Polyps and Tumors of the Esophagus
Most tumors of the esophagus that cause symptoms are malignant. Of these, over 95% are either squamous cell carcinoma or adenocarcinoma. Squamous cell carcinoma has been the most common esophageal malignancy worldwide in the past and continues to be so in Eastern countries and in many developing countries. However, the incidence of adenocarcinoma has increased dramatically in the Western world with approximately a sixfold increase from 1975 to 2001 in the United States where currently adenocarcinomas constitute 50% to 80% of esophageal cancers diagnosed and have replaced squamous cell carcinoma as the predominant type of esophageal cancer.1, 2 The majority of these cancers arise on the background of the columnar-lined (Barrett’s) esophagus, or intestinal metaplasia in native cardiac mucosa, which may be related, at least in some instances. A classification of esophageal tumors is presented in Table 11-1.
Table 11-1 Classification of Esophageal Tumors | ||||||||||||||||||||||||||||||||||
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ROLE OF THE PATHOLOGIST
In the biopsy diagnosis of tumors, the major challenge for the pathologist is in being aware of diagnostic pitfalls, particularly at the edge of an ulcer, where, in squamous mucosa, severe basal cell hyperplasia can be mistaken for carcinoma in situ or even early invasion; on frozen sections, endothelial channels in granulation tissue can be mistaken for adenocarcinoma; and in any form of erosion, bizarre stromal cells can be mistaken for an undifferentiated neoplasm.
In resections of all esophageal carcinoma, if there is any possibility of extending the proximal resected margin, frozen section of the proximal margin should be considered so that if tumor extends close to it, an additional margin can be resected. The presumption is that this provides at least the possibility for the resection to be curative and is less likely to result in anastomotic recurrences. A practical problem is whether the frozen section should be taken transversely or longitudinally, and arguments for and against both ways can be made. A transverse section may need to be partially or completely circumferential in several frozen sections. Longitudinal sections immediately proximal to the epicenter of the tumor have the advantages that the submucosa is more readily visualized and the resected margin is clear, but several frozen sections may be required to increase the chance of detecting focal lymphatic involvement. Some surgeons begin a thoracoabdominal approach by requesting a frozen section of a celiac lymph node, knowing that if it is positive, a curative resection will not be carried out.
Many unusual tumors of the esophagus are polypoid. For this reason, when polypoid lesions are encountered, the index of suspicion that an unusual tumor such as spindle cell carcinoma and melanoma may be present should be high. It is therefore wise to anticipate that these tumors may well require electron microscopy and immunohistochemistry for diagnosis.
The pathologist has come to have an increasing role in the diagnosis of dysplasia and microinvasive carcinoma in both squamous and Barrett’s esophagus. In addition, the apparent increase in the prevalence of adenocarcinoma of the lower esophagus requires accurate documentation in distinguishing tumors that are primarily in the lower esophagus, from those in the gastric cardiac, or from those in the stomach. Although this distinction may seem academic, it may be of much greater significance epidemiologically; it is best accomplished at the time of resection. The epicenter of the tumor in relationship to the upper end of the gastric folds internally as this provides the best landmarks. This is discussed with adenocarcinoma
SQUAMOUS CELL CARCINOMA
Squamous cell carcinoma is a malignant epithelial tumor with squamous differentiation, which is microscopically characterized by keratinocyte-like cells with or without intercellular bridges, keratinization, or both. This type of esophageal cancer is declining in Western countries but is still most common in the Eastern countries. Most carcinomas of the esophagus still present at an advanced stage, frequently with transmural spread, lymph node metastasis, or both; either of these features portends a very poor prognosis. The approximate percentage of each tumor stage is stage I in 8%, stage II in 42%, stage III in 33%, and stage IV in 13%.3 In parts of the world where this tumor is very common, attempts at early detection have yielded tumors
of earlier pathologic stages. The incidence of stage IV tumors has also been declining in the United States and survival has been steadily improving, independent of all other risk factors. Part of this may be due to finding early tumors endoscopically, especially with more early lesions being found and resected endoscopically. In advanced tumors, neoadjuvant chemoradiotherapy mostly with cisplatin and 5-fluorouracil improves local tumor control leading to more R0 curative resections with clear margins. However, this may not significantly improve overall survival.2, 4, 5, 6, 7
of earlier pathologic stages. The incidence of stage IV tumors has also been declining in the United States and survival has been steadily improving, independent of all other risk factors. Part of this may be due to finding early tumors endoscopically, especially with more early lesions being found and resected endoscopically. In advanced tumors, neoadjuvant chemoradiotherapy mostly with cisplatin and 5-fluorouracil improves local tumor control leading to more R0 curative resections with clear margins. However, this may not significantly improve overall survival.2, 4, 5, 6, 7
Pathogenesis and Clinical Features
In general, half of squamous cell carcinomas occur in the middle third of the esophagus, a third in the lower third, and the rest in the upper third. Tumors arising at the gastroesophageal junction are called exactly that and are judged by their center and relation to the esophagi gastric junction externally and from the upper end of the gastric folds and relationship to the squamoesophageal junction internally.
The median age for esophageal carcinoma is around 65 in both males and females, and males are affected far more frequently than females.8 In the United States, squamous cell carcinoma is two to three times more frequent among African Americans than among Whites, Asians, or Native Americans.9
The most common clinical symptom is dysphagia, which is usually progressive and frequently accompanied by anorexia and weight loss. While carcinomas limited to the mucosa or submucosa are frequently asymptomatic, dysplasia sometimes produces odynophagia, possibly because of failure of keratinization.
Retrosternal pain, food sticking, dry throat, and back soreness may occur. These symptoms suggesting an esophageal tumor are usually investigated initially with barium swallow or endoscopy. However, if barium testing is used initially, ultimately an upper endoscopy will be required to facilitate biopsy. In screening programs in high-risk populations, esophageal balloon cytology, endoscopy, iodine stain, and multipoint biopsy may be the best approach for early detection of carcinoma.10 Balloon cytology is reported to have a sensitivity of 89% and a specificity of 91%.11
Risk Factors
Geographic distribution: association with smoking and alcohol. There are several high-incidence regions throughout the world; however, the likely major predisposing cause varies markedly from one to the other. These areas include northwestern France, northern Italy, parts of southern and eastern Africa, and southern Brazil as well as the Asian belt stretching from Iran through Afghanistan to central China. The incidence varies from about 30 to 200/100,000 with a strong male predominance of up to 6:1.12, 13 In these regions, esophageal cancer is usually the most prevalent cancer and results in 30% of all cancer-related deaths. The comparable figure for North America and remaining Europe does not exceed 8/100,000.14
Smoking and alcohol drinking appear to be the major risk factors with dose-response.15, 16, 253 Several studies have suggested that smoking increases the likelihood of developing squamous cell carcinoma of the esophagus two to six times.14, 17, 18 Chewing tobacco may well be as harmful as smoking it, and in India it seems to be associated with about a threefold increase in the disease. In Africa, North America, and the rest of Europe, it is quite unusual to encounter squamous cell carcinoma in patients who are not heavy drinkers.17 This association is independent of tobacco use; in France, alcohol alone seems to be the major predisposing factor.
Although much work has been done on dietary factors, the major etiologic links seem to be with opium in Iran and possibly in the Transkei region of Africa. In Iran, households with a patient having esophageal cancer have much higher levels of urinary opiate metabolites than control households from the same village.19
Diet. A variety of dietary deficiencies resulting from malnutrition have been postulated as predisposing to esophageal cancer, including deficiencies in vitamins A, C, E, and riboflavin, as well as in trace elements such as zinc and molybdenum; indeed these have been postulated for the weak association with celiac disease. A low-protein or low-calorie diet is a possible risk factor. Indeed, increased consumption of meat, eggs, and increased BMI have been reported to be protective factors for squamous cell carcinoma.20 In high-risk areas of China, drinking shallow ground water and frequent intake of pickled vegetables and fermented fish sauce are associated with the development of esophageal cancer.16, 21 Consumption of fresh fruits and fresh vegetables may decrease the risk.16, 20, 21 Although drinking of very hot beverages, which causes thermal injury leading to chronic esophagitis, has also been proposed, these beverages are not associated with risk of esophageal squamous cell carcinoma or adenocarcinoma in a Western population.22
Genetic factors. Family history of esophageal squamous cell carcinoma is a risk factor for this disease.23, 24 A meta-analysis using data from three case-control studies conducted in Italy and Switzerland shows that the alcohol- and tobacco-adjusted odds ratio for a family history of esophageal cancer was 3.2 in first-degree relatives; an odds ratio is more than 100 for subjects who currently intake both tobacco and alcohol and
also have the family history.24 The risk of esophageal squamous cell carcinoma is increased in subjects with a family history of cancer of the oral cavity/pharynx and stomach, but not of other cancers.24
also have the family history.24 The risk of esophageal squamous cell carcinoma is increased in subjects with a family history of cancer of the oral cavity/pharynx and stomach, but not of other cancers.24
Human papillomavirus infection. Although human papillomavirus (HPV) is well known to be strongly associated with dysplasia and squamous cell carcinoma of the uterine cervix, its role in esophageal cancer is controversial. In high-risk areas of China, the incidence rate for HPV in squamous cell carcinoma tissue is 17% by in situ hybridization and 65% by polymerase chain reaction.25, 26 Further analysis in the latter study shows that the high-risk HPV type 16 and 18 are found in the cancer cells (43%), whereas the low-risk HPV type 6 and 11 are seen mainly in the normal mucosa (52%).25 HPV and p16 silencing may have an etiologic role in esophageal carcinogenesis at least in the high-incidence areas such as China, Korea, Iran, and Greek.25, 26, 27, 28, 29. The silencing of p16 was reported also from the United States.30 However, conflicting results with the incidence rates of 0 to 5% have been reported mainly from Western countries.31, 32
Other risk or protective factors. Free silica dust is suggested to be a possible etiologic factor of esophageal cancer. Among caisson workers who had a higher exposure to silica dust, the relative risk of esophageal cancer has been reported to be more than four and significantly high even after adjusting for the effects of smoking and alcohol drinking.33 In contrast, chronic intake of rofecoxib and celecoxib (selective cyclooxygenase 2 [COX-2] inhibitors) and nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) appears to be associated with a decreased incidence of esophageal cancer.34 A randomized control trial suggested that selenomethionine, a synthetic form of organic selenium, might have a protective effect.35 Infection with Helicobacter pylori may reduce the risk of esophageal adenocarcinoma, but gastric atrophy and infection with CagA-positive strains may increase the risk for esophageal squamous cell carcinoma.36
Predisposing Conditions
Celiac sprue. This may be associated with squamous carcinoma of the esophagus,37 possibly because of deficient absorption of vitamins and trace metals38
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