Candidal esophagitis
Candida, a yeast that is part of normal oropharyngeal flora, is the most frequent cause of esophageal infections in immuno-compromised patients. Most cases of candidal esophagitis are caused by C. albicans, although other candidal species, such as C. tropicalis and C. glabrata, occasionally infect the esophagus. Approximately 85% of patients with candidal esophagitis have oral thrush, and the combination of oral thrush and esophageal symptoms has a high positive predictive value for candidal esophagitis.
Typically, endoscopic evaluation of patients with candidal esophagitis reveals raised, white plaques that resemble cottage cheese clinging to the esophageal mucosa. On barium swallow, coating of the raised plaques and their interstices with barium gives the esophageal mucosa a characteristic irregular, shaggy appearance. Confirmation of the diagnosis requires the demonstration of budding yeast cells, hyphae, or pseudohyphae in brush cytology or biopsy specimens of the esophagus.
Several antifungal agents are available for the treatment of Candida infections. The decision regarding which agent to choose is influenced principally by the severity of the infection and the severity of the patient’s immunocompromise. A patient who has a mild esophageal infection and minimal im-munocompromise (e.g., a young patient who develops mild candidal esophagitis during a limited course of steroid therapy for asthma) often can be treated effectively with a topical anti-fungal agent such as clotrimazole. In contrast, a patient with moderately severe candidal esophagitis and substantial im-munocompromise (e.g., a patient with troublesome odynopha-gia and AIDS) usually requires the oral administration of a systemic antifungal agent such as fluconazole. Patients who have severe infection and profound immunocompromise (e.g., disseminated candidiasis or candidal esophagitis in the setting of severe granulocytopenia) generally require treatment with intravenous amphotericin B [see 7:XXXVIII Mycotic Infections in the Compromised Host].
Herpes simplex virus esophagitis
Primary HSV infections of the oropharynx are common in the general population, and they result when oral mucous membranes or breaks in the facial skin are exposed to secretions from a person with an active HSV infection. The virus enters the nerves that supply the infected epithelium, where it remains in latent form after healing of the primary infection. The latent virus in the neurons can be reactivated and spread to epithelial cells through the nerve fibers. In immunocompetent persons, HSV reactivation commonly causes cold sores of the lips (herpes labialis). When reactivation of latent virus occurs in the setting of immunodeficiency, however, HSV can spread to involve the squamous epithelium of the oropharynx and esophagus.
The endoscopic findings in persons with HSV esophagitis vary with the duration of infection.72 The earliest lesions are small (1 to 3 mm), rounded vesicles that usually involve the middle to distal esophagus. Sloughing of the vesicles results in small, sharply demarcated ulcers that have raised margins and a yellowish base. In severe cases, the small ulcers coalesce to form large ulcers that can be covered with dense exudates resembling candidal plaques.
Histologic diagnosis is best accomplished by examining biopsy and brush cytology specimens from the squamous epithelium at the edges of ulcerated areas. Specimens obtained from the ulcer base often contain only nonspecific granulation tissue and exudates. Typical histologic changes in HSV infection include multinucleated giant cells and intranuclear Cowdry type A inclusion bodies.
In immunocompetent patients, HSV esophagitis usually is a short-lived illness that may require no therapy other than supportive care and expectant management. HSV esophagitis often does not resolve spontaneously in immunocompromised patients, however, so such patients should receive systemic antiviral therapy. Acyclovir currently is the drug of choice for HSV infections of the esophagus.
Cytomegalovirus esophagitis
CMV is a ubiquitous herpesvirus that usually is transmitted from person to person by exposure to infected secretions. The virus can also be transmitted through transfused blood that carries infected leukocytes or through transplanted infected organs. CMV can infect virtually any tissue in the body, and after recovery from the primary infection, evidence of latent CMV infection can be found in most organs. With the development of immunodeficiency, the latent virus can reactivate and cause esophagitis.73 Immunocompromised patients can also develop CMV esophagitis during primary CMV infections. CMV esoph-agitis is extremely uncommon in immunocompetent persons.
Patients who have CMV esophagitis often have widespread CMV infection, with systemic symptoms such as fever, weight loss, nausea, vomiting, and diarrhea. CMV tends to cause discrete, shallow esophageal ulcerations that are very elongated (up to 15 cm in length) and surrounded by normal-appearing esophageal mucosa. Tissue sampling for histologic examination and culture is necessary to distinguish these giant CMV ul-cerations from the giant idiopathic esophageal ulcerations that can be associated with HIV infection.
Histologic examination of cells infected with CMV reveals distinctive abnormalities that include cellular enlargement and inclusion bodies in both the nucleus and the cytoplasm. Although the virus is found most often in fibroblasts and endothe-lial cells, biopsy specimens from granulation tissue in the base of the esophageal ulcer have a higher yield on histology and culture than specimens from squamous epithelial cells at the edges of the ulcer. Unfortunately, no single test for CMV infection is highly sensitive. In a study of 14 bone marrow transplant recipients who developed CMV disease, for example, conventional and centrifugation cultures of endoscopic biopsy specimens identified the organism in only 57% of patients, and conventional histologic examination of the specimens revealed characteristic findings in only 30%.74 For patients with negative test results, therefore, repeated diagnostic testing may be necessary if the suspicion of CMV infection is high. However, evidence of CMV infection is not proof of the presence of CMV disease. The mere identification of CMV in an inflamed esophagus does not establish that CMV is the cause of the inflammation.
CMV disease can respond to treatment with ganciclovir. Maintenance therapy with ganciclovir may be indicated for patients who have recurrences of CMV disease or who have a high risk of recurrence (e.g., patients with advanced AIDS). Prophylactic antiviral therapy is commonly recommended for recipients of solid-organ and bone marrow transplants.
Esophageal disease in hiv infection
Within 2 to 3 weeks after primary exposure to HIV, some patients develop a self-limited, infectious mononucleosis-like illness with malaise, fever, myalgias, pharyngitis, and rash. This acute HIV seroconversion syndrome can be complicated by the development of esophageal ulcerations that cause odynopha-gia.75 Endoscopically, the ulcers are typically multiple, round, 3 to 15 mm in diameter, well demarcated, and surrounded by normal-appearing esophageal mucosa. Usually, the ulcers heal and the symptoms of the acute HIV seroconversion syndrome resolve spontaneously within 2 weeks. Patients then may remain asymptomatic for years until the development of AIDS.
Symptoms of esophageal disease occur in 30% to 40% of AIDS patients.76 Although the symptoms are usually from infections with Candida, HSV, or CMV, these patients can also have large esophageal ulcerations in which no pathogenic microorganism can be identified by culture or by histologic and immunohistochemical tests. Radiographically and endoscopi-cally, HIV-associated idiopathic ulcerations of the esophagus closely resemble the large esophageal ulcerations caused by CMV. HIV-associated idiopathic esophageal ulcerations can be found in approximately 10% of patients with AIDS who complain of esophageal symptoms and in up to 40% of such patients who have discrete esophageal ulcerations on endoscopic examination.
HIV-associated idiopathic ulcerations generally do not respond to therapy with antimicrobial agents. Rather, patients with these lesions usually experience symptomatic relief and ulcer healing during treatment with systemic corticosteroids. Al though corticosteroid therapy entails substantial risk for patients who already are profoundly immunosuppressed, the treatment is surprisingly well tolerated in most cases. The injection of methylprednisolone through the endoscope directly into idio-pathic ulcerations also has resulted in relief of esophageal symptoms in some cases, but experience with this treatment is limited. Finally, thalidomide, which has immunomodulatory effects, has been used successfully to treat idiopathic ulcerations.
Candida is by far the most common cause of esophageal infection in AIDS, and candidal esophagitis is found in more than 50% of AIDS patients who have esophageal symptoms. Although CMV and HSV esophagitis also occur commonly in AIDS patients, these viruses often are not the sole pathogens that can be identified in the inflamed esophagus. CMV usually is discovered in biopsy specimens from an esophagus that is also infected by Candida, and most patients with coexistent CMV and candidal esophagitis respond well to antifungal therapy alone. Consequently, authorities have recommended that patients with AIDS who have esophageal symptoms should be treated empirically with antifungal therapy, usually flucona-zole; endoscopy is reserved for patients who fail to respond to empirical treatment.
Esophageal Cancer
Epidemiology
The two major histologic types of esophageal cancer, squa-mous cell carcinoma and adenocarcinoma, differ profoundly in their epidemiologic features.Squamous cell carcinoma of the esophagus has a strong predilection for blacks and Asians, whereas esophageal adenocarcinoma is predominantly a disease of whites. In the United States, the incidence of squamous cell carcinoma of the esophagus is six times greater in African Americans than in whites, whereas esophageal adenocarcino-ma is at least four times more frequent in whites than in African Americans. Worldwide, more than 90% of all esophageal cancers are squamous cell carcinomas; this tumor ranks among the world’s 10 most frequent malignancies. Exceptionally high incidence rates of squamous cell carcinoma are found in the Transkei region of South Africa, in southern Brazil, in parts of northern France and Italy, and throughout an esophageal cancer belt that extends from the shores of the Caspian Sea of Iran across northern China. In the Henan province of China, the incidence of esophageal squamous cell carcinoma exceeds 100 per 100,000. In the United States, in contrast, the incidence of this tumor in the general population is less than 4 per 100,000. In most countries, cancer of the esophagus affects men two to four times more often than women.
Risk factors
GERD and Barrett esophagus are the major risk factors for adenocarcinoma of the esophagus.70 For squamous cell carcinoma, cigarette smoking and alcoholism are the major risk fac-tors.78 The combination of cigarette smoking and alcoholism appears to have a synergistic (rather than merely additive) effect in esophageal carcinogenesis, but the mechanism of this synergy is not known. Generalized malnutrition and a variety of specific nutritional deficiencies, including deficiencies in vitamin A, vitamin C, magnesium, selenium, and zinc, have been associated with squamous cell carcinoma. In contrast, obesity is a risk factor for adenocarcinoma. Carcinogens such as N-ni-troso compounds can be formed from the nitrates and amines in pickled vegetables and cured meats, and ingestion of these foods has been linked to esophageal cancer. Regional practices such as opium smoking and the long-term ingestion of very hot foods and beverages may contribute to the pathogenesis of squamous cell cancers. Also, some high-incidence areas for squamous cell carcinoma have soils that are deficient in certain elements, such as molybdenum and zinc.
Local differences in endemic microflora have been proposed as underlying reasons for some of the regional variations in the incidence of esophageal squamous cell carcinoma. For example, the food and water in some high-incidence areas are contaminated with fungi and bacteria that promote the formation of N-nitroso compounds from dietary nitrates. The human pa-pillomavirus (HPV) can infect squamous epithelial cells, and HPV infection has been implicated in the development of squa-mous cell carcinoma of the esophagus. In high-incidence regions for esophageal cancer, such as China and South Africa, researchers have found HPV DNA in more than 20% of squa-mous cell carcinomas. In low-incidence areas, such as the United States, however, esophageal tumors generally do not show evidence of HPV infection.
A number of medical conditions predispose to the development of esophageal squamous cell carcinoma. Patients with ty-losis, a rare heritable disorder characterized by hyperkeratosis of the palms and soles, are at very high risk for development of the esophageal tumor. These patients have mutations in the ty-losis esophageal cancer gene, a putative tumor suppressor gene located on the long arm of chromosome 17. Achalasia, lye stricture of the esophagus, and Plummer-Vinson, or Paterson-Kelly, syndrome also are risk factors for squamous cell cancers, perhaps because these conditions are associated with stasis of esophageal contents that leads to chronic inflammation of the mucosa. Squamous cell cancer of the esophagus is strongly associated with malignancies of the head, neck, and lungs, probably because these tumors share the strong risk factor of cigarette smoking. Finally, celiac sprue has been associated with esophageal cancer, for reasons that are not clear.
Diagnosis
Clinical Features
Most patients with cancer of the esophagus present with dysphagia and weight loss. The dysphagia usually involves solid foods only and progresses rapidly in severity (over a period of weeks to months). Approximately 60% of patients who have esophageal adenocarcinoma have a long-standing history of GERD symptoms. Proximal esophageal tumors can invade the recurrent laryngeal nerve, causing vocal cord paralysis with hoarseness. The development of coughing associated with swallowing may indicate that the tumor has invaded the airway and caused an esophagobronchial fistula. Ulcerated tumors can cause odynophagia, and tumor necrosis occasionally causes esophageal hemorrhage. Local tumor invasion can cause chest pain, and metastatic disease can cause bone pain. Symptoms of esophageal cancer generally develop only when the tumor has grown to the extent that it has narrowed the lumen of the esophagus substantially, has invaded local structures, or has metastasized. Therefore, the presence of symptoms usually indicates advanced disease and a poor prognosis.
Figure 8 Barium swallow showing an extensive cancer of the esophagus.
Diagnostic Studies
Barium swallow and endoscopy Both barium swallow and endoscopy are useful for the evaluation of patients with esophageal cancer. Radiographic features that suggest malignancy include irregular borders and sharp angles [see Figure 8]. Endoscopically, esophageal cancers typically appear as nodular lesions that protrude into the lumen of the esophagus [see Figure 9]. In Asian countries where there is a high incidence of esophageal cancer, endoscopists often recognize early esopha-geal cancers that cause either slight elevations or shallow depressions in the mucosal surface. Staining of the esophagus with vital dyes such as toluidine blue or Lugol iodine (chro-moendoscopy) can be useful for finding such early lesions during endoscopic evaluation. These superficial esophageal cancers are diagnosed infrequently in western countries.
Imaging studies Computed tomography of the chest and abdomen generally is recommended to assess the extent of disease within the chest and to look for metastases. However, the sensitivity and specificity of CT for determining the depth of esophageal tumor penetration (the T level) and the presence of regional lymph node metastases (the N status) are poor. Endo-scopic ultrasonography (EUS) is superior to CT in this regard, accurately predicting the T level and N status in 70% to 80% of patients.
Invasive modalities In addition to EUS, invasive diagnostic modalities sometimes used for the staging of esophageal cancer include bronchoscopy, laparoscopy, thoracotomy, and thoracoscopy. There is little consensus regarding the need for these procedures in the routine evaluation of patients with esophageal cancer, and usage of the procedures varies widely among different institutions.
Management
Cancer of the esophagus usually is disseminated at the time of diagnosis, and because there is no treatment that reliably eradicates metastatic disease, cure is not possible in most cases. Furthermore, patients are often elderly, and many have severe comorbidities (e.g., malnutrition or pulmonary, cardiac, or liver disease) that further limit their treatment options. Initial treatment usually involves a choice between surgery, radiation therapy, chemotherapy, and some combination of these three modalities.79,80 Squamous cell cancer and adenocarcinoma are treated similarly, with similarly poor survival rates. Despite recent advances in therapeutic options, overall cure rates for cancer of the esophagus remain below 10%.
Surgical therapy Esophagectomy, with or without lymph-adenectomy, can provide immediate palliation of symptoms and, arguably, the best potential for cure of esophageal cancer. Mortality for esophagectomy ranges from 3% to more than 12%, and serious complications of the operation (e.g., pneumonia, atelectasis, arrhythmias, myocardial infarction, heart failure, wound infections, and anastomotic leaks) can be expected in 30% to 50% of patients. Cure rates vary widely among institutions. Prognostic factors include tumor stage and the number of positive lymph nodes. Surgery generally is not recommended for patients who have metastatic disease.
Radiation therapy The acute mortality of radiation therapy is low, and radiation can cover a wider treatment area than is practical with surgery (to eradicate local and regional disease). However, radiation therapy usually takes 2 to 8 weeks to complete; palliation can be delayed for weeks; there can be substantial radiation damage to surrounding normal tissues; and the overall cure rate is low. Trials of radiation therapy as the sole treatment modality for esophageal cancer have involved primarily patients with advanced squamous cell carcinomas that were deemed unresectable. Results appear to be comparable to surgery, but there are no randomized trials directly comparing radiation therapy alone with surgery alone.
Figure 9 Endoscopic photograph of an esophageal adenocarcinoma.
Figure 10 Management of patients with cancer of the esophagus. (CRT—chemoradiotherapy)
Chemotherapy Chemotherapy has the potential to reach the disseminated disease that usually is present in symptomatic patients. Unfortunately, chemotherapy is associated with substantial morbidity and considerable mortality; it is often ineffective; and the tumor response, if any, is often brief. Studies of chemotherapy as the sole treatment modality have included primarily patients with unresectable tumors. Modern studies have used cisplatin-based regimens, and response rates appear to be better with combination regimens than with single agents. Chemotherapy alone does not appear to improve survival, however.
A number of studies have explored the role of radiation therapy or chemotherapy used either before (neoadjuvant) or after (adjuvant) definitive surgery for squamous cell carcinoma of the esophagus. Unfortunately, most randomized, controlled trials have shown no convincing benefit for neoadjuvant or adjuvant treatment with either radiation therapy or chemotherapy for patients with potentially resectable tumors. One recent trial showed a modest survival benefit for patients who received preoperative chemotherapy in a relatively low dose, however.80
Combination therapy Much recent interest has focused on the role of combining chemotherapy with radiation therapy (chemoradiotherapy) for esophageal cancer.81 In some studies of patients treated with chemoradiotherapy followed by esophagectomy, complete histologic response (defined as no histologic evidence of tumor in the resected specimen) has been observed in almost 30% of cases. Complete histologic response is not tantamount to cure, however, and even complete responders frequently succumb to recurrent disease. Furthermore, chemoradiotherapy is associated with serious toxicity. Some randomized trials of chemoradiotherapy for patients with potentially resectable tumors have shown significant improvements in survival, whereas others have not. Consequently, the role of chemoradiotherapy remains unclear. Preliminary studies suggest that patients who have locally advanced tumors might benefit from preoperative chemoradiotherapy.
Palliative therapy Purely palliative therapies include esophageal dilatation and the placement of intraluminal stents. There also are palliative techniques designed to ablate the portion of the neoplasm that obstructs the esophageal lumen. These ablative therapies include endoscopic laser irradiation, the application of tumor probes that burn the neoplasm directly, the injection of caustic chemicals directly into the tumor body, and photodynamic therapy that uses photochemical energy to destroy the tumor.
Given that the optimal treatment for cancer of the esophagus is not clear, patients should be treated according to well-designed, established research protocols whenever possible. If the initial use of research protocols is not feasible, management should be individualized [see Figure 10]. After staging of the tumor that includes at least EUS and a CT scan of the chest and abdomen, the next step is to decide whether the patient is fit enough to undergo surgery. If surgery is not a viable option because of advanced age or comorbidity, primary therapy might include chemoradiation or supportive care alone. In general, surgery is not indicated for patients with metastatic disease. For tumors that do not invade beyond the muscularis propria and do not involve local lymph nodes, surgery appears to offer the best hope for cure. For lesions that are more advanced (i.e., with lymph node involvement or invasion to the esophageal adventitia and beyond), the choices for primary therapy include chemoradiation with or without surgery.
If these primary treatments fail or if the tumor recurs, there are a number of palliative treatment options. For patients who are severely debilitated and have advanced disease, the most humane option may be supportive care only, with careful attention to pain control. If there are no apparent metastases and complete excision of the tumor is possible, surgery can be considered for palliation. The other options are ablative therapies or stents. Stents may not provide good palliation for patients with proximal tumors, bleeding tumors, and necrotic tumors; ablative therapy may be preferable in these circumstances. Alternatively, ablative therapy has little to offer for a patient with an esophagobronchial fistula or for a patient with a tumor that is extrinsic or infiltrative. Also, ablative therapy may be difficult and time-consuming for patients with very long tumors. Stenting may be preferable in these circumstances.
