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
Etiology and Associations
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
Squamous cell dysplasia is categorized as low grade when the thickness of mucosa involved with basaloid undifferentiated cells is less than 50% (A) and as high grade when it exceeds 50% (B).
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.
Gross Pathology of Squamous Cell Carcinoma
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
Microscopic Pathology of Squamous Cell Carcinoma
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
The spectrum of invasive squamous cell carcinoma ranges from well-differentiated tumors (A) with bland, monomorphic nuclei with minimal cytological atypia to those that are poorly differentiated (B) and show marked nuclear hyperchromasia, pleomorphism, and abundant atypical mitoses.
Histologic Variants of Squamous Cell Carcinoma
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
Verrucous carcinomas show papillary fronds of extremely well-differentiated squamous cells with marked parakeratosis and hyperkeratosis. Invasion is typically along a broad front with pushing margins and may be difficult to demonstrate even in resection specimens.
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
Carcinosarcomas are biphasic tumors with epithelial and sarcomatous elements. The latter is usually in the form of intersecting fascicles of spindle-shaped cells but cartilaginous or osseous differentiation may also be present in some cases.
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 carcinomas with basaloid features may demonstrate microcystic spaces that impart a pseudoglandular appearance to the tumor. Basaloid tumors with this morphology have been mistaken for adenoid cystic carcinomas in the past.
Natural History and Prognosis of Squamous Cell Carcinoma
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
Table 11-1Tnm Staging Of Esophageal Carcinoma (7Th Edition, 2010) ||Download (.pdf) Table 11-1Tnm Staging Of Esophageal Carcinoma (7Th Edition, 2010)
|T—Primary tumor |
|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 |
|M—Distant metastasis |
|M1 ||Distant metastasis present |