunt dissection of the thoracic esophagus, and esophagogastric anastomosis in the neck. This approach saves the patient the cardiopulmonary complications of a thoracotomy, but no prospective clinical trials have demonstrated superiority of this procedure over a thoracoabdominal approach.²⁰ In patients with tumors of the gastroesophageal junction and significant gastric involvement, a total gastrectomy and Roux-en-Y esophagojejunostomy may be required.

Radiation therapy has been used in the past as a single-modality approach with curative intent. However, except for those with very early-stage disease, radiation has had very little impact on long term survival.²¹ For more advanced disease, single-modality radiation therapy should, in general, be considered a palliative intervention in patients whose underlying medical comorbidities preclude either surgical resection or aggressive multimodality treatment.

Multimodality treatment approaches have evolved over recent years in response to the frequent locoregional and distant recurrences identified after surgery or radiation therapy alone. Several different combinations and sequences of treatment modalities have been tried, with mixed results.

Chemotherapy has been given either preoperatively, postoperatively, or both. A cisplatin-based regimen is often used. Preoperative chemotherapy has been studied in several randomized clinical trials that compared surgery alone with chemotherapy followed by surgery. These studies demonstrated that induction chemotherapy can produce up to a 50% clinical response rate but less than a 10% pathologic complete response rate, and that the 2-year survival after subsequent surgery is approximately 35%. However, the results of these studies have been mixed, and no clear survival advantage has been identified with the induction regimens.²²

More-intensive multimodality approaches have attempted to exploit the radiosensitizing properties of chemotherapy by using concurrent cisplatin-based chemotherapy and radiation as either definitive treatment or as a preoperative adjuvant. In 1992, Herskovic et al ²¹ reported a phase 3 prospective, randomized trial that compared chemotherapy given concurrently with radiation to radiation therapy alone. Surgery was not a planned part of disease management in this trial. A clear survival benefit for the combined approach was identified, with a 5-year survival of 25% compared with radiation therapy alone, which produced no long-term survivors.²¹ How this approach can be integrated with surgery has remained unclear, however.

Three small phase 3 trials have randomized patients to either surgery alone or to preoperative concurrent chemoradiation followed by surgery. Unfortunately, the results have been conflicting, with no consistent survival advantage identified for one approach or another. It is of note, however, that 25% to 30% of patients treated in this fashion achieved a pathologic complete response after concurrent chemoradiation therapy. For obvious reasons, this trimodality approach produces considerable toxicity, with some series reporting treatment-related mortality in excess of 12%.²³

Patients with metastatic disease are treated with palliative intent. Palliation should first be directed toward relief of dysphagia and esophageal obstruction. This can be achieved in several ways, including palliative radiation, endoscopic dilatation, endoscopic stenting, endoscopic laser therapy, or other light-based therapy (eg, photodynamic therapy).²⁴ Palliative chemotherapy has only a limited role in this setting and only a marginal impact on survival. Current efforts are directed toward developing targeted therapies that may prove more active in esophageal cancer.

Return to Medicine Index

REFERENCES

Disclaimer

Ahmed Absi, MD

Department of Hematology & Medical Oncology

David J.
Adelstein, MD

Department of Hematology & Medical Oncology

Print Chapter

Introduction

Definition

Prevalence

Pathophysiology

Signs & Symptoms

Diagnosis

Therapy Outcomes

References

National Guidelines

Ahmed Absi, MD

Department of Hematology & Medical Oncology

David J. Adelstein, MD

Department of Hematology & Medical Oncology

National Guidelines

David J.
Adelstein, MD