128 - Endoscopy of the Esophagus
Editors: Shields, Thomas W.; LoCicero, Joseph; Ponn, Ronald B.; Rusch, Valerie W.
Title: General Thoracic Surgery, 6th Edition
Copyright 2005 Lippincott Williams & Wilkins
> Table of Contents > Volume II > The Esophagus > Section XXIV - Malignant Lesions of the Esophagus > Chapter 150 - Carcinoma of the Esophagus
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Chapter 150
Carcinoma of the Esophagus
Jules Lin
Shahab A. Akhter
Mark D. Iannettoni
Many features of esophageal neoplasms have remained constant for several decades. Most tumors are malignant, and the usual presenting symptom is dysphagia. Although surgical resection offers the best chance for cure, most patients who present with symptoms already have systemic disease that is incurable. There are also important new issues to consider. Esophageal cancer is no longer synonymous with squamous cell carcinoma. Adenocarcinoma of the esophagus and the gastroesophageal junction are now more frequent in the United States and represent the fastest growing solid malignancy. The estimated incidence of esophageal cancer in the United States for 2002 was 13,100 with about 12,600 cancer-related deaths according to Jemal and associates (2002). The most important prognostic factor for esophageal cancer remains the stage of disease at the time of diagnosis. Currently, the best strategy for improving survival is early diagnosis. As the molecular biology of esophageal cancer is better understood, novel diagnostic, therapeutic, and prognostic modalities will be developed. The aim of this chapter is to provide an overview of squamous cell carcinoma and adenocarcinoma of the esophagus.
SQUAMOUS CELL CARCINOMA OF THE ESOPHAGUS
Epidemiology
In the United States, the overall annual incidence of squamous cell carcinoma is 2.6 per 100,000 according to Yang and Davis (1988) and is shown in Fig. 150-1 for the years 1977 to 1996. The age-specific rates are extremely low in persons younger than 40 years of age and continue to rise with each decade of life. The incidence of esophageal cancer varies among different racial groups and is four to five times higher in African Americans than Caucasians and has become the second most common malignancy among African-American men younger than 55, as noted by Blot and Fraumeni (1987). Age-adjusted mortality for squamous cell carcinoma has remained relatively stable among Caucasians, whereas the rate in African Americans has nearly doubled over the same 30-year period. Yang and Davis (1988) and Chalasani and associates (1998) found that regardless of race, men are affected three to four times as often as women. Mason and colleagues (2001) note that the overall 5-year survival rate of about 5% may be slightly improving.
Ribeiro and associates (1996) found geographic and cultural variations in the incidence of squamous cell carcinoma of the esophagus suggesting that environmental exposure is causally important. Regions with a high incidence are generally located in poorer parts of the world. In China, where about 60% of the world's cases occur annually, the incidence is clustered into sharply demarcated geographic areas. In Central Asia, Day (1984) described an esophageal cancer belt extending from northern Sinkiang through the former Soviet republics of Kazakhstan, Uzbekistan, and Turkmenistan and including northern Afghanistan and northeastern Iran. High rates have also been noted in the Indian subcontinent, and intermediate to high rates exist in the Caribbean and portions of Latin America, as reported by Vassallo and co-workers (1985). In the United States, where the disease is relatively uncommon, Fraumeni and Blot (1977) found that urban African-American men seem particularly affected, especially in Washington, D.C., and coastal South Carolina. Marked regional clustering has also been reported by Lanier and associates (1985) among Alaskan natives.
Etiology
Nutrition
Worldwide, nutritional deficiencies have been implicated in the pathogenesis of esophageal squamous cell carcinoma, along with a number of other etiological factors listed in Table 150-1. Low levels of retinol, riboflavin, ascorbic acid, and -tocopherol are prevalent in the population of Linxian, China, where esophageal cancer is endemic,
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as noted by Yang and Davis (1988). Diets low in fruits, particularly citrus, and low vitamin C intake have been repeatedly associated with an increased risk for esophageal cancer according to Guo and colleagues (1990). Deficiencies in various mineral elements, such as selenium, zinc, and molybdenum, have also been cited by Jaskiewicz (1988) and Burrell (1966) and their co-workers as possible etiologic factors. Ziegler and associates (1981) also found poor nutrition to be a risk factor for esophageal cancer among African-American men in Washington, D.C., although no specific micronutrient deficiency was identified. These deficiencies are believed to make one more susceptible to the carcinogenic effects of exogenous factors.
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Fig. 150-1. A. Age-adjusted incidence rates per 100,000 population in the United States from the Surveillance, Epidemiology, and End Results Program of the National Cancer Institute between 1977 and 1996 for esophageal squamous cell carcinoma (circles), carcinoma of the gastric cardia (triangles), gastric cancer (squares), and esophageal adenocarcinoma (stars). B. Age distribution of patients diagnosed with esophageal adenocarcinoma between 1977 and 1981 (white bars) and 1992 and 1996 (black bars) in the United States. C. Age-adjusted incidence of esophageal adenocarcinoma by gender and ethnicity for Caucasian men (white bars) and women (black bars) and African American men (light gray bars) and women (dark gray bars). D. Trends in the stage of esophageal adenocarcinoma. (Light gray, unstaged; black, distant; white, regional; dark gray, in situ). From El-Serag HB: The epidemic of esophageal adenocarcinoma. Gastroenterol Clin N Am 31:422, 2002. With permission. |
Table 150-1. Etiologic Factors in Squamous Cell Carcinoma of the Esophagus | |
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Environmental Carcinogens
Nitrates and nitrites can be converted within the body to carcinogenic N-nitrosamines and are suspected etiologic factors in the development of esophageal cancer. Low molybdenum levels in the soil may cause higher nitrate and nitrite levels in plants because molybdenum functions as a cofactor for the plant enzyme nitrate reductase, as noted by Burrell and colleagues (1966). Citrus fruits and vitamin C, on the other hand, may inhibit endogenous nitrosation and reduce the risk for esophageal squamous cell carcinoma according to Lu and co-workers (1986). Amer and associates (1990) found a correlation between the high prevalence of esophageal cancer in the Gassim region in Saudi Arabia and contamination of water by impurities such as petroleum.
Alcohol and Tobacco
Numerous studies have linked alcohol and tobxacco use with the development of esophageal cancer in Western countries, including those by Ziegler (1986), Notani (1988), and
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Yu (1988) and co-workers. Ziegler (1986) found that ethanol is associated with nearly 80% of the neoplasms among esophageal cancer patients, and the relative risk increases with the amount of alcohol consumed. There is also an association between increasing alcohol consumption and poor nutrition. The risks associated with tobacco use appear to increase with the number of cigarettes smoked per day, duration of smoking, and tar content. Opium smoking may also produce potentially carcinogenic substances by pyrolysis and has been implicated by Ghadirian and associates (1985) in the etiology of esophageal cancer in northern Iran. Ex-smokers have a reduced risk, and after 10 years, their risk returns to baseline. A synergistic effect of alcohol consumption and tobacco use has been reported by Notani (1988). Among well-nourished North American and European men who do not smoke or consume alcohol, esophageal squamous cell carcinoma is virtually nonexistent according to Day (1984).
Achalasia
Achalasia also appears to be a risk factor for the development of esophageal cancer, with a prevalence of about 3% to 6%. The average duration between symptoms and detection of esophageal carcinoma is 17 years, and esophageal cancer occurs at an earlier age in patients with achalasia when compared with the remainder of the population according to Carter and Brewer (1975). In patients treated with dilation or esophagomyotomy, Wychulis and co-workers (1971) found that esophageal cancer developed at a rate only slightly higher than that for the general population. Current clinical guidelines of the American Society for Gastrointestinal Endoscopy (1998) suggest endoscopic surveillance for untreated patients with achalasia.
Caustic Injury
It has been estimated by Isolauri and Markkula (1989) that the incidence of esophageal cancer among patients with a history of caustic ingestion is 1,000-fold greater than that of the general population. Squamous cell carcinoma is the most common subtype and typically occurs in the middle third of the esophagus at the level of the tracheal bifurcation according to Iyomasa and colleagues (1990). Most cases present four to five decades after the initial injury and 10 to 20 years earlier than in the general population as reported by Appelqvist and Salmo (1980). Carcinoma should be suspected with any change in the ability to dilate a chronic stricture or in the presence of increasing dysphagia.
Scarring of the esophagus may actually alter the natural history of the esophageal cancer. Because the lumen is less distensible, dysphagia is more likely to present earlier in the course of the disease. In addition, damage to submucosal lymphatics and the presence of dense scar tissue within the esophageal wall may limit lymphatic spread according to Lansing and co-workers (1969).
Genetic Factors
The molecular biology of esophageal cancer is an area of active research. Much research has centered around p53, a tumor suppressor gene important in cell cycle control, DNA repair and synthesis, genomic stability, and apoptosis. Mutations in p53 and allelic losses are common abnormalities in many human neoplasms. Wang and colleagues (1996) found p53 mutations in the early stages of human esophageal carcinogenesis and postulated that independent somatic mutations in different regions of the esophagus might be key molecular events in multifocal esophageal carcinogenesis. Chaves and co-workers (1997) found p53 in 57% of esophageal cancer patients, whereas Safatle-Ribeiro and associates (2000) reported increased p53 levels in all patients with dysplasia. Mutant p53 protein expression was also increased in the nonmalignant mucosa of patients after gastrectomy (68%) and in patients with advanced achalasia (44%), two conditions considered to be risk factors for esophageal squamous cell carcinoma. Uchino and colleagues (1996) showed that mutant p53 overexpression correlated with poorer patient survival.
Tylosis, an autosomal dominant disorder characterized by hyperkeratosis of the palms and soles, appears to be the only well-documented genetic disorder associated with esophageal cancer, as noted by Schwindt and colleagues (1970). According to Howel-Evans and co-workers (1958), affected patients have an about 95% chance of developing cancer during their lifetime.
Miscellaneous
Esophageal cancer has also been associated with several other risk factors. Patients with a history of exposure to ionizing radiation, head and neck cancer, Plummer-Vinson syndrome, celiac disease, and thyroid disease have been reported by Shimizu (1990), Atabek (1990), Selby and Gallagher (1979), and Arnott (1971) and their associates to be at increased risk for developing esophageal squamous cell carcinoma. Ahsan and Neugut (1998) also found an increased risk for esophageal cancer among women who receive radiation for breast cancer.
Pathology
Macroscopic Features
Esophageal squamous cell carcinoma is most commonly located in the middle third of the thoracic esophagus and was the site of about 50% of squamous cell lesions reported by Postlethwait (1986). This region of the esophagus extends from the level of the carina to the inferior pulmonary veins. Thirty to 40% of lesions arise in the lower third of the esophagus, including the abdominal portion, whereas
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only 10% to 20% of squamous cell carcinomas occur in the upper esophagus.
The early stages of esophageal carcinoma are infrequently encountered in North America and Europe and are seen more commonly in China and other endemic areas where routine screening is practiced. The early lesions are generally small but may involve the entire circumference of the mucosa and appear as plaquelike, erosive, or papillary lesions, as shown in Fig. 150-2. Early cancers may also be occult with no grossly visible lesions and generally invade only the mucosa and submucosa, although the papillary type may invade the muscular wall of the esophagus.
Mannell (1982) described the more advanced lesions as fungating, ulcerative, or infiltrative tumors, as demonstrated in Fig. 150-3. Fungating lesions project into the lumen and appear as filling defects on barium swallow. These lesions may also present as flat plaques. Ulcerated lesions have regular or irregular everted edges with a deep base and associated infiltration of the esophageal wall. Infiltrative tumors are characterized by extensive intramural spread. A desmoplastic response is usually present and can produce a tight esophageal stricture. Occasionally, tumor spread is only superficial, resulting in the superficial spreading type. Other investigators have used a variety of gross classification schemes. Akiyama and colleagues (1981) divided the various types into protuberant, ulcerative, superficial, exophytic, and miscellaneous types. Liu and Zhou (1984) classified squamous cell carcinomas into medullary, fungating, ulcerative, scirrhous,
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and intraluminal lesions. Descriptions of the different types overlap, but the extent of invasion and the presence or absence of lymph node metastases are the critical features that determine patient prognosis.
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Fig. 150-2. Early esophageal carcinoma. A. Erosive type. B. Plaquelike type. C. Papillary type. From Liu FS, Zhou CN: Pathology of carcinoma of the esophagus. In Huang GJ, Wu YK (eds): Carcinoma of the Esophagus and Gastric Cardia. Berlin: Springer, 1984, pp. 80, 82. With permission. |
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Fig. 150-3. Late esophageal carcinoma. A. Scirrhous type. B. Medullary type. C. Fungating type. From Liu FS, Zhou CN: Pathology of carcinoma of the esophagus. In Huang GJ, Wu YK (eds): Carcinoma of the Esophagus and Gastric Cardia. Berlin: Springer, 1984, pp. 83 85. With permission. |
Microscopic Features
Early squamous cell carcinomas can be divided into intraepithelial, intramucosal, and submucosal tumors. Intraepithelial lesions are typical carcinoma in situ with an intact basement membrane. In intramucosal carcinomas, the tumor cells penetrate the basement membrane and infiltrate the lamina propria or part of the muscularis mucosa. Once the cells have penetrated the muscularis mucosa, the lesions are classified as submucosal carcinomas, as depicted in Fig. 150-4. In the more advanced stages of squamous cell carcinoma, there is invasion into or through the muscular layers of the esophagus and into the adventitia. The degree of tumor differentiation varies from well to poorly differentiated, with 60% of tumors being moderately differentiated.
Metastases
In the advanced pathologic stages of the disease, direct extension through the wall of the esophagus is common, as are lymphatic metastases. Akiyama and colleagues (1981) found lymphatic metastases in about 60% of patients undergoing esophagectomy. In an autopsy series, Mandard and associates (1981) reported lymphatic metastasis in 75%. Hematogenous spread was also common in autopsy specimens. Liu (1980) found an incidence of 63%, and Mandard and associates (1981) reported an incidence of 50%.
Intraesophageal Spread
Microscopically, most tumors have spread more extensively than their gross appearance would indicate. Wong (1987) noted the correlation between the proximal resection margin and the incidence of anastomotic recurrence as shown in Table 150-2. Microscopic spread distal to the gross tumor, for reasons that are unclear, extends for a shorter distance and has been reported by Burgess and associates (1951) to be about 4 cm from the tumor. Submucosal lymphatic spread occurs often and may result in tumor emboli producing satellite nodules, as described by Watanabe and associates (1979), with significant prognostic implications.
Table 150-2. Proximal Resection Margin and Anastomotic Recurrence | ||||||||||||||||||||||||
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Direct Extension
After penetration of the adventitial layers covering the esophagus, the tumor may invade adjacent structures, including the pleura, trachea, left main-stem bronchus, pericardium, great vessels, thoracic duct, and the anterior ligaments of the vertebral column. In the upper esophagus, the recurrent laryngeal nerves may also be involved, whereas in the lower esophagus, tumors may invade the diaphragm, stomach, and liver. However, Roberts (1980) noted at postmortem examination of untreated patients that the extent of invasion in one third of the tumors was restricted to the periesophageal tissues.
Lymphatic Spread
The direction of flow in the extensive lymphatic network of the esophagus is primarily longitudinal. Using lymphoscintigraphy, Tanabe and associates (1986) demonstrated that lymph
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from the upper third of the esophagus drains primarily to the upper mediastinum and neck, whereas lymph from the lower esophagus flows to the abdomen. However, despite the predominantly unidirectional flow seen normally, cervical, supraclavicular, and abdominal lymphadenopathy are seen in both upper and lower esophageal cancers.
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Fig. 150-4. Esophageal squamous carcinoma. A. In situ with an intact basement membrane. B. Submucosal carcinoma. C. Well-differentiated carcinoma with pearl formations. From Liu FS, Zhou CN: Pathology of carcinoma of the esophagus. In Huang GJ, Wu YK (eds): Carcinoma of the Esophagus and Gastric Cardia. Berlin: Springer, 1984, pp. 88, 90, 91. With permission. |
Table 150-3. Degree of Invasion and Lymph Node Status of 504 Resected Specimens of Esophageal Cancer | |||||||||||||||||||||||||||||||
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As shown in Table 150-3, the incidence of lymphatic metastases in surgical specimens ranges from 30% to 70% and is related to the depth of invasion of the primary tumor as reported by Lu and associates (1987). Postlethwait (1986) found supraclavicular nodal involvement in 6.9% based on a series of autopsy studies. In two smaller surgical series, Sannohe (1981) and Ide (1974) and their associates showed supraclavicular nodal involvement in about 19%. Kato and colleagues (1991) reported that 26% of patients who underwent resection of a carcinoma in the thoracic portion of the esophagus and bilateral cervical lymph node dissection had one or more involved cervical nodes. In contrast, spread below the diaphragm is more common. Akiyama and associates (1981) reported nodal metastases in the superior epigastrium in 31.8% of patients with tumors located in the cervical esophagus, 32.8% with tumors in the middle third, and 61.5% with tumors in the lower third of the esophagus, as depicted in Fig. 150-5. Ide and associates (1974) reported similar results.
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Fig. 150-5. Sites of lymph node metastases from esophageal squamous carcinoma. From Akiyama H, et al: Principles of surgical treatment for carcinoma of the esophagus: analysis of lymph node involvement. Ann Surg 194:438, 1981. With permission. |
Distant Metastatic Disease
Visceral metastases may be present in up to 30% of patients at the time of diagnosis and are manifestations of advanced disease. In an autopsy series by Mandard and associates (1981), 40% of the patients with well-differentiated squamous cell carcinoma of the esophagus had visceral metastases, and 87% of those with undifferentiated squamous cell carcinoma had widespread disease. Metastases were found in the lungs, liver, pleura, bone, kidneys, and adrenal glands in order of decreasing frequency. The nervous system was involved in 2.7% of specimens, excluding the undifferentiated tumors, and Anderson and Lad (1982) reported a 1% incidence of metastases to the brain.
ESOPHAGEAL ADENOCARCINOMA
Esophageal adenocarcinoma is the most rapidly increasing solid malignancy in the United States and is the seventh leading cause of cancer-related deaths according to Jemal and associates (2002). There were about 12,600 deaths from esophageal carcinoma in 2002. In the mid-1990s, adenocarcinoma overtook squamous cell carcinoma as the most common cancer of the esophagus in America, as reported by Blot (1993) and Devesa (1998) and their colleagues. Surgical resection remains the only chance for cure, and about 90% of those diagnosed ultimately die of their disease. Although there have been significant improvements in surgical technique and perioperative care, the prognosis remains poor, with an overall 5-year survival rate of only 5% to 12% according to Mason and associates (2001). However, new multimodality treatments, as well as novel diagnostic and prognostic techniques, are being developed, providing hope that survival rates will improve in the future.
Epidemiology
The incidence of esophageal adenocarcinoma has increased progressively since the 1970s. According to the Surveillance, Epidemiology, and End Results (SEER) study, the incidence has increased more than 350% from 0.7 per 100,000 between 1974 and 1976 to 2.5 per 100,000 between 1992 and 1996, as reported by Devesa and associates (1998) and El-Serag (2002) and depicted in Fig. 150-1. The reason for these increases is unclear. Although the use of diagnostic techniques such as endoscopy have increased, it is believed that there has been a true increase in incidence. According to Eloubeidi and co-workers (2002), the median age at diagnosis was 68 years among patients entered into the SEER database after 1988. Men are affected six to eight times more
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often than women, and Caucasians are affected three to four times as often as African Americans. Incidence rates are also higher in developed countries, and there may be geographic variations. According to SEER data from 1973 to 1998 analyzed by Kubo and Corley (2002), the incidence in Seattle was twice as high as in Utah, with an 800% increase versus 300%. Rates of esophageal adenocarcinoma were also significantly higher among African-American males in Connecticut at 3.1 per 100,000 versus 0.8 per 100,000 nationwide.
Etiology
Barrett's Metaplasia
In an autopsy study by Cameron and colleagues (1990), Barrett's metaplasia was found in 0.4% or 376 per 100,000 Caucasians, which is significantly higher than the clinically diagnosed prevalence of only 80 per 100,000. This suggests that most cases of Barrett's esophagus have not been diagnosed. According to Cameron (1997), there are about 3 million Americans with Barrett's metaplasia.
Barrett's mucosa is the precursor lesion to esophageal adenocarcinoma, as illustrated in Fig. 150-6, and the risk is increased 30 to 125 times the age-matched population with an incidence of one to two cancers per 100 patient-years according to Cameron (1985) and O'Connor (1999) and their colleagues. Esophageal adenocarcinoma develops in about 7% to 20% of patients with Barrett's metaplasia, as noted by Heitmiller (2001). Although Barrett's epithelium is seen in 24% to 64% of surgical specimens, its absence in the remaining specimens is believed by Hamilton (1988) and Sarr (1985) and their co-workers to indicate either overgrowth of the Barrett's mucosa by tumor or sampling errors.
On endoscopy, these lesions appear as red, velvety areas. In the past, Barrett's mucosa has been described as columnar epithelium extending more than 3 cm above the gastroesophageal junction and was originally believed to be congenital. However, short-segment Barrett's less than 3 cm above the gastroesophageal junction has been increasingly recognized as a risk factor for esophageal adenocarcinoma, and 35% of tumors arise in short-segment Barrett's according to Jankowski and co-workers (1999). Although there are three types of columnar epithelium, including the gastric fundic, gastric junctional, and intestinal type, only the intestinal type is associated with an increased risk of esophageal adenocarcinoma. As noted by Spechler and colleagues (1994), intestinal metaplasia is also seen in 15% of biopsy samples from below the squamocolumnar junction, and although the cancer risk appears low, it is not well documented.
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Fig. 150-6. Risk factors leading to esophageal adenocarcinoma. From El-Serag HB: The epidemic of esophageal adenocarcinoma. Gastroenterol Clin N Am 31:425, 2002. With permission. |
Barrett's esophagus appears to be an acquired condition resulting from chronic inflammation due to gastroesophageal reflux. Nebel (1976) and Locke (1997) and their colleagues reported that 18% of the U.S. population experiences heartburn once per week and that 7% have daily symptoms. At endoscopy for reflux, Barrett's mucosa was found in 12% to 18% of patients, as reported by Spechler (1994) and Winters (1987) and their co-workers. A large population study in Sweden by Lagergren and associates (1999b) revealed an odds ratio for esophageal adenocarcinoma of 7.7 for recurrent reflux and 44 for long-standing reflux. There may also be a hereditary component to gastroesophageal reflux, with first-degree relatives 2.2 to 4.8 times as likely to have reflux symptoms as noted by Romero (1997) and Trudgill (1999) and their colleagues.
Although the esophageal mucosa appears to be relatively resistant to acid except at high concentrations, Kauer and associates (1995) reported that mixed reflux with bile acids, pepsin, trypsin, gastric acid, and lysolecithin appears to be more harmful and has been implicated in mucosal injury, as depicted in Fig. 150-7. Although primary bile acids are not carcinogenic, Kobori and co-workers (1984) noted that secondary bile acids are potential carcinogens depending on the pH and conjugation status. Game and colleagues (1988) reported that 67% of patients with Barrett's metaplasia have duodenogastric reflux stained with bile.
Surveillance
Although there is no direct evidence supporting surveillance programs for Barrett's mucosa, indirect evidence is available. Esophageal adenocarcinoma is believed to have a 4- to 5-year preclinical phase, according to Guanrei and colleagues (1988), indicating that surveillance may be effective. Cancers detected during surveillance tend to be less advanced and to have a better prognosis, with a 5-year survival rate of 35% to 45% as noted by Provenzale (1994) and Streitz (1993) and their associates. However, caution must be taken in evaluating these nonrandomized studies, which may be affected by lead-time bias. Eloubeidi and Provenzale (1999) also note that the endoscopist's impression is often incorrect, with a positive predictive value in one study of only 34% when compared to histopathology. Others
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argue that current surveillance measures have had a minimal impact on public health. In a literature review of 752 studies including 1,053 cases, Dulai and associates (2002) reported that only 4.7% 2.9% of patients had a prior diagnosis of Barrett's metaplasia preoperatively.
Despite these limitations, surveillance is currently the standard of care and commonly involves yearly endoscopy with four-quadrant biopsies every 2 cm and biopsies of all visible lesions. If biopsies are indefinite or positive for low-grade dysplasia, locations are documented, and patients are treated with 3 months of acid suppression. If changes persist on biopsies, DeMeester (2002) suggests an antireflux procedure with continued surveillance every 6 months. If lesions continue to persist, Salo and associates (1998) recommend consideration for mucosal ablation.
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Fig. 150-7. Illustration of the development of Barrett's mucosa. A. Damage to differentiated esophageal cells in the superficial and parabasal compartments. B. Damage in the basal compartment involving the epithelial stem cells (speckled nuclei). C. Generation of mucin-secreting acid-bile-resistant clones. From Jankowski JA, et al: Molecular evolution of the metaplasia-dysplasia-adenocarcinoma sequence in the esophagus. Am J Pathol 154:968, 1999. With permission. |
There has also been consideration for expanding the surveillance intervals based on recent data. A meta-analysis by Shaheen and colleagues (2000) suggests a risk of 0.5% per year for the development of adenocarcinoma in Barrett's metaplasia, which is lower than previously thought. Recommendations
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from the American College of Gastroenterology suggest reducing the frequency of surveillance to every 2 to 3 years if no evidence of dysplasia is found on two consecutive esophagoscopies. If low-grade dysplasia is found, surveillance is continued twice every 6 months and then yearly.
Antireflux Therapy
Although medical and surgical antireflux therapies are often evaluated in terms of symptomatic relief, the goals in the management of Barrett's mucosa also include prevention, healing, and stabilization of metaplastic lesions. Using medical therapy, Wetscher and associates (1997) found that up to 34% of patients developed Barrett's metaplasia while on long-term acid suppression. In a series of 32 patients, Sharma and co-workers (1997) found a 5.7% incidence of progression to dysplasia and concluded that medical therapy does not prevent the development of dysplasia.
Proponents of antireflux surgery argue that medications do not correct the underlying reflux because acid is not the only injurious agent. Antireflux surgery restores lower esophageal sphincter function, and randomized studies by Spechler (1992) and by Ortiz and associates (1996) have confirmed superior reflux control. In a series of 21 patients, Luostarinen and associates (1993) performed follow-up esophagoscopy 20 years after Nissen fundoplication. Two of the 15 patients with intact repairs had Barrett's epithelium, whereas 5 of 6 patients with defective wraps showed Barrett's metaplasia. Although preoperative biopsies were not performed, DeMeester (2002) concludes that de novo Barrett's metaplasia is rare after effective antireflux surgery. In addition, Brand and associates (1980) have reported complete regression of Barrett's epithelium in 4 of 10 patients after antireflux surgery, although most studies have found complete regression only occasionally. In a literature review, DeMeester and DeMeester (2000) found that 13 of 340 patients had complete regression, whereas 256 remained unchanged.
Surgical therapy may also prevent progression of Barrett's metaplasia to dysplasia and cancer. DeMeester and associates (1998) described 60 patients who underwent antireflux surgery. Ten were found to have low-grade dysplasia preoperatively. On postoperative endoscopy, 7 of 10 had reverted to Barrett's epithelium. McCallum and associates (1991) described a series of 181 patients. Of the 29 patients who underwent surgical therapy, 2.4% developed dysplasia. In the medically treated group, 19.7% developed dysplasia. No adenocarcinoma was found in the surgical group as opposed to the medically treated patients. Hofstetter and colleagues (2001) found no high-grade dysplasia or adenocarcinoma in 410 patient-years of follow-up and concluded that antireflux surgery results in long-lasting relief and prevention of high-grade dysplasia and adenocarcinoma.
Spechler and associates (2001), however, found no significant differences among 247 patients randomized to medical or surgical therapy in a Veteran's Administration study and concluded that antireflux therapy does not prevent adenocarcinoma. Objective measures and precise definitions of reflux and regression of Barrett's epithelium are needed before firm conclusions can be made.
Chemoprevention
Cycloxygenase-2 (COX-2) has been found to be upregulated in Barrett's metaplasia and continues to increase in the progression to dysplasia and adenocarcinoma as described by Wilson and co-workers (1998). Bile acids may activate COX-2 through the protein kinase C pathway according to Zhang and associates (1998). These changes may result in decreased cell-to-cell adhesion, increased angiogenesis, or inhibited apoptosis. In a study by Souza and colleagues (2000), aspirin and specific COX-2 inhibitors were found to suppress growth and induce apoptosis, and in a large case-control study, Farrow and associates (1998) found a decreased incidence of esophageal adenocarcinoma in patients taking aspirin. COX-2 inhibitors are currently being investigated in the chemoprevention of esophageal adenocarcinoma.
Other Risk Factors
Associations have also been found between obesity and esophageal adenocarcinoma. In a Swedish study by Lagergren and colleagues (1999a), esophageal adenocarcinoma was 7.6 times more common in the heaviest quartile. Other risk factors include ectopic gastric mucosa and esophageal diverticula. There may also be associations with iron overload, alcohol use, polysaturated fats, and diets high in red meat, as noted by Wang (1998) and Gammon (1997) and their co-workers. In a study from the National Cancer Institute, Gammon and co-workers (1997) reported a 2.2 times higher risk for esophageal adenocarcinoma in smokers that persisted for up to 30 years after quitting. In addition, Lagergren and associates (1999b) found an increased risk for esophageal adenocarcinoma in patients on medications that reduce lower esophageal sphincter pressure such as calcium channel blockers.
Concerns have also been raised about acid-suppressing medications and continued reflux. In case-control studies, however, Farrow (2000) and Chow (1995) and their associates did not find significant associations between acid suppression and esophageal adenocarcinoma. In addition, there is concern that eradication of Helicobacter pylori may actually lead to increased esophageal adenocarcinoma. According to Chow and co-workers (1998), the acid-suppressing effects of Cag A+ strains have been inversely correlated with esophageal adenocarcinoma. Labenz and co-workers (1997) have also reported erosive esophagitis in 26% of patients who were cleared of H. pylori, compared with 13% of those with persistent infections. In the United States, increasing obesity and
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decreasing H. pylori infections could contribute further to the rising incidence of esophageal adenocarcinoma.
Pathogenesis
After the squamous epithelium is injured by reflux, there is an inflammation-stimulated hyperplasia and metaplastic change to a columnar epithelium. One hypothesis is that pluripotent stem cells in the basal layers undergo metaplasia after repeated stimulation from reflux, as described by Li and associates (1994). Other possible origins of columnar cells are the gastric cardia and propagation of columnar cells from the esophageal gland ducts. Replacement by long-segment Barrett's is believed to occur rapidly and reaches its maximal proximal extent within 3 years according to Morales and co-workers (1997). With further injury and multiple genetic changes, further progression occurs in a stepwise fashion in a metaplasia-dysplasia-adenocarcinoma sequence, as described by Geboes (2000).
Molecular Basis
A number of molecular mechanisms are involved in the progression from Barrett's metaplasia to adenocarcinoma, and multiple genetic alterations are necessary to generate a malignant phenotype according to Wijnhoven and colleagues (2001), as depicted in Fig. 150-8. Increased proliferation is seen and may lead to the clonal expansion of neoplastic cells and tumor growth as noted by Arai and Kino (1995). In studies by Brito (1995) and Soslow (1999) and their associates, various growth factors and receptors are increased in the progression to esophageal adenocarcinoma, including epidermal growth factor (EGF), EGF receptor, and fibroblast growth factor (FGF). Walch (2001) and Brito (1995) and their co-workers also reported that increased expression of CerbB2 and transforming growth factor- (TGF- ) have been associated with distant metastases and poor survival.
According to Barrett (1996), Coppola (1999), and Jankowski (1999) and their colleagues, tumor suppressors, including p16, Rb, VHL, CDKN2, and DCC, are decreased in adenocarcinomas. APC, another tumor suppressor, accumulates in the nucleus in its mutated form, as noted by Bektas and associates (2000). Changes have also been seen in cell-to-cell adhesion facilitating tumor invasion. Bailey and colleagues (1998) reported that decreased expression of E-cadherin and -catenin have been correlated with a poor prognosis, and Hughes and associates (1998) found an amplicon at 8p22 23 that results in overexpression of cathepsin B.
Inhibition of apoptosis is also seen in dysplastic cells. Hughes and co-workers (1997) found decreased expression of Fas receptor at the cell surface in dysplasia and adenocarcinoma leading to a decrease in apoptosis. Bcl-2, an antiapoptotic protein, was found by Katada and colleagues (1997) to be overexpressed in 72% of Barrett's metaplasia and 100% of low-grade dysplasia, although only 20% to 40% of high-grade dysplasia or adenocarcinoma showed overexpression. Bcl-2 may be important early in the dysplasia-carcinoma sequence in allowing dysplastic cells to proliferate. The p53 gene is one of the most commonly mutated genes in cancer. Accumulation of mutated p53 increases with progression to dysplasia and adenocarcinoma as described by Gimenez and associates (1998), and loss of heterozygosity is found in more than 50% of adenocarcinomas according to Altorki and co-workers (1997b). Casson and associates (1998) have reported a correlation between p53 mutations and decreased patient survival.
The p53 gene has also been implicated in the development of tetraploid and aneuploid cells in esophageal adenocarcinomas. Other chromosomal changes seen in esophageal adenocarcinoma include a number of genomic amplifications reported by Lin (2000a, 2000b) and al-Kasspooles (1993) and their colleagues, deletions, and microsatellite instability. Loss of chromosome Y is found in 31% to 93% of tumors according to Wijnhoven (2001). In addition, repression of gene expression through promoter hypermethylation
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is frequently seen. Kawakami and associates (2000) reported hypermethylation of the APC promoter in 94% of esophageal adenocarcinomas and found an association with advanced stage and reduced survival.
 |
Fig. 150-8. Genetic changes involved in the progression from Barrett's metaplasia to esophageal adenocarcinoma. From Wijnhoven BP, Tilanus HW, Dinjens WN: Molecular biology of esophageal adenocarcinoma. Ann Surg 233:331, 2001. With permission. |
According to Barrett and colleagues (1999), using clonal ordering of neoplastic lineages, numerous intermediate clones were identified, suggesting multiple genetic routes to cancer from Barrett's metaplasia. In one pathway, diploid metaplastic cells developed loss of heterozygosity at 17p and 9p with mutations in p53 and p16. Cell populations then arose, with an elevated 4N fraction. These cells developed aneuploid populations that became cancer cells with additional loss of heterozygosity. Studies of the genetic changes involved in the pathogenesis of esophageal adenocarcinoma not only should improve our understanding of this cancer but also may provide novel methods of diagnosis, staging, and treatment.
Pathology
Barrett's Esophagus
On endoscopy, these lesions appear as red, velvety areas between smooth, pale esophageal squamous mucosa, as shown in Fig. 150-9A and B. Microscopically, columnar epithelium is seen with mucosal glands that often contain intestinal goblet cells, as seen in Fig. 150-10A. Barrett's metaplasia is the precursor to esophageal adenocarcinoma, and high-grade dysplasia seen on histopathology remains the best predictor of progression to adenocarcinoma according to Reid and associates (2000). Dysplasia is classified histologically according to guidelines devised for inflammatory bowel disease by Riddell and co-workers (1983) and that have been modified for esophageal pathology as described by Schmidt and colleagues (1985). Dysplasia is defined as cytologic and structural abnormalities that are distinguishable from reactive changes and that extend to the luminal surface, as shown in Fig. 150-10B. Lesions are classified as low or high-grade dysplasia and are distinguished by the nuclear orientation along the base of the epithelium as well as other characteristics, as illustrated in Table 150-4. In fact, Kim and co-workers (1997) noted that lesions are often a mosaic of low- and high-grade dysplasia adjacent to nondysplastic mucosa. In addition, there is significant interobserver and intraobserver variability. Although pathologists are relatively good at distinguishing high-grade dysplasia and cancer from no dysplasia with 86% to 87% concordance rates, there is less agreement in distinguishing high-grade from lower grades of dysplasia with a 58% to 61% concordance according to Reid and associates (1988).
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Fig. 150-9. Endoscopic view of Barrett's metaplasia (A, B) and an esophageal adenocarcinoma (C). |
Esophageal Adenocarcinoma
Esophageal adenocarcinomas usually arise in the distal esophagus. According to Yang and Davis (1988), using SEER data, 79.3% of adenocarcinomas arise from the lower esophagus, 17.9% from the middle, and 2.8% from the upper third. Lesions are initially flat or raised patches of mucosa that may become infiltrative or deeply ulcerated lesions. Nodular masses up to 5 cm in diameter can also be seen. Microscopically, most tumors are composed of mucin-producing
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intestinal-type glands, as shown in Fig. 150-10C. Diffusely infiltrating gastric-type signet-ring cells can be seen but are less common.
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Fig. 150-10. Microscopic view of Barrett's metaplasia (A), high-grade dysplasia (B), and invasive adenocarcinoma (C). |
Table 150-4. Grading Dysplasia in Barrett's Esophagus | ||||||||||||||||||||||||||||||
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Metastases
The number of esophageal adenocarcinomas detected at an early stage is small. According to SEER data reported by Mason and colleagues (2001), carcinoma in situ was found in 2.3% of patients between 1993 and 1997. Even when tumors are confined by the muscularis mucosa, Goseki and associates (1992) found that 8% to 30% have nodal disease, and 30% to 58% have lymph node metastases when the submucosa is involved. Of 295 patients, Rice and associates (1998) found nodal disease in 10% of patients with T1 lesions, 46% of T2, and 83% of T3. The sites of lymph node metastases are depicted in Fig. 150-11. Lymph node status is a major prognostic factor and influences survival, as shown in Fig. 150-12.
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Fig. 150-11. Sites of lymph node metastases in patients with transmural esophageal adenocarcinoma. From Nigro JJ, et al: Node status in transmural esophageal adenocarcinoma and outcome after en bloc esophagectomy. J Thorac Cardiovasc Surg 117:962, 1999. With permission. |
Lymphatic channels begin in the mucosa and drain into the submucosa, forming long collecting channels. Numerous valves direct the lymphatic flow longitudinally. Although in normal conditions lymph above the carina flows into the thoracic duct or subclavian lymphatic trunks and lymph below the carina drains into the cisterna chyli in the abdomen, reversal of flow can occur when nodes are blocked by tumor. Because of this extensive lymphatic network, a large number of patients have unresectable disease at the time of diagnosis. According to Quint and co-workers (1995), the most common sites of distant metastases include the liver (35%), lungs (20%), bone (9%), brain or adrenal glands (2%), and pericardium, pancreas, spleen, or stomach (1%), as shown in Table 150-5.
ADENOCARCINOMA OF THE GASTROESOPHAGEAL JUNCTION
Inconsistent classification schemes and definitions have caused confusion when comparing adenocarcinoma of the esophagus and the gastroesophageal junction. Studies by Morales (1997) and El-Serag (1999) and their associates suggested that risk factors for intestinal metaplasia in the cardia may be different from those involved in Barrett's mucosa and failed to find a strong association with reflux. There are also epidemiologic differences. Although the incidence of adenocarcinoma of the cardia has increased, with an incidence of 3.3 per 100,000 from 1987 to 1991, it has increased to a lesser extent and has remained stable according to SEER data between 1987 and 1996, according to Blot (1991) and El-Serag (2002) and their co-workers. The ethnic and gender differences are also smaller. Patients with intestinal metaplasia of the cardia are more likely to be non-Caucasians and to have gastritis, as noted by El-Serag and associates (1999). Some studies have found strong associations
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between H. pylori infection, gastritis, and the presence of intestinal metaplasia in the distal stomach as described by El-Serag (1999) and Morales (1997) and their colleagues. However, Blot and McLaughlin (1999) and Pera (2000) found common risk factors, a poor prognosis with 5-year survival rates from 22% to 38%, and increasing incidence rates similar to esophageal adenocarcinoma. In a study by Hansen and associates (2000) in Norway of 100,000 patients, a fivefold decreased incidence of adenocarcinoma of the cardia was found in patients infected with H. pylori, similar to results reported by Chow and co-workers (1998) in esophageal adenocarcinoma.
DIAGNOSTIC EVALUATION
Presentation
The initial evaluation of a patient with a suspected esophageal carcinoma is depicted in Fig. 150-13. The symptoms of esophageal cancer are usually nonspecific and similar regardless of the histologic subtype. Dysphagia is the most common initial symptom. Typically, difficulty swallowing is noted with solid foods, which may progress to include semisolids and eventually liquids over a period of weeks to months. Odynophagia is the next most common symptom and may be caused by an ulcerated lesion or invasion of surrounding mediastinal structures. Constant pain in the midback or midchest also suggests mediastinal invasion. Regurgitation of food immediately after swallowing may occur as the growing neoplasm narrows the esophageal lumen. The constitutional symptoms of anorexia and weight loss are often present by the time the patient seeks medical attention. Hoarseness may also occur with proximal tumors and indicates involvement of the recurrent laryngeal nerves.
Table 150-5. Occurrence of Metastases in Patients with Esophageal Cancer | ||||||||||||||||||||||||
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Fig. 150-12. Kaplan-Meier survival plots for 1340 patients stratified by the number of positive lymph nodes. From Eloubeidi MA, et al: Prognostic factors for the survival of patients with esophageal carcinoma in the U.S.: the importance of tumor length and lymph node status. Cancer 95:1440, 2002. With permission. |
Patients with esophageal adenocarcinoma often have a history of reflux symptoms, although clinical features do not distinguish patients with and without Barrett's mucosa, which is frequently asymptomatic. Patients often present at an advanced stage unless the diagnosis is made fortuitously on endoscopy performed for other reasons. The signs and symptoms of advanced esophageal carcinoma are shown in Table 150-6. In a series of 115 patients, van Sandick and associates (2002) reported dysphagia in 67% of patients, an 11% incidence of retrosternal or epigastric pain, and a 5% incidence of hematemesis or melena. Seven percent of cases were asymptomatic and discovered during surveillance, and 47% of patients experienced more than a 5% weight loss.
Physical examination may reveal entirely normal findings and generally does not aid in the diagnosis. Temporal wasting, weight loss, and dehydration are commonly seen. It is not clear whether this is simply malnutrition resulting from an obstructed esophageal lumen or whether the tumor is secreting factors that promote cachexia. The ability of patients to gain weight after successful palliation of dysphagia
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suggests the former. It is important to look for physical findings that may alter the therapeutic approach, including supraclavicular or cervical adenopathy, a discrete abdominal mass, or fullness that may indicate involvement of the celiac nodes or metastatic disease to the liver.
Laboratory examinations may reveal anemia from chronic blood loss, hypoproteinemia from malnutrition, and hypercalcemia and abnormal liver function tests from distant metastases. Hypercalcemia is more common than previously appreciated and was seen in about 15% of patients with esophageal squamous cell carcinoma according to Stephens (1973), Benrey (1974), and Chandrasekhara (1975) and their associates.
Table 150-6. Signs and Symptoms Produced by Advanced Esophageal Carcinoma | ||
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Fig. 150-13. Diagnostic evaluation of a patient with suspected esophageal carcinoma. From Putnam JB Jr, et al: Neoplasms of the esophagus. In Bell RH Jr, et al (eds): Digestive Tract Surgery: A Text and Atlas. Philadelphia: Lippincott-Raven, 1996, p. 50. With permission. |
Endoscopy
Esophagoscopy
Endoscopic evaluation is essential in all patients suspected of having a carcinoma of the esophagus. The location of the lesion, degree of obstruction, and longitudinal as well as circumferential extent of the lesion should be determined in all patients. The endoscopic features of late carcinoma are generally easily recognized, although the associated stenosis by submucosal infiltration of the tumor can prevent actual identification of the tumor in some cases. Biopsy and cytologic smears should be performed routinely for all visible lesions. The biopsy specimen should be taken from the edge of the lesion and not from the necrotic center.
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With multiple biopsy specimens, a positive tissue diagnosis is obtained in 95% of tumors, as noted by Orringer (2001).
In patients with early carcinoma identified by surveillance, the endoscopic changes are subtle and may be difficult to recognize. Changes include mucosal erosion, focal congestion, and roughness of the mucosa. A small nodule, ulcer, or even a small tumor mass may be seen, as shown in Fig. 150-9C.
Bronchoscopy
Bronchoscopy is important in the evaluation of possible tracheal or bronchial invasion by a carcinoma in the cervical and the upper or middle thirds of the thoracic esophagus. Postlethwait (1985) noted tracheobronchial invasion in 26 of 153 patients with carcinoma of the cervical esophagus, in 82 of 487 patients with carcinoma located in the upper thoracic esophagus, and in 6 of 268 patients with tumor in the distal thoracic esophagus. Of the 114 patients with tracheobronchial invasion, 60 had tracheal involvement, and 54 had bronchial invasion. Thirty-seven patients developed a tracheoesophageal or bronchoesophageal fistula. Angorn (1981) noted tracheobronchial invasion in 184 of 1,045 patients with carcinoma of the upper thoracic esophagus, and a fistula was present in 75 patients. Tracheal invasion was present in 57% of patients, bronchial invasion in 40%, and direct involvement of the lung parenchyma in 3%.
Patients with infracarinal bulky tumors or subcarinal lymphadenopathy on CT should undergo bronchoscopy to evaluate for carinal involvement. Bronchoscopic findings may range from simple bulging, loss of striations, bulging with fixation of the posterior wall of the trachea or the main bronchi (most commonly the left main bronchus), frank tumor invasion, or the presence of a fistula. The carina may also appear widened due to metastatic disease to the subcarinal nodes, and simple bulging does not necessarily indicate invasion. A cytologic or histologic diagnosis obtained by bronchial brushings or biopsies is helpful in confirming invasion.
Radiographic Studies
Chest Radiographs
Standard chest radiographs reveal an abnormal finding in 47.5% of patients with esophageal cancer, according to Lindell and associates (1979). The more important abnormalities seen are an abnormal azygoesophageal line, widened mediastinum, posterior tracheal indentation or mass, and a widened retrotracheal stripe. In addition, findings may suggest hilar or superior mediastinal adenopathy or provide evidence of pulmonary metastases. Compression, displacement, or irregularity of the tracheal air column may appear, as may pulmonary infiltrates caused by aspiration and secondary infection. A metastatic pleural effusion or empyema is rarely seen at presentation, and in general, chest radiographs are not useful in the initial evaluation of esophageal carcinoma.
Contrast Studies
Barium is the most commonly used contrast agent for fluoroscopic examination of the esophagus and the gastrointestinal tract. It permits a safe, expedient study of the esophageal mucosa, luminal distensibility, motility, and any anatomic pathology, as shown in Fig. 150-14. The barium swallow is an essential diagnostic study for the evaluation of dysphagia. Early cancer appears as small intraluminal plaquelike or polypoid protrusions or as an area of discrete ulceration and is best seen on a double-contrast esophagogram.
There are several radiologic patterns seen on barium swallow in patients with esophageal carcinoma. The infiltrative type is most commonly seen. Depending on the extent of circumferential infiltration, the esophageal lumen is eccentrically or concentrically narrowed. An indentation caused by the margin of the tumor may be seen at either end of the narrowed segment and occasionally forms shelflike borders producing an apple-core appearance. The polypoid type appears as a large filling defect (>3.5 cm) within the lumen of the esophagus. In the ulcerative type, most of the tumor mass is replaced by a large ulcer. When shown in profile, this appears as a well-defined meniscoid ulcer with a radiolucent rim. The varicoid type is produced by diffuse submucosal spread of the tumor, resulting in marked thickening and tortuosity of the mucosal folds, simulating esophageal varices. Differentiation from true varices can be made by the tumor location (middle or upper third) and its failure to change size with peristalsis or respiration. The border between varicoid tumor and the adjacent normal mucosa is also more distinct than for varices.
Computed Tomography
Staging CT scans of the chest and upper abdomen are important studies in the initial evaluation of esophageal carcinoma and assessing the response to adjuvant therapy. CT is used to determine the local extent of the tumor, the relationship to adjacent structures, and distant metastases, as shown in Fig. 150-15. Moss and associates (1981) classified CT findings into four stages: stage I, intraluminal mass without esophageal wall thickening; stage II, esophageal wall thickening; stage III, contiguous spread of the tumor into adjacent structures (trachea, bronchi, aorta, pericardium); and stage IV, evidence of distant metastases.
Normally, the esophagus appears as a thin-walled structure with or without contained air. CT cannot distinguish the layers of the esophageal wall and is not as useful in determining the T stage. However, preservation of fat planes can be useful in determining invasion of adjacent structures. When the nutritional status of a patient was adequate and the fat plane was
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obliterated, Thompson and associates (1983) found that tumor extends to the adjacent structures in at least 90% of patients. Only 21% of patients in whom fat planes were preserved had tumor extension beyond the esophageal wall.
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Fig. 150-14. Barium esophagogram demonstrating late esophageal squamous cell carcinoma. A. Polypoid lesion. B. Multiple polypoid tumors. C. Long, ulcerative tumor. D. Stenotic, infiltrative tumor. |
Indentation of the trachea or of a main-stem bronchus causes suspicion for airway involvement, as shown in Fig. 150-16. Thickening of the wall of the tracheobronchial tree abutting the tumor or loss of fat planes in that region while the fat planes are preserved above and below the tumor also suggests invasion. Involvement of the aorta is uncommon and was present in only 2% of 2,440 patients at autopsy in a study by Postlethwait (1986). However, aortic invasion is suggested by the amount of circumferential contact with the tumor. Picus and associates (1983) reported that greater than
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90 degrees of contact suggests invasion, whereas less than 45 degrees does not. Although invasion of the pericardium is difficult to detect, obliteration of the intervening fat planes can be diagnostic.
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Fig. 150-15. Computed tomography (CT) scans of patients with esophageal carcinoma. A. Tumor in contact with the thoracic aorta. B. CT-guided biopsy of nodal disease. C. Metastatic hepatic nodules. D. Local invasion of the right main-stem bronchus. |
Sensitivity for detecting abnormal lymph nodes (>1 cm) is 34% to 61% in the mediastinum and 50% to 76% in the abdomen, according to Saunders and colleagues (1997), although inflammation may lead to false-positive findings. Thompson and associates (1983) found that computed tomography (CT) identified 69% of patients with positive subdiaphragmatic lymph node involvement. However, there was a 23% false-negative rate. Although celiac nodal disease is important prognostically, Reed and co-workers (1999) found that CT was not sensitive for detecting disease at this level. For metastatic disease, Rice (2000) reported a sensitivity of 70% to 80% for identifying metastases larger than 2 cm.
Magnetic Resonance Imaging
Based on studies by Lehr (1988) and Quint (1985) and their associates, magnetic resonance (MR) imaging does not appear to be as accurate as CT in the staging of esophageal cancer. The capability of MR imaging to demonstrate a tumor in the coronal and sagittal planes is superior in the estimation of the tumor length, but this information has only limited clinical value. Imaging in the coronal plane may be used to evaluate for invasion of the trachea or bronchus, and any area of contact with the tumor longer than 3 cm is suspicious. As with CT, MR imaging is poor for detection of tumors restricted to the mucosa or submucosa. Identification of spread into the periesophageal tissue by MR imaging is also unreliable because its detection depends on the existence of the surrounding fat layer, which may or may not be present normally. Regional lymph node involvement also tends to be understaged by MR imaging. Evaluation of a prototype MR imaging endoscope in assessing esophageal cancer by Inui and co-workers (1995) demonstrated local and regional findings consistent with CT and endoscopic ultrasound (EUS) as well as surgical and pathologic findings.
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Fig. 150-16. A. Computed tomography scan of a patient with esophageal adenocarcinoma invading the trachea. B. Palliative placement of a tracheal stent. |
Positron Emission Tomography
Positron emission tomography (PET) scans identify increased glycolysis using 18F-fluorodeoxyglucose (FDG), which accumulates in 97% of esophageal adenocarcinomas according to studies by Kim (2001) and Luketich (1997b) and their co-workers. Block and associates (1997) noted that in 56 of 58 patients, FDG uptake was identified at the site of the primary tumor, whereas Kole and co-workers (1998) observed that the primary tumor was visualized in 81% of 26 patients by CT and in 96% by PET. However, like CT scans, PET cannot define the layers of the esophagus. Block (1997) and Luketich (1997b) and their colleagues reported a sensitivity of 45%, specificity of 100%, and accuracy of 48% for detection of nodal metastases by PET, as seen in Fig. 150-17. Thirty-five patients in a series reported by Block and co-workers (1997) underwent surgical exploration, and 21 were found to have lymphatic spread. Surgically assessed nodal status corresponded in 62% with CT and in 90% with PET scan.
Luketich and co-workers (1999) found PET to be 69% sensitive and 93% specific in identifying distant metastases, compared with CT, which was 46% sensitive and 74% specific. PET can detect 15% to 20% additional metastases compared with CT scan. Block and colleagues (1997) reported that PET scan identified metastatic disease in 17 patients, whereas CT scan was positive for metastasis in only 5 patients. The diagnostic accuracy of CT in determining resectability was 65%, compared with 88% with PET and 92% when both modalities were used. In addition, PET may have a role in selecting therapy. Responses to induction chemotherapy on PET scans were predictive of a complete surgical resection and longer survival according to Weber and colleagues (2001). However, availability and cost remain issues in its widespread use.
Endoscopic Ultrasound
Endoscopic ultrasound (EUS) provides accurate T staging and is able to detect local, perigastric, and celiac lymph nodes. EUS has resulted in a reduction in incomplete
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staging and improved detection of celiac nodal disease. EUS is able to identify five distinct layers in the esophageal wall, permitting assessment of the depth of tumor invasion, as depicted in Fig. 150-18. As noted by Reed and Eloubeidi (2002), T1m lesions are confined to the mucosa and rarely spread to lymph nodes, while T1sm lesions involve the submucosa and metastasize to lymph nodes in 15% to 30% of cases. The accuracy of T staging is about 84% and depends on both the stage and operator. Tio and co-workers (1989) reported a study of 74 patients and showed that EUS had an overall accuracy of 89%, compared with 59% for CT. Accuracy was most notable in the staging of early carcinoma and in evaluating the extent of periesophageal invasion.
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Fig. 150-17. Positron emission tomography (PET) scan reveals a middle esophageal primary tumor (arrow) and a positive upper mediastinal lymph node (arrowhead). From Kato H, et al: Comparison between positron emission tomography and computed tomography in the use of the assessment of esophageal carcinoma. Cancer 94:921, 2002. |
Accuracy in the assessment of regional lymph nodes with EUS was 80%, compared with 51% with CT. A study by Catalano and associates (1994) found that EUS is 89% sensitive and 75% specific for nodal staging and is better for celiac rather than mediastinal disease. Regional lymph nodes can be evaluated for their size, shape, margin, and internal structure, as reported by Ogino (1984) and Kumegawa (1985) and their associates. Curvilinear arrays also assist in performing fine-needle aspiration (FNA), as described by Vickers (1998). EUS-guided FNA is 98% sensitive and 100% specific.
EUS may also be useful in assessing response to neoadjuvant therapy. Lightdale and Botet (1990) and Rice and associates (1991) have also reported the accuracy of EUS in monitoring tumor response to chemotherapy and in detecting late recurrence of tumor at the anastomotic site or in the esophageal bed. Although standard EUS criteria are not as accurate after therapy owing to difficulty differentiating tumor, necrosis, and inflammation, patients with a reduction in maximal cross-sectional area greater than 50% are more likely to survive, as reported by Chak and co-workers (2000).
In up to one third of patients, the 13-mm endoscope cannot be passed because of esophageal stenosis, although a narrow caliber EUS can be used, as noted by Eloubeidi and colleagues (2001). Miniprobes that can be passed in nearly all patients are available in 12-, 15-, and 20-MHz frequencies. Unlike dedicated EUS, a probe can be passed through the biopsy channel, and endoscopic evaluation can be performed while the tumor is being visualized, obviating the need to exchange instruments. Higher-frequency probes can provide greater detail of a superficial lesion, but deeper structures such as regional lymph nodes may not be visualized, as described by Waxman (1998) and Hunerbein (1998) and their associates. EUS has recently gained popularity owing to its diagnostic accuracy but has not yet become the standard of care at this time in the management of esophageal carcinoma.
Thoracoscopy and Laparoscopy
Many investigators have evaluated the use of thoracoscopy and laparoscopy as staging tools in esophageal cancer. These procedures are generally more accurate in determining nodal status than noninvasive techniques and are helpful in evaluating the extent of local invasion and detecting metastatic disease. Thoracoscopy and laparoscopy offer direct visualization and the ability to document disease histologically. Krasna and associates (1996) found thoracoscopy to be accurate in 93% and laparoscopy in 94% of patients in identifying metastatic disease. Six cases of unsuspected celiac nodal disease were identified in 19 patients despite preoperative CT and EUS. Similar results were confirmed by Luketich and associates (1997a) in 26 patients. A prospective multiinstitutional study of 107 patients found that CT, EUS, and MR imaging failed to detect positive nodal disease in 25% of patients identified using thoracoscopy and laparoscopy, as reported by Krasna and co-workers (2001). Minimally invasive techniques changed the staging in 32% of patients according to Luketich and associates (2000). Laparoscopy is also useful for identifying peritoneal metastases and was 96% sensitive.
Laparoscopy alone is more effective in patients with adenocarcinoma than with squamous cell carcinoma of the
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esophagus. Stein and associates (1997) found a 22% incidence of previously unidentified hepatic metastases and a 25% incidence of positive fluid cytology in patients with adenocarcinomas, whereas laparoscopy provided minimal additional information in the evaluation of patients with squamous cell tumors. Thoracoscopy through the right hemithorax, particularly in combination with laparoscopy, is of value in patients with both types of carcinoma.
In a multiinstitutional study, Krasna and colleagues (1996) reported that 88% of patients surgically explored were correctly staged using minimally invasive techniques. In a later report, Krasna (1998) noted only a 7% error rate in thoracoscopic staging of esophageal tumors and found that laparoscopy, when performed, was correct in 94% of patients. Luketich and associates (1997a) have found these minimally invasive procedures superior to EUS staging. In the average patient with carcinoma of the esophagus, it remains unclear whether this strategy is cost effective and whether it actually changes the management of the individual patient with regard to the use of neoadjuvant therapy. Nonetheless, thoracoscopy and laparoscopy may be useful in evaluating the response to various neoadjuvant regimens in clinical trials for which there have been conflicting results.
Laparoscopic Ultrasound
Laparoscopic ultrasound (LUS) is also being investigated as a staging modality and may provide improved accuracy in T and N staging. In a study by Flett and colleagues (2001), LUS improved staging accuracy of celiac nodal disease to 92%, compared with final pathology in 44 patients. There was a significant difference in disease-free survival between node-positive and node-negative patients identified by LUS. LUS may also be more accurate for staging celiac nodes because the EUS probe is more distant and does not provide direct inspection.
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Fig. 150-18. A. Illustration of the endoscopic sonographic (EUS) views shown in B and C of a T2 esophageal adenocarcinoma with metastatic celiac nodes. |
With increased cost and invasiveness, the role of these techniques will require further assessment. In a comparison of health-care costs by Wallace and colleagues (2002), CT scan followed by EUS-FNA when necessary was the most inexpensive evaluation and provided the most quality-adjusted years of life, except for PET with EUS-FNA, which was slightly more effective but more expensive. At the current time, CT should be the initial staging exam, followed by EUS-FNA if necessary.
Molecular Markers
The identification of molecular markers may offer earlier diagnosis than currently available through radiology or pathology and may provide prognostic information on tumors that are more advanced and likely to metastasize. Molecular markers could also be useful in identifying micrometastases. Luketich and associates (1998) describe using reverse transcriptase polymerase chain reaction (RT-PCR) to identify micrometastases in 49% of histologically negative lymph nodes.
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There have been a number of potential markers identified in the literature. One of us (M.D.I.) and co-workers (1996) reported that the assessment of sucrase-isomaltase might improve detection of Barrett's metaplasia and dysplasia. Several studies have found associations between aneuploid or increased tetraploid fractions and metastases, advanced disease, and poor survival, and Wijnhoven (2001) and Reid (1992) and colleagues reported that 70% of patients develop high-grade dysplasia or adenocarcinoma. Although p53 mutations have been reported by Altorki and associates (1997b) in more than 50% of esophageal adenocarcinomas, and Casson and co-workers (1998) have reported decreased patient survival, a p53 mutation is not sufficient by itself to predict progression to adenocarcinoma. Urokinase plasminogen activator is a serine protease involved in the breakdown of the extracellular matrix and was found in one study to identify patients who develop early tumor recurrences as described by Wijnhoven and co-workers (2001).
Table 150-7. Staging of Esophageal Carcinoma | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Currently, a reliable biomarker is not available, and the prevalence of most markers is low. Because of the diverse genetic changes seen in esophageal adenocarcinoma, a panel of biomarkers may be most useful. Molecular markers may allow for the identification of early recurrence or advanced disease and the selection of subgroups that may benefit from surgical resection or chemoradiotherapy, and it remains an active area of research.
Staging
Accurate staging is essential for treatment selection and prognosis. The evaluation of patients with suspected esophageal cancer should include appropriate diagnostic studies as well as biopsies of any suspected metastatic lesions. Biopsy of mediastinal nodes should be guided by findings on CT. Laparoscopy should be considered in patients with intrathoracic, locally advanced esophageal cancers or suspected intraperitoneal metastases to assess the celiac and left gastric lymph nodes, the liver, and the peritoneum for tumor implants and obtaining peritoneal fluid for cytology.
Both esophageal squamous cell and adenocarcinomas are staged according to the American Joint Committee for Cancer TNM system as shown in Table 150-7. Fleming (1998) updated the system to include M1a and M1b for regional nodal metastases. Although there is currently no subclassification of N1 in the present staging system, N1 lymph node status is a prognostic factor, as reported by Eloubeidi (2002) and Nigro (1999) and their associates. Many physicians assign a substage of N1 depending on the total number of positive nodes (less than four) and the percentage of resected lymph nodes that are positive. Adenocarcinomas of the cardia are staged as gastric cancers.
TREATMENT
Surgical Therapy for Esophageal Cancer
History of Surgical Therapy
The first successful resection of esophageal cancer was performed in 1877 by Czerny, professor of surgery at Heidelberg. An annular stricture in the cervical esophagus caused by cancer was removed with the creation of a distal cervical esophagostomy. The patient survived for 1 year. Torek (1913) performed the first successful intrathoracic esophagectomy in 1911 at the French Hospital in New York. The esophagostomy and gastrostomy were connected with a rubber tube 1 week later for alimentation. The patient survived for 13 years and died of unrelated causes. In Vienna, Denk described a pull-through operation without thoracotomy in 1913, but it was not successfully performed
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until Turner (1931) resected the esophagus of a 58-year-old miner who survived for 19 months. The procedure was not widely accepted for years but was reintroduced and popularized by Orringer and Sloan (1978). Oshawa (1933), from Kyoto, reported the use of a transthoracic esophagectomy with immediate reconstruction in 19 patients, 8 of whom survived. This report received minimal publicity in the West, and Adams and Phemister (1938) are mistakenly credited with performing the first intrathoracic esophageal resection with immediate reconstruction. In 1946, Lewis (1946) introduced his approach using an initial laparotomy to mobilize the stomach followed by a right thoracotomy for resection of the esophagus and immediate esophagogastric anastomosis.
Surgical Treatment of Esophageal Cancer
Surgical therapy currently offers the best chance for cure with a complete resection and also provides effective palliation with relief of dysphagia. Although Begg and co-workers (1998) have reported a significant decrease in perioperative mortality rates from 29% in the 1950s to 1970s to below 5% in the 1990s, relatively high postoperative morbidity remains. Edwards and co-workers (1996) reported a mortality rate of 6%, although 47% of patients experienced complications, including anastomotic leaks and strictures, dumping syndrome, delayed gastric emptying, and injury to the recurrent laryngeal nerves.
Controversy continues to surround the optimal surgical approach to esophagectomy as well as the extent and necessity of regional lymph node dissection. Currently, no data exist that make one approach clearly superior to another, as noted by Orringer (1987), Gluch (1999), and Chu (1997) and their associates. The choice of approach depends on the location of the tumor, planned extent of lymphadenectomy, and preference of the surgeon.
Transthoracic Esophagectomy
Some have had excellent results with a transthoracic approach to esophagectomy. Visbal and associates (2001) reported a series of 220 patients using the thoracotomy and laparotomy approach described by Ivor Lewis (1946) with an intrathoracic anastomosis. Operative mortality was 1.4%, and complications occurred in 37.7%, including pneumonia in 12.3%, anastomotic leaks in 3.6%, and recurrent laryngeal nerve palsy in 0.9%. Median survival was 1.9 years, with a 5-year survival rate of 25.2%. Local recurrence rates were 5%, and the median length of stay was 11 days. Visbal and associates (2001) concluded that the Ivor Lewis approach is safe, and proponents emphasized the direct visualization during the mediastinal dissection, an en bloc resection, and a wider lymph node dissection, resulting in improved staging.
Akiyama and associates (1981) used a modified Lewis (1946) technique with a total thoracic esophagectomy and esophagogastric anastomosis in the neck. An extensive thoracic and abdominal lymph node dissection was done, including resection of the lesser curve of the stomach in almost all cases. Swanson and colleagues (2001) described a series of 250 patients using a similar approach and believe that this technique combines the advantages of the transhiatal and Ivor Lewis esophagectomies. They reported a 56% 3-year survival rate. An anastomotic leak occurred in 8%, and pneumonia developed in 5%. The local recurrence rate was 5.6%. Wong (1981) reported using multiple approaches for tumors at different levels. For middle-third lesions, he also used the modified Lewis technique but often constructed the anastomosis high in the apex of the chest (Wong, 1987). A left thoracoabdominal approach can also be used and provides excellent visualization. The anastomosis can be constructed within the thorax below the aortic arch or through a separate cervical incision. However, this approach also involves the morbidity of a thoracotomy.
Transhiatal Esophagectomy
The transhiatal approach may avoid the morbidity of a thoracotomy in debilitated patients with the potential occurrence of a disastrous intrathoracic anastomotic disruption. Proponents argue that the cervical anastomosis is safer and that survival after transhiatal esophagectomy, shown in Fig. 150-19, is as good in most series as a transthoracic resection, as noted by Orringer (2001). In addition, this approach provides maximal vertical resection margins.
This has been the preferred approach at the University of Michigan since 1976, and 1,085 cases have been reported by Orringer and associates (1999), with more than 1,800 performed to date. Seventy-four percent of patients had cancer, and 19% had high-grade dysplasia. Transhiatal esophagectomy (THE) was technically possible in 98.6% of cases despite instances of prior operations, history of perforations, and radiation treatment. In-hospital mortality was 4%. There was a 2% incidence of pneumonia and an anastomotic leak rate of 13%. After the institution of the stapled side-to-side cervical anastomosis illustrated in Fig. 150-20, the leak rate
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decreased to less than 3%. Most cervical leaks are treated conservatively by opening the wound at the bedside with saline dressing changes. Intrathoracic hemorrhage, recurrent nerve paralysis, and tracheal laceration all occurred in less than 1% of cases. Average length of stay was 7 days, with no routine admissions to the intensive care unit.
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Fig. 150-20. Cervical stapled side-to-side anastomosis after transhiatal esophagectomy. A. The esophagogastrostomy is aligned using stay sutures. B. An Endo-GIA is inserted. C. The semimechanical anastomosis is completed. D. The completed cervical side-to-side anastomosis. E. Postoperative barium swallow. |
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Fig. 150-19. Survival after transhiatal esophagectomy without thoracotomy stratified by histologic diagnosis. From Orringer MB, et al: Transhiatal esophagectomy: clinical experience and refinements. Ann Surg 230:398, 1999. With permission. |
Other authors have reported similar results. In a review of 1,353 patients, Katariya and colleagues (1994) reported a 30-day mortality rate of 7.1% and a 15.1% leak rate. Gandhi and Naunheim (1997) reviewed eight series of 1,192 patients and reported a mortality rate of 6.7% with a 12% rate of anastomotic leaks. In addition, Casson and co-workers (2002) reported a leak rate of 22.6% after a hand-sewn cervical anastomosis with a decrease to 7.9% after the initiation of a side-to-side semimechanical anastomosis.
Orringer and colleagues (1993) advocate the transhiatal approach for tumors at any site in the esophagus. Peracchia and Bardini (1986), as well as Tryzelaar (1982) and Gotley (1990) and their associates, among others, have also supported this approach. Proponents argue that transhiatal esophagectomy can be performed with fewer complications than a transthoracic approach by avoiding a thoracotomy and the associated respiratory complications as well as the dangers of an intrathoracic leak. In a meta-analysis of 50 studies comparing transthoracic and transhiatal resection, Hulscher and associates (2001) found significantly higher early morbidity and mortality rates after transthoracic resections. In a later randomized study of 220 patients, Hulscher and co-workers (2002) confirmed that transhiatal esophagectomy was associated with a lower morbidity than transthoracic esophagectomy with extended en bloc lymphadenectomy, as shown in Table 150-8.
Although accessible subcarinal, paraesophageal, and celiac axis lymph nodes are sampled, no attempt is made to perform an en bloc resection. Although critics have questioned the oncologic principles arguing for the need to perform an aggressive mediastinal lymphadenectomy, as noted by Altorki (1997a), Hagen (1993), Akiyama (1994) and colleagues, survival after transhiatal esophagectomy was equivalent to or exceeded the survival after a transthoracic resection, as reported by Orringer and associates (1999). Although Hulscher and colleagues (2002) found a trend toward improved long-term survival after extended transthoracic resection, the difference was not statistically significant, as shown in Fig. 150-21. Van Sandick and co-workers (2002) reported that 73% of margins were microscopically negative, which is similar to results found by Junginger and Dutkowski (1996) and Roder and colleagues (1994) after transthoracic esophagectomy.
Esophageal Substitutes
The stomach is used most commonly for esophageal replacement either intact or tubularized by excision of the cardia and lesser curvature. The stomach is well vascularized and usually has sufficient length to reach the neck. It is also relatively easy to mobilize and requires only a single anastomosis. However, there is potential for aspiration of acid and bile, and recurrent Barrett's can occur with continued reflux into the esophageal remnant, as noted by DeMeester (2001). The fundus of the stomach may also be involved in the field of radiation, which may affect healing and lead to strictures, and the distal margin may also be compromised in the resection of large tumors.
Colonic interposition provides excellent length and resistance to acid and allows a wide resection margin. Proponents of colonic interposition recommend the procedure for benign conditions because of better long-term function, as reported by DeMeester and co-workers (1988). Use of the colon requires preoperative colonoscopy or barium enema and angiography, when necessary, to evaluate the vascular supply. DeMeester (2001) and Thomas (1997) and their associates found a decrease in stricture rates and no significant difference in anastomotic leak or overall mortality rates reported in the literature. Furst and co-workers (2001) reviewed their experience with 53 colonic interpositions and also found no differences in complication rates. However, the procedure involves three anastomoses, and DeMeester (1988) and Wain (1999) and their associates have reported redundancy of colonic grafts occasionally requiring revision, ranging from 3.4% to 25% of cases. In addition, colonic grafts are contraindicated in patients with prior abdominal aortic aneurysm repair, colonic resection, inflammatory bowel disease, or extensive diverticulosis.
Extent of Surgical Resection
Proximal and Distal Margins
Because of the rich lymphatic network, there is often extensive longitudinal spread of disease along the esophagus. Several studies, including those by Tsutsui (1995) and Law (1998)
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and their colleagues, have evaluated the proximal extent of invasion. Miller (1962) found microscopic tumor in 3% of patients at 10.5 cm proximal to the primary tumor, and a 12-cm proximal resection margin has been recommended for a complete resection. Casson and co-workers (2000) retrospectively evaluated the distal resection margin in 189 patients and found that 12% of patients had a positive distal margin at a median of 2 cm. Patients with negative margins had a median 4-cm distal margin. Inadequate resection margins have been implicated in anastomotic leaks, recurrence, and possibly decreased survival. Casson and associates (2000) recommend a 5-cm distal margin of grossly normal foregut.
Table 150-8. Early Postoperative Course in 220 Patients Randomly Assigned to Transhiatal Esophagectomy or Transthoracic Esophagectomy with Extended En Bloc Lymphadenectomy | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Fig. 150-21. Kaplan-Meier plot showing overall survival of patients randomly assigned to transhiatal or transthoracic esophagectomy with en bloc lymphadenectomy. From Hulscher JB, et al: Extended transthoracic resection compared with limited transhiatal resection for adenocarcinoma of the esophagus. N Engl J Med 347:1667, 2002. With permission. |
En Bloc Resection
Skinner and associates (1983) proposed an extended en bloc resection for carcinoma of the esophagus. Both the respiratory tract and esophagus originate in the foregut, suggesting a common lymphatic and vascular supply to the middle and upper portions of the esophagus and lungs. As a result of these observations, Skinner and colleagues (1983) advocated removal of the local and regional lymphatic drainage, vascular supply, and serosa-like tissue abutting the esophagus. In 181 patients with carcinoma of the esophagus
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and gastric cardia, an en bloc resection was performed in 80 patients, with a mortality rate of 11%. Collard and colleagues (1991a, 1991b) reported that a posterior mediastinectomy, an en bloc resection, could be achieved in 79% of their patients, irrespective of the location of the tumor in the thoracic esophagus.
The fundamental difference between an en bloc resection of the esophagus and an esophagectomy without thoracotomy is that the mediastinal nodes are not radically removed during a transhiatal esophagectomy. The abdominal dissection is similar in both procedures. The completeness of the lymph node dissection and resection of the esophagus during an Ivor Lewis procedure lies somewhere between the previously described operations. Goldminc and colleagues (1993) reported no difference in morbidity, mortality, or the incidence of pulmonary complications in a prospective study of 67 patients randomly assigned to transthoracic esophagectomy with en bloc resection or transhiatal esophagectomy.
Three-Field Dissection
Altorki and Skinner (1997) reported unsuspected metastases to cervical lymph nodes in 35% of patients with esophageal squamous cell or adenocarcinoma, suggesting that at least one third of patients undergoing a standard or en bloc esophagectomy would not be disease free. Kato and associates (1991) reported a 30% 5-year survival rate, and Matsubara and co-workers (1994) found a 68% 5-year rate survival in patients undergoing a three-field lymph node dissection in whom cervical lymph nodes were the only site of metastasis. Ide and associates (1995) reported no significant difference in survival between patients with node-negative disease who underwent two-field or three-field dissection, whereas Tabira and associates (1999) reported no benefit in survival with five or more positive intrathoracic lymph nodes. They conclude that the three-field dissection is contraindicated in patients with more than four involved intrathoracic nodes (diagnosed by EUS), in tumors that extend beyond the esophagus to involve adjacent structures, and in elderly people. The absence of intrathoracic nodal involvement and the presence of supraclavicular lymphadenopathy could also be contraindications.
These reports have suggested a survival benefit in selected groups of patients after aggressive lymphadenectomy. For patients with one to four involved intrathoracic nodes, the 5-year survival rates were 55% versus 22% for the three-field and two-field dissections, respectively. There have been some reports of increased morbidity associated with these procedures, including injury to the recurrent laryngeal nerves. Isono and associates (1991) found that recurrent nerve paralysis occurred more often after three-field dissection but that there was no difference for anastomotic leak. Kato and colleagues (1991), however, found recurrent nerve paralysis with equal frequency, but anastomotic leak occurred more often with three-field dissection (34% versus 23%). Fujita and colleagues (1995) found recurrent laryngeal nerve paralysis in 70% of patients after three-field dissection. Nerve paralysis was temporary in more than half of these patients, and function recovered spontaneously.
Critics of this procedure believe that metastasis to the cervical lymph nodes implies systemic disease and that attempts at aggressive local control are not justified. Although Altorki and Skinner (1997) reported that 35% of patients are found to have occult cervical nodal metastases after three-field dissection, Orringer (1984) believes that it is the biological nature of the tumor rather than the extent of the resection that determines survival. Many patients have systemic disease at the time of resection, and O'Sullivan and co-workers (1999) found micrometastases in 88% of bone marrow specimens from rib resections performed at esophagectomy. In addition, Hulscher and associates (2000) report that cervical recurrence only occurred in 8.5% of 149 patients after transhiatal esophagectomy. Recurrence rates are similar after three-field dissection, with an 8.6% cervical recurrence rate as described by Fujita and colleagues (1994). Chemoradiotherapy may be an alternative to extensive nodal dissections. Although most surgeons currently agree with a wide resection around the lesion with sampling of involved and suspicious lymph nodes, to date, there have been no controlled, prospective trials to clarify the role and benefits of a three-field lymph node dissection.
Minimally Invasive Techniques
Minimally invasive approaches have resulted in shorter hospital stays and decreased postoperative pain for many procedures. Minimally invasive approaches to esophagectomy are technically challenging and only available in a few medical centers. Initially, thoracoscopy was combined with a laparotomy. Collard and associates (1993) described an en bloc thoracoscopic dissection and laparotomy for gastric mobilization. Two of 12 patients were converted for bleeding or respiratory compromise. Cuschieri and colleagues (1992) used a right thoracoscopic approach in 5 patients with a laparotomy and cervical incision. When compared with open resections, they found similar numbers of pulmonary complications.
Law and associates (1997b) described their experience with a combined thoracoscopic and laparoscopic approach and found decreased blood loss but no significant differences in complications or survival. DePaula and co-workers (1995) described performing a transhiatal esophagectomy laparoscopically in 11 of 12 patients. Although technically feasible, there were no clear decreases in morbidity or mortality. Nguyen and associates (2000) initially performed a laparoscopic transhiatal esophagectomy but switched to a combined laparoscopic and thoracoscopic approach for improved visibility. They compared a minimally invasive series to historical open transthoracic and transhiatal controls and reported decreased intensive care use, blood loss, operating
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times, and lengths of stay, although complication rates were similar. They concluded that there are significant advantages to a minimally invasive approach.
Fernando (2000) and Nguyen (2000) and co-workers have evolved to a combined thoracoscopic and laparoscopic approach. They argue that a laparoscopic esophageal mobilization is difficult and that thoracoscopy allows improved dissection of mediastinal lymph nodes with an increased number of nodes obtained. Glasgow and Swanstrom (2001) described a hand-assisted approach that may also serve as a bridge to more advanced experience. Melvin and co-workers (2002) described a single case using the robotic telemanipulator to perform an esophagectomy with an intrathoracic anastomosis. The three-dimensional visualization and multiarticulated arms, as shown in Fig. 150-22, may provide technical benefits, although this approach has not been extensively evaluated.
Although port site recurrence was initially reported after laparoscopic colectomy by Wexner and Cohen (1995), port site recurrence has not been widely reported for minimally invasive esophagectomy. Law and colleagues (1997b) reported two port site recurrences in 22 patients, but Litle and associates (2002) found none in a series of 400 patients at the University of Pittsburgh, nor were there any in more than 300 patients at the University of Maryland described by Krasna and co-workers (1996). All biopsies and specimens should be placed in a retrieval bag before removal. Minimally invasive esophagectomy is technically demanding. Several studies have found no significant improvement in postoperative complications or length of stay. The benefit of smaller port sites compared with open thoracotomy may be offset by the increased time under single-lung anesthesia. Tsui and associates (1997) reported that improvements in pain relief and perioperative care may have also decreased the deleterious effects of thoracotomy and laparotomy. As results continue to improve with increasing experience, further prospective studies are needed to determine whether there are significant differences in costs, complication rates, and postoperative pain and recovery.
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Fig. 150-22. Dissection of the gastroesophageal junction using a robotic telemanipulator allowing three-dimensional visualization and improved dexterity using multiarticulated arms. |
Adenocarcinoma of the Gastroesophageal Junction
Cancers of the gastroesophageal junction are now classified according to the system described by Rudiger Siewert and colleagues (2000). Type I tumors are within 1 to 5 cm of the anatomic gastroesophageal junction, type II tumors lie between 1 cm above and 2 cm below, and type III tumors are between 2 and 5 cm below the junction. Recent series have based the extent of surgical resection and lymph node dissection on the Siewert classification.
In a series of 126 patients, Mariette and co-workers (2002) reported a 25.1% 5-year survival rate. Survival was associated with a complete resection, nodal status, and tumor differentiation. Type I tumors were resected by transhiatal or en bloc transthoracic esophagectomy, proximal gastrectomy, a D2 abdominal (splenic, left gastric, and celiac axis) lymph node dissection, and reconstruction using a gastric tube or colonic interposition. Type II and III tumors were resected using a total gastrectomy, transhiatal resection of the distal esophagus, a D2 or D3 (hepatoduodenal and mesenteric) lymph node dissection, and an esophagojejunostomy. Postoperative morbidity, mortality, and long-term survival were not dependent on the surgical approach. De Manzoni and colleagues (2002) reviewed 96 patients using similar surgical protocols. Mortality rates were not significantly different regardless of the surgical approach used. Although a complete resection was achieved in 85.4% of cases, the 5-year survival rate was poor at 24%, and survival was related to nodal status.
High-Grade Dysplasia
The management of high-grade dysplasia is controversial. Although there is an increased risk for esophageal adenocarcinoma, the natural history is unknown. Levine (1996) and Reid (2000) and co-workers reported that 19% to 59% of patients with high-grade dysplasia subsequently developed cancer on surveillance. DeMeester (2002), among others, recommends an esophagectomy because of elevated risks for cancer. However, some suggest continued surveillance and believe that aggressive biopsies can detect adenocarcinoma. Schnell and colleagues (2001), in a study of 75 patients with high-grade dysplasia, found that only 16% developed cancer with frequent surveillance biopsies over 7 years. Cameron and associates (1997) followed 23 patients with preoperative biopsies. Only 1 of 15 esophagectomy specimens was found to have adenocarcinoma.
There are inherent false-negative diagnoses, however, because random biopsies may miss dysplasia and carcinomas separated by large areas of Barrett's epithelium. Several retrospective studies have shown difficulty in differentiating
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high-grade dysplasia from adenocarcinoma using endoscopic surveillance. The incidence of missed cancers ranges from 0% to 73% of specimens removed for high-grade dysplasia. Heitmiller and colleagues (1996) reported that 43% of 30 specimens resected for high-grade dysplasia were found to have adenocarcinoma and that 17% were stage II or III. Rice and associates (1993) reported a 38% incidence and Pera and colleagues (1992) found a 50% incidence of missed adenocarcinomas on surveillance, as shown in Table 150-9. Although some reports have been criticized for not reporting the extent of preoperative biopsies, Peters and co-workers (1994) described 23 patients referred for high-grade dysplasia who underwent extensive repeat biopsies. Nine patients were found to have adenocarcinoma. However, esophagectomy still revealed a 43% biopsy error rate, with 6 additional patients with adenocarcinoma.
Currently, histopathology is the most reliable way to identify patients with adenocarcinoma. Vital stains and magnified views to improve diagnosis are under investigation. In addition, the search for reliable molecular markers is an active area of research. Newer ablative therapies show promise and are being evaluated for the ablation of dysplastic lesions and even intramucosal adenocarcinomas. Although surveillance may be a reasonable approach in selected patients and certain centers, it carries the risk for missing an early adenocarcinoma. Until more accurate surveillance methods, molecular markers, and effective ablative techniques are available, esophagectomy remains the standard in the treatment of high-grade dysplasia.
Mucosal Ablation
Some investigators have had success with mucosal ablation in limited trials with squamous reepithelialization, but effective antireflux therapy is critical. Techniques include thermal heater probes and lasers, mucosal resection, and photodynamic therapy. Salo and associates (1998) reported successful neodymium:yttrium-aluminum-garnet (Nd:YAG) laser ablation after antireflux surgery in 11 patients who had complete squamous regeneration after a mean of 26 months. However, most series, including a study by Wang and Sampliner (2001), have found persistent areas of intestinal metaplasia underlying the squamous epithelium.
Table 150-9. Incidence and Stage of Incidental Esophageal Cancer Found in Patients with Barrett's Esophagus after Esophagectomy for High-Grade Dysplasia | ||||||||||||||||||||
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Mucosectomy was first reported in Japan and involves injecting saline and epinephrine into the submucosal space to elevate the target area, which is then removed with a polypectomy snare. Endoscopic mucosal resection has been described by Kodama and Kakegawa (1998) for early-stage esophageal squamous cell carcinoma but should only be used for lesions confined by the lamina propria, for which there is a minimal risk for lymph node metastases, and with close follow-up by CT scan and EUS. Mucosectomy can also be used in debilitated patients who would not tolerate an esophagectomy. However, lesions must be visibly identifiable to be targeted using this technique.
Photodynamic therapy is the most attractive method of mucosal ablation and involves the systemic injection of a photosensitizer targeting dysplastic cells. After 24 to 48 hours, light is used to produce oxygen radicals. All devitalized tissue is irrigated away 48 hours later. Using this technique, Overholt and associates (1999) reported that 90% of lesions cleared or down-staged to low-grade dysplasia, although 83% required repeat laser treatment 3 to 6 months later for residual Barrett's mucosa. Esophageal mucosal repair occurred over 2 to 3 months and was complicated by strictures in 34% of cases.
Some investigators are evaluating the ablation of intramucosal adenocarcinomas. However, in 25 patients with intramucosal adenocarcinoma on biopsy without visible endoscopic lesions, 12% were found on operative pathology to involve the submucosa, and 1 of 10 patients had a positive lymph node metastasis. Of 12 patients with visible lesions and intramucosal adenocarcinoma on biopsy, two involved the muscularis propria, two penetrated the esophageal wall, and five of nine had positive lymph nodes. Overholt and co-workers (1999) followed 13 patients who underwent photodynamic therapy for superficial esophageal adenocarcinoma. Two patients developed cancer and underwent esophagectomy. DeMeester (2002) concluded that the lack of a visible lesion on endoscopy does not eliminate the possibility of invasion beyond the muscularis mucosa and that patients with high-grade dysplasia or intramucosal adenocarcinoma should undergo esophagectomy.
Multimodality Therapy
Radiation Therapy
Many surgeons advocate adjuvant therapy for patients with esophageal carcinoma owing to the poor survival rates following resection, except in patients with early disease. Radiation therapy alone used to be the only effective alternative
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to surgery. Pearson (1977) reported the best results for radiation therapy as the primary therapeutic modality for esophageal cancer with a 1-year survival rate of 44% and a 5-year survival rate of 22%. This series included mainly tumors of the cervical esophagus, and similar results have not been confirmed by others. Results of a large review published by Earlam and Cunha-Melo (1980) with more than 8,000 patients show 1-, 2-, and 5-year survival rates of 18%, 8%, and 6%, respectively, with irradiation as the primary treatment for esophageal carcinoma. The treatment dose is typically 55 to 65 Gy. Radiation therapy tends to be given because of high surgical risk or to patients with advanced or metastatic disease who are not amenable to surgical therapy. Although many still recommend irradiation as primary treatment, the emphasis has been shifted to multimodality treatment, in which chemotherapy is given in addition to radiation therapy.
Several trials of neoadjuvant radiation therapy from Arnott (1992), Nygaard (1992), Wang (1989), Gignoux (1987), and Launois (1981) and their associates have failed to show increased resection rates or improved survival compared with surgery alone. Postoperative irradiation has been shown to decrease local recurrence rates but has not improved survival rates, as reported by Zieren (1995), Fok (1993), and Teniere (1991) and their colleagues.
Chemotherapy
Law and associates (1997a) showed that neoadjuvant chemotherapy resulted in significant down-staging of disease in nearly 50% of patients, but a pathologic complete response rate was seen in less than 10%. A marginal survival benefit was noted for this subgroup of patients. Kelsen and associates (1998) reported a large multicenter study of neoadjuvant chemotherapy versus surgery alone, which included 440 patients. At 2-year follow-up, no significant survival benefit was seen.
Chemoradiation Therapy
The role of chemoradiation therapy is a topic of recent interest, and combined chemoradiation therapy is now the standard for nonsurgical management of locally advanced disease, as described by Herskovic and colleagues (1992). The Radiation Therapy Oncology Group randomized trial reported by Al-Sarraf and associates (1997) is widely believed to provide convincing evidence of the superiority of chemoradiation over radiation therapy alone. The 2- and 5-year survival rates were 36% and 27% in the chemoradiation group, compared with 10% and 0% in the group treated with radiation alone. There was also a reduction in both local recurrence and distant disease. Toxicities, however, were substantial.
The combination of chemoradiation with surgery has resulted in significant down-staging of disease, but a consistent survival advantage has not yet been demonstrated. Most regimens are cisplatin based and are commonly combined with 5-fluorouracil. Urba and associates (1997) followed 100 patients who underwent transhiatal esophagectomy following neoadjuvant chemoradiation therapy (75% with adenocarcinoma), as shown in Table 150-10. Twenty-eight percent had a pathologic complete response, and a 3-year survival advantage was seen (32% versus 15%) as well as a reduction in locoregional recurrence (39% versus 19%). Similar results were not observed in trials that included only squamous cell cancers, including those by Bosset (1997) and Apinop (1994) and their associates.
Although some trials have shown long-term survival only in complete responders, others have reported long-term survival in partial responders after surgical resection, as reported by Forastiere and co-workers (1993). In a review by Coia and associates (2000) of 400 patients with locally advanced disease, there was a trend toward improved survival with surgery and chemoradiation. Studies reported by Coia (2000) and Cooper (1999) and their colleagues
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have evaluated chemoradiation therapy without surgery but found local recurrence rates as high as 40% to 60%, with no improvement with increased doses.
Table 150-10. Phase III Trials in Preoperative Chemoradiotherapy | ||||||||||||||||||||||||||||||||||||||||||||||||
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Fig. 150-23. Survival stratified by stage after esophagectomy for esophageal adenocarcinoma in 88 patients. From Moon MR, et al: Transhiatal and transthoracic esophagectomy for adenocarcinoma of the esophagus. Arch Surg 127:953, 1992. With permission. |
Newer agents, including taxanes and irinotecan, are being evaluated in chemoradiation therapy trials and may have promising antitumor activity as well as improved tolerance. In addition, new, targeted therapies against growth factor receptors, angiogenesis, or the prevention of tumor invasion are being investigated in the treatment of esophageal carcinoma. No randomized trials to date have directly compared chemoradiation therapy with surgery alone as monotherapy, and further clinical studies are needed to identify the best multimodality regimens. At this time, surgery remains the standard treatment for resectable esophageal cancer. For patients with locally advanced disease and those unfit for surgery, chemoradiation therapy appears to be a reasonable alternative.
Outcomes
Prognostic Factors
Overall survival for patients with esophageal carcinoma at 5 years remains poor at 5% to 12% according to Mason and colleagues (2001), and the median survival is 23 months. The stage at diagnosis is the strongest determinant of prognosis, as reported by Farrow and Vaughan (1996) and depicted in Fig. 150-23. Five-year survival rates greater than 80% can be seen after surgical resection in patients with lesions identified early and with invasion limited to the mucosa. However, most lesions are diagnosed at an advanced stage, and according to SEER data between 1989 and 1995, Ries and colleagues (1999) found a 5-year survival rate of 24.9% for localized disease, 12.7% for regional disease, and 1.9% with distant metastases. Similar results were reported by Eloubeidi and co-workers (2002) in Fig. 150-24.
Eloubeidi and associates (2002) identified other prognostic factors, including increased age, African-American race, length of the lesion, lower esophageal tumors, and depth of invasion based on 10,441 patients in the SEER database. Metastatic spread to more than five lymph nodes was also an indicator of poor prognosis. Nigro and co-workers (1999) found a 5-year survival rate of 23% with less than four positive lymph nodes and 12% in patients with greater than four positive nodes. In addition, van Sandick and co-workers (2002) reported that the ratio of positive to negative lymph nodes is a strong predictor of mortality.
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Fig. 150-24. Kaplan-Meier survival curves for 7,575 esophageal carcinoma patients stratified by tumor stage. From Eloubeidi MA, et al: Prognostic factors for the survival of patients with esophageal carcinoma in the U.S.: the importance of tumor length and lymph node status. Cancer 95:1437, 2002. With permission. |
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Hospital Volume
Several studies have evaluated the relationship of hospital volume to outcomes for a variety of complex procedures, including coronary artery bypass grafting, heart transplantation, aortic aneurysm repair, and pancreatic resections. Esophagectomy is technically demanding and has been shown in a number of reports to be related to hospital volumes. In a review of 1,136 patients in a Maryland statewide database, Dimick and colleagues (2001) found that high-volume centers, defined as hospitals performing greater than 15 esophagectomies per year, had a fivefold reduction in hospital mortality, as depicted in Fig. 150-25. Kuo and associates (2001) reviewed 1,193 patients in Massachusetts and found similar results with a 2-day decrease in length of stay and a 3.7-fold decrease in hospital mortality in centers performing more than six esophagectomies per year. This may be due to a number of factors, including improved operative and organizational resources. Outcomes are also clearly associated with the experience of the individual surgeon. Miller and co-workers (1997) found significantly decreased in-hospital mortality rates in patients treated by surgeons who perform greater than six esophagectomies per year.
CONCLUSIONS
The evaluation and management of esophageal cancer continue to present significant challenges to thoracic surgeons. The incidence of esophageal adenocarcinoma has increased rapidly during the past three decades and represents the fastest growing solid malignancy in the United States. Significant advances have been made in surgical techniques and patient care resulting in markedly improved perioperative mortality rates, although morbidity remains relatively high. Despite recent advances, the prognosis of both esophageal squamous cell and adenocarcinoma remains poor. Improved understanding of the molecular changes involved will improve our understanding of the pathogenesis of esophageal cancer as well as providing novel methods of diagnosis, staging, and treatment that will allow surgeons to identify patients who will benefit from early surgical resection or neoadjuvant therapy.
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Fig. 150-25. In-hospital mortality for patients in low-, medium-, or high-volume hospitals after esophagectomy in Maryland from 1984 to 1999. From Dimick JB, et al: Hospital volume is related to clinical and economic outcomes of esophageal resection in Maryland. Ann Thorac Surg 72: 337, 2001. With permission. |
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