Esophageal cancer is a gastrointestinal malignancy that encompasses a range of pathologic entities. Squamous cell carcinomas constitute at least 90% of all cancers worldwide.1 Adenocarcinoma is the second most common type of cancer. Other types, such as small cell carcinoma and malignant melanoma are rare. The incidence of esophageal adenocarcinoma has increased in the United States from 0.5 to 0.9/100,000 in the 1970s to 3.2 to 4.0/100,000 in the 1980s and 1990s. Although esophageal adenocarcinoma accounted for about 16% of all esophageal cancers among White men in the United States in the mid-1970s, by the late 1990s, this number approached 50%. This increase has been seen across all socioeconomic groups2 but has been most pronounced in affluent populations.3–7 Over the same period of time, there has been a decline in both esophageal squamous cell carcinomas and adenocarcinomas of the distal stomach.8,9 Barrett esophagus is a metaplastic condition in which normal squamous mucosa of the distal esophagus is transformed into intestinalized columnar epithelium. Barrett esophagus is the established precursor lesion for nearly all esophageal adenocarcinomas.
Squamous Cell Carcinoma and Variants
Squamous cell carcinoma of the esophagus is relatively infrequent in much of Western Europe and North America, but is a major disease for a large proportion of the world’s population. About 80% of cases occur within developing countries.10 In the United States, squamous cell carcinoma continues to represent the most common type of esophageal cancer in African Americans. The highest rates are found in the Asian esophageal cancer belt region, which extends from Turkey to Iran, Iraq and Kazakhstan to Northern China. Squamous cell carcinoma is the most prevalent type of esophageal cancer in this region. However, even within this region, there are sharp gradients of incidence between regions that lie only a few hundred miles apart. In Europe, where the incidence of squamous cell carcinoma is low, pockets of high incidence occur, such as in Normandy and Brittany.11
The etiology of squamous cell carcinoma is most likely multifactorial. Epidemiological studies have provided evidence that causative agents may act synergistically and may differ between geographical regions and between high-risk versus low-risk areas.
Cigarette smoking and alcohol consumption have both been associated with an increased predisposition for esophageal cancer, and the association is stronger with squamous cell carcinoma compared to adenocarcinoma. Smokers are at three to seven times greater risk of developing squamous cell carcinoma compared with the general population.12–15 There is a statistically higher incidence of esophageal carcinomas among patients who smoke or chew tobacco, and this is equally true for pipe users, cigar, and cigarette smokers.16 Among combined drinkers and smokers, the risk rises considerably with increased alcohol consumption, compared to increasing tobacco consumption.15 In the United Kingdom, variations in the rate of esophageal cancer have closely paralleled total alcohol consumption, with only a short lag, suggesting that the effect of alcohol may be on the later stages of carcinogenesis, as a tumor promoter.
Esophageal carcinomas are frequently associated with multiple primary tumors in the mouth, pharynx, stomach, or intestine.17,18 It has been suggested that this finding may be related to ingestion of nicotine and other carcinogenic substances.18 In some high-risk populations in South Africa and India, tobacco appears to play a more important role than alcohol.19,20
Fungal esophagitis, mostly due to Candida spp., is very common in the Linxian province of China and has been postulated as a possible etiological factor in esophageal carcinogenesis. Recent research has focused on the role of human papillomavirus (HPV) infection in esophageal carcinoma.21–27 Histological changes in esophageal squamous cell carcinomas similar to condylomatous genital lesions have been observed.28 The reported prevalence of HPV in squamous cell carcinoma of the esophagus has varied widely from 0% to 71%. The variation may be due to true geographic variation in pathogenesis, variation in techniques used to detect HPV, different thresholds to classify cases as being HPV positive, and, in some instances, it may simply reflect sample contamination. The marked difference in association of esophageal cancer with HPV infection has led the International Agency for Research on Cancer to recently conclude that “there is inadequate evidence in humans for carcinogenicity of HPV in the esophagus.”29
There is an increased risk of esophageal carcinoma after ingestion of lye (crude sodium hydroxide with sodium carbonate), typically after a time interval of 40 years.30,31 The evidence for development of cancer in strictures from other causes is less convincing.32 Esophageal cancer has been reported following therapeutic radiation for neck and spinal diseases,33 after radiation to the chest for breast carcinoma and, less frequently, for lymphoma.34 Polycyclic aromatic hydrocarbons may also play a role in the pathogenesis of esophageal cancer.35,36
A study from Northern Iraq found a positive family history of esophageal cancer in 47.1% of patients in high-risk regions, compared with only 2% among the low-risk population.37 Familial esophageal cancer in families associated with keratosis palmaris and plantaris (tylosis), inherited as a dominant trait, have been described.38–40 The tylosis esophageal cancer (TOC) gene locus was recently mapped to chromosome 17q25.41 This locus is also commonly deleted in sporadic esophageal squamous cell carcinomas, suggesting the existence of a tumor suppressor gene for esophageal squamous cell carcinoma at this site.42
Acetaldehyde, produced during alcohol metabolism, is eliminated from the body by aldehyde dehydrogenase which is a product of the ALDH2 gene. The *1/*2 heterozygous polymorphism of the ALDH2 gene has been shown to confer an increased risk of esophageal squamous cell carcinoma.43,44 In addition, the *2/*2 homozygous genotype of ALDH2 gene is associated with a lower risk of squamous cell carcinoma.45 Another example of genetic susceptibility for esophageal cancer involves the C677 T polymorphism in the MTHFR (methylenetetrahydrofolate reductase) gene. The TT and TC genotypes of this gene have been shown to confer an increased risk of squamous dysplasia, and cancer, compared to the CC genotype.46
Other conditions associated with an increased risk of esophageal cancer include achalasia, diverticulosis,47,48 Plummer-Vinson syndrome,49 and celiac disease.50,51 Esophageal carcinoma is also associated with tumors of the oropharynx and larynx,52,53 presumably due to shared risk factors such as heavy smoking and high alcohol intake.54
Chronic esophagitis is common in populations with a high incidence of esophageal carcinoma, and usually involves the middle and lower thirds of the esophagus. “White” patches are seen at endoscopy, which corresponds to acanthosis and swollen clear squamous cells. Squamous dysplasia is a precursor of esophageal squamous cell carcinoma. Dysplasia may appear endoscopically as areas of friable or erythematous mucosa, erosions, plaques, or nodules. Ill-defined irregularities of the mucosal surface, or white patches, also may be present. In a very small proportion of cases, foci of dysplasia, or cancer, may appear endoscopically normal.55 The age distribution of dysplasia and carcinoma suggested a continuous progression from mild to severe dysplasia and carcinoma in situ. Further evidence of the role of dysplasia as a precancerous lesion comes from its frequent occurrence in areas adjacent to, or distant from, invasive squamous carcinoma when esophagectomy specimens have been studied in detail.56–59 Prevalence of dysplasia at the margins of invasive carcinoma is reported to be inversely related to the depth of invasion of the main lesion. This suggests that dysplasia represents a precursor lesion rather than cancerization of overlying benign epithelium by the invasive carcinoma.60 Multicentric tumors may be present in 15% to 30% of squamous cell carcinomas further supporting the idea of a “field effect” in carcinogenesis.61,62
The histological criteria for dysplasia include architectural and cytological abnormalities. Two classifications have been used. The original classification defined dysplasia as mild when <25% of the epithelium was involved, moderate when 25% to 50% of the epithelium was involved, and severe when more than 50% of the mucosa was involved. A two-tiered system, where low-grade dysplasia is defined as <50% and high-grade dysplasia as >50% involvement of the epithelium with neoplastic cells, is preferred (Fig. 11-1A,B). Cytological features of dysplasia include high nuclear-cytoplasmic ratio, nuclear hyperchromasia and pleomorphism, and increased mitotic activity. Dysplasia also may spread in a pagetoid fashion or into underlying esophageal gland ducts.63,64 In some cases, the presence of koilocytotic change may reflect an underlying HPV infection.65,66
In the presence of significant inflammation, a diagnosis of dysplasia should be made with caution because regenerative changes secondary to inflammation, radiation, or chemotherapy may mimic dysplasia. Unlike dysplasia, regenerative epithelium shows surface maturation and does not show significant nuclear crowding and loss of polarity, and atypical mitoses are typically absent. Vesicular chromatin, with prominent nucleoli, is often present in regenerating epithelium. In cases of uncertainty, a diagnosis of “indefinite for dysplasia” should be rendered.
Squamous cell carcinoma is rare in the upper third of the esophagus, most common in the middle third, and less frequent in the lower third. The distribution in one large series was in the upper third of the esophagus in 11.7%, the middle third in 63.3%, and the lower third in 24.9%.67 Macroscopically, squamous carcinomas may be exophytic, ulcerating or infiltrating, or show a combination of these features. Irregular, friable and, hemorrhagic strictures may be present. Papillary or verrucous squamous cell carcinomas are uncommon, and occur as large, warty, slowly growing neoplasms.68 Most have been reported in the upper third.69–71 Rarely, a diffuse infiltrative pattern, resembling a “leather bottle stomach,” may involve the esophagus. Superficial spreading carcinomas, with extensive intramucosal involvement and a propensity to permeate lymphatics and metastasize to lymph nodes, have also been described.72
Esophageal squamous cell carcinomas show all grades of differentiation. Well-differentiated lesions are composed of well-defined nests of tumor cells with keratinization while poorly differentiated tumors show sheets of undifferentiated tumor cells without any evidence of keratinization (Fig. 11-2A,B). Some tumors may show a predominance of basaloid tumor cells with peripheral palisading similar to a basal cell carcinoma. In most tumors, keratin pearls or intercellular bridges are present. Variation of cellular differentiation in different parts of the tumor is common. Histochemical, immunohistochemical, and ultrastructural studies have confirmed morphological heterogeneity. Focal adenocarcinomatous differentiation may be present in some tumors.73–75
Verrucous Squamous Cell Carcinoma of the esophagus is extremely rare. These are large, exophytic neoplasms with a papillary or warty appearance and are often associated with stricture formation. The age range of patients is broad, but there is a male predilection. These tumors can arise at any site in the esophagus. But in most cases occur in the upper third.69 Histologically, verrucous carcinoma consists of papillary projections of well-differentiated squamous cells, with parakeratosis and hyperkeratosis most prominent between papillae (Fig. 11-3). Evidence of invasion is frequently lacking in biopsies. Pathologists may interpret the “bland” features as a benign process if they are unaware of the endoscopic appearance. Invasion is typically in the form of a broad pushing front, and may be difficult to diagnose with certainty even in resection specimens. Despite low-grade morphology, and a low risk of distant metastases,68 this tumor has a poor prognosis because of its propensity to invade locally, and develop fistulas.76
Carcinosarcoma (Spindle Cell Carcinoma) was first described by Virchow in 1865. It is also termed “polypoid carcinoma,” “sarcomatoid carcinoma,” and “spindle cell carcinoma.” These tumors represent about 2% of all esophageal carcinomas. It affects predominantly adult men between 40 and 90 years of age, and presents as a bulky polypoid tumor in the middle or lower esophagus. Microscopically, the tumors show a mixture of “sarcomatous” and epithelial elements, the former showing interlacing bundles of spindle-shaped cells. Osseous and cartilaginous differentiation and bizarre giant cells may occur as well (Fig. 11-4). An epithelial component of squamous or undifferentiated carcinoma is typical, but these foci may be small and difficult to detect. Occasionally, an adenocarcinomatous,70 adenocystic,78 neuroendocrine, or glandular component may be present.79 In most tumors, the sarcomatous pattern predominates, and the squamous cell carcinoma component is inconspicuous and confined to small areas at the base of the pedicle. Areas of transition from typical squamous carcinoma to sarcoma are often present.78,80 The demonstration of tonofibrils and well-developed desmosomes in the spindle cells77,81 on ultrastructural examination, suggests that the sarcomatous cells are squamous in origin. Immunohistochemical studies have demonstrated disparate findings. Some authors have shown immunoreactivity to keratin in the spindle cell component82,83 whereas others have reported negative reactions to keratin and variable positivity for desmin, smooth muscle actin, vimentin, alpha-1-antichymotrypsin, and alpha-1-antitrypsin.79,84,85 Although hematogenous spread is more common in carcinosarcomas than pure squamous cell carcinoma, the overall 5-year survival rate has been shown to be similar.77,86
Basaloid Squamous Cell Carcinomas comprise about 2% to 11% of all squamous cell carcinomas87,88 and usually occur in elderly males, in the mid or distal esophagus. Presentation at an advanced stage is typical. There is, by definition, a variable amount of undifferentiated basaloid component in the form of solid sheets, anastomosing trabeculae, festoons or microcystic structures, and these areas are associated with a high mitotic index, comedo-type necrosis, and stromal hyalinization (Fig. 11-5). The neoplastic, in situ or invasive squamous component may be inconspicuous. The prognosis of patients with basaloid–squamous carcinoma does not differ significantly from conventional squamous cell carcinoma.88 The majority of cases in the literature reported as “adenoid cystic carcinomas” of the esophagus probably represent basaloid–squamous cell carcinomas. True esophageal adenoid cystic carcinoma has a less aggressive clinical course (see below).89,90
Squamous cell carcinoma confined only to the mucosa or the submucosa, with or without lymph node metastasis, is referred to as “superficial cancer.” However, the prognosis of early esophageal cancer differs from early gastric cancer, with 5-year survival rates for esophagus in the 50% to 60% range for tumors with submucosal infiltration. This is related to the fact that 30% to 40% of esophageal tumors with submucosal invasion also have lymph node metastasis.91–93 This has led some authors to suggest that the term “early” esophageal cancer should be restricted to cases in which there is carcinoma in situ (intraepithelial dysplasia/neoplasia), or mucosal carcinoma only, in which the prognosis approaches 100%.93–95 The presence of an elevated component in superficial esophageal cancer may be predictive of submucosal invasion, and a high probability of lymph node involvement.96 Superficial carcinomas may occupy a large area of the esophagus64,97,98 in some cases. Endoscopic ultrasonography has been used in cases of superficial esophageal carcinoma to assess depth of invasion and lymph node metastasis.99 Nonsurgical interventions such as photodynamic therapy100 and endoscopic mucosal resection101 are being increasingly used in the treatment of precursor lesions and superficial cancer.
The risk of nodal metastasis increases with depth of invasion and rises dramatically once tumors have penetrated the submucosa. Thus, intramucosal tumors have a <5% risk of nodal metastasis compared to tumors that invade the submucosa, where the risk approaches 45%.102,103 Skip metastases may be present in esophageal cancers and distant metastasis to lungs and liver have been reported in up to 50% of all squamous cell carcinomas.53 Overall, the 5-year survival rate in squamous cell carcinoma is about 26%. Tumor stage remains the most significant prognostic factor in patients treated with esophagectomy. The TNM (tumor, node, metastasis) staging system proposed by the American Joint Committee on Cancer (AJCC) has been revised recently and is significantly different from the prior edition (see Chapter 12). The staging criteria in the new proposal are outlined in Table 11-1. The number of lymph nodes examined in esophagectomy specimens has been shown to be an independent prognostic factor in a number of studies.104–106 Histopathologic examination for extent of residual tumor has also been proposed as a prognostic factor following neoadjuvant therapy for esophageal squamous cell carcinoma.107
|pT1||Tumor invades lamina propria, muscularis mucosa, or |
|T1a: invades lamina propria or muscularis mucosa|
|T1b: invades submucosa|
|pT2||Tumor invades muscularis propria|
|pT3||Tumor invades adventitia|
|pT4||Tumor invades adjacent structures|
|T4a: resectable tumor invading pleura, pericardium, or |
|T4b: unresectable tumor invading other structures |
(aorta, vertebra, trachea, etc.)
|N—Regional lymph nodes|
|pN0||No regional lymph node metastasis|
|pN1||Regional lymph node metastasis involving 1–2 nodes|
|pN2||3–6 positive lymph nodes|
|pN3||7 or more positive lymph nodes|
|M1||Distant metastasis present|
Adenocarcinoma and Variants
Barrett esophagus is a metaplastic precancerous lesion involving the distal esophagus that occurs in patients with chronic gastroesophageal reflux disease and is present in the majority of patients with esophageal adenocarcinoma. The distal third of the esophagus is the most common location for esophageal adenocarcinoma. The overall incidence of esophageal adenocarcinoma has increased from 3.6 per million in 1973 to 25.6 per million in 2006.2,8,108 The incidence of adenocarcinoma has also risen among Black males and women during this period, but the rates have remained at much lower levels. Increasing rates of esophageal adenocarcinoma have also been reported from the United Kingdom, Scandinavia, France, Switzerland, Australia, and New Zealand.109–114 Interestingly, recent incidence trend analysis for esophageal adenocarcinoma using the SEER database shows that the increase in incidence of esophageal adenocarcinoma may have slowed down and possibly reached a plateau. The rising trend appears to have slowed down from an annual 8.2% increase prior to 1996 to 1.3% in subsequent years. This is largely due to changes in incidence of early stage disease, which has changed from a 10% annual increase prior to 1999, to a 1.6% decline subsequently.115
The underlying risk factors for adenocarcinoma of the distal esophagus and the gastroesophageal junction are significantly different from those of esophageal squamous cell carcinoma. Gastroesophageal adenocarcinomas show an association with reflux disease, obesity, dietary factors, smoking, and alcohol consumption, and are inversely associated with gastric colonization by Helicobacter pylori. Obesity and overweight have been consistently shown to be associated with esophageal adenocarcinoma, but not to squamous cell carcinoma.116,117 This may be related to increased abdominal pressure predisposing to gastroesophageal reflux disease and increasing likelihood of developing Barrett esophagus.118,119 The impact of smoking on risk of esophageal adenocarcinoma is weak compared to squamous cell carcinoma. There is a two- to threefold increased risk in smokers, but unlike squamous cell carcinoma, the risk of esophageal adenocarcinoma does not decrease substantially after cessation of smoking.120–122 Alcohol consumption has not been consistently related to an increased risk for esophageal adenocarcinoma. The use of aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs) may reduce the risk of esophageal cancer. A 35% decrease in the risk of esophageal cancer among NSAID users compared with nonusers was shown in a recent meta-analysis.123–127 Single nucleotide polymorphisms (SNPs) involving Caspase-7 and Caspase-9 genes are reported to be significantly associated with an increased risk of esophageal adenocarcinoma. SNP in the PR (progesterone receptor) gene among women carrying the variant G allele may exert a protective effect.128
The majority of esophageal adenocarcinomas involve the distal third of the esophagus and present as ulcerating, infiltrative lesions (40%–50%), frequently associated with stenosis of the esophageal lumen. Others are fungating (20%–25%), flat (10%–15%), or polypoid (5%–10%) in appearance.129,130 A diffusely infiltrative growth pattern resembling linitis plastica in the stomach is seen in rare instances.131 Early cancers detected during surveillance of patients with Barrett esophagus may be invisible on endoscopy or appear as small depressed or elevated lesions.132 Multicentric tumors have also been described.130,133 Barrett esophagus is often apparent in the background, although in large tumors this may be obliterated completely by the tumor mass. Patients in whom esophagectomy is performed after neoadjuvant chemoradiation therapy may not show any residual lesion upon gross examination. Only a flat ulcerated lesion or an indurated scar may be present at the primary tumor site.134
Histologically, these tumors show a similar spectrum of changes as adenocarcinomas that develop in the stomach. High-grade dysplasia is commonly seen in adjacent columnar epithelium.129,135 The majority of tumors show a tubular or papillary growth pattern with variable grades of differentiation. Well-differentiated tumors show >95% gland formation, with columnar to cuboidal cells, hyperchromatic or vesicular nuclei, and a variable amount of eosinophilic or clear cytoplasm. Moderately differentiated tumors show gland formation in 50% to 95% of the tumor and poorly differentiated tumors show <50% glandular differentiation (Fig. 11-6A,B). The degree of nuclear pleomorphism parallels the grade of differentiation. Large, bizarre pleomorphic nuclei are more commonly seen in poorly differentiated tumors. About 5% to 10% tumors are of the mucinous (colloid) type and show prominent pools of extracellular mucin with floating clusters of tumor cells (Fig. 11-7). Signet ring cell carcinoma is less common (5% of cases) than in the stomach. Foci of squamous, neuroendocrine, and Paneth cell differentiation have been described in esophageal adenocarcinomas and represent multidirectional differentiation in the tumor.136 Pagetoid spread into overlying squamous epithelium occurs, at times, in poorly differentiated adenocarcinomas.137 The presence of a double muscularis mucosa in patients with Barrett esophagus may lead to errors in staging of early adenocarcinomas. The deep layer of muscularis mucosae is often thick and may be mistaken for muscularis propria138–140 in an endoscopic mucosal resection specimen which may lead to over staging of invasive carcinomas in about 7% cases.139 Carcinomas that invade between the two layers of muscularis mucosae are associated lymphovascular invasion in about 10% of cases.139,140
A. The majority of esophageal adenocarcinomas arise in a background of Barrett esophagus (BE) in which esophageal squamous mucosa is replaced by a metaplastic columnar epithelium with goblet cells (top). The esophageal location of the metaplastic epithelium can be confirmed by the presence of esophageal submucosal glands/ducts (bottom). B, C. Adenocarcinomas are graded on the basis of the degree of gland formation. At one end of the spectrum are well-differentiated adenocarcinomas with more than 95% gland formation (B) whereas at the other end are poorly differentiated tumors with a solid architecture barely recognizable as an adenocarcinoma (C).
In esophagectomies performed after neoadjuvant therapy, residual tumor is often present in small, isolated clusters in association with dense fibrosis or pools of acellular mucin. Tumor cells may appear more pleomorphic and show neuroendocrine differentiation as a consequence of treatment. Large pools of mucin without any viable tumor cells, with or without calcific deposits, may be present and should not be reported as residual tumor141 since these are not associated with an increased risk of recurrence or distant metastasis. The amount of residual carcinoma (0%, 1%–50%, and >50%) seen in resections performed after preoperative chemoradiation has been shown to be a reproducible predictor of survival in some studies.142
Isolated tumor cells in postneoadjuvant therapy resection specimens may be difficult to distinguish from reactive mesenchymal cells. Immunostains for keratins can be helpful in these cases. Keratin stains may also help determine the deepest extent of tumor invasion for accurate staging when the residual tumor is present predominantly as single cells. In small biopsy specimens, distinction of primary esophageal adenocarcinoma from secondary tumors may be an issue. Esophageal spread from gastric, pulmonary, or breast carcinoma is the most common consideration in the differential diagnosis. Immunoreactivity for TTF-1 and estrogen receptor is useful in distinguishing esophageal tumors from pulmonary and breast primaries, respectively. Distinguishing gastric carcinomas with extension into the esophagus from primary esophageal adenocarcinoma is virtually impossible using immunohistochemical studies. The presence of Barrett esophagus with dysplasia adjacent to the carcinoma is the only truly reliable form of evidence in favor of an esophageal primary.