appear as multiple, small, irregular, wartlike mucosal projections. Their histology resembles that seen in isolated papillomas. In children, esophageal papillomatosis is often associated with recurrent respiratory papillomatosis, which is usually related to HPV infection (6). Esophageal papillomatosis can result from chronic inflammation from HPV infection, gastroesophageal reflux, prolonged nasogastric intubation, or the use of esophageal self-expanding metal stents. Papillomatosis is thought to have higher malignant potential than do single lesions (15,16). Papillomatosis may also be associated with SCCs at other sites (17). Florid cutaneous and mucosal papillomatosis can be seen in association with malignant acanthosis nigricans, most often due to gastric carcinoma.
TABLE 3.1 WORLD HEALTH ORGANIZATION CLASSIFICATION OF ESOPHAGEAL EPITHELIAL TUMORS
underlie the decreasing prevalence of ESCC in many Western countries. Conversely, increased rates of tobacco and alcohol use in Taiwan are suspected to be the cause of that country’s recent increase in ESCC cases (37).
TABLE 3.2 TNM CLASSIFICATION OF ESOPHAGEAL CARCINOMAS
FIG. 3.1 Esophageal papilloma composed of vascular connective tissue cores covered by hyperplastic squamous epithelium with surface koilocytes. (Courtesy of Dr. Barbara Winkler, New York, NY.)
FIG. 3.2 Squamous papilloma in an adult with multiple lesions involving the upper respiratory tract due to human papilloma virus types 6 and 11. Cytopathic epithelial changes consist of koilocytosis and minimal nuclear atypia.
TABLE 3.3 ENVIRONMENTAL RISK FACTORS FOR ESOPHAGEAL CARCINOMA
nourished Chinese population (56). Moreover, a large metaanalysis found no benefit for supplementation with vitamin A, vitamin C, vitamin E, beta-carotene, riboflavin, zinc, or selenium, alone or in various combinations (57). Therefore, a causal role for micronutrient deficiency in ESCC has not been definitively established.
substance) emerges on average 30 years after the initial injury, usually near the site of tracheal bifurcation. These so-called corrosion carcinomas may have a better prognosis than does routine ESCC, possibly due to the younger age of the patients and the presence of disease-limiting scar tissue (79). Postprandial food retention causes esophagitis and a subsequent increased risk of ESCC in patients with diverticula (such as Zenker) (80) and motility disorders, including achalasia (81) and systemic sclerosis (82). The esophagitis that accompanies Plummer-Vinson syndrome is also associated with an increased risk of SCC in the hypopharynx and upper esophagus (83). Celiac disease, which may cause iron deficiency anemia leading to Plummer-Vinson syndrome, has also been associated (83). Somewhat surprisingly, atrophic gastritis is associated with a twofold increase in ESCC (84). This is thought to be due to achlorhydria, which may allow proliferation of bacteria and increased production of acetaldehyde and N-nitroso compounds. However, the extent of atrophy does not correlate with the risk of ESCC, and some authors have proposed that the association is not causal but due to mutual association with smoking (85). Interestingly, Helicobacter pylori infection has been associated with an increased risk of ESCC in Western populations (86) but may be protective in Asian populations (87,88). The reasons for this dichotomy are not clear, but may be related to dietary and lifestyle factors as well as genetic differences.
but studies from a high-risk Chinese population found that the risk of progression to ESCC after 3.5 years was 5%, 27%, and 65% for mild, moderate, and severe dysplasia (104). This risk increased to 24%, 50%, and 74% after 13.5 years (98).
FIG. 3.4 Diagram of the progressive acquisition of molecular abnormalities as the epithelium progresses from normal to invasive cancer.
as well as abnormal mitotic figures, including ring mitoses. Typically, radiation change is associated with a maintained (low) nuclear:cytoplasmic ratio. If one is unable to distinguish between dysplastic and regenerative changes, one can use the term “indefinite for dysplasia” to describe the changes that are present. Subsequent biopsies, particularly those obtained once the inflammation has been treated, often help clarify the nature of the underlying process. Immunostaining for p53 may also help distinguish dysplasia from reactive changes. While this test is by no means specific, the presence of large numbers of p53 immunoreactive cells (as opposed to only isolated positive cells) is much more likely to occur in areas of dysplasia than in reactive lesions.
TABLE 3.4 FEATURES USEFUL IN DISTINGUISHING REACTIVE FROM NEOPLASTIC SQUAMOUS EPITHELIUM
pathologists. These pathologists use the term early esophageal cancer to designate a neoplastic process that is confined to the mucosa or submucosa. Therefore, in Japan, ESCCs can include cases judged to be noninvasive, low-grade dysplasia in the West. This difference may contribute to widely variant incidence rates and predictions of prognosis. In an effort to address these differences, the Vienna Classification was developed (Table 3.5) (110), although it has not been widely adopted.
TABLE 3.5 VIENNA CLASSIFICATION
odynophagia, weight loss, coughing, choking, pain, and dehydration (115). Frequently, patients do not complain of dysphagia but make subtle changes in their eating habits without realizing it. Other symptoms include fever, anemia, hematemesis, melena, hoarseness, or the sensation of food “becoming stuck in the throat.” A persistent hiccup may indicate the presence of laryngeal nerve paralysis, a sign of advanced disease. Local tumor extension beyond the esophagus often leads to substernal or high back pain. Aortic erosion results in rapid exsanguination. Aspiration of esophageal contents through a tracheoesophageal fistula is a common cause of death in patients with advanced ESCC. Palpable lymph nodes in the cervical or supraclavicular regions may be noted.
thickening. Rarely, the pattern resembles the linitis plastica pattern seen in gastric carcinoma.
FIG. 3.9 Well-differentiated keratinizing squamous cell carcinoma. A: Note the infiltrating nests with prominent central keratinization. B: The nuclear-to-cytoplasmic ratio is increased relative to normal.
FIG. 3.10 Moderately differentiated invasive squamous cell carcinoma. Note the absence of marked atypia, keratinization, and pearl formation.
FIG. 3.11 Poorly differentiated invasive squamous cell carcinoma. Note the high degree of atypia and the brisk mitotic index.
In Western populations, up to 61% of patients show local extension and nodal involvement at the time of diagnosis (124). Previous staging guidelines emphasized the location of involved nodes, but data suggest that the number of involved lymph nodes is the more important prognostic factor. Many authors have reported a high rate (30% to 40%) of lymph node micrometastases (detected by immunohistochemistry) in ESCCs originally classified as node negative by routine histopathologic examination (125,126,127,128). In most studies, micrometastases were associated with decreased survival or time to recurrence.
FIG. 3.15 Well-differentiated squamous cell carcinoma of the esophagus. A-D: Variably shaped cells are found singly and in small groups.