Heavy consumption of strong liquors, such as whiskey and calvados, shows a dose-dependent increased SCC risk (19,22). The combined use of alcohol and tobacco incurs a multiplicative increase in the risk of SCC. In Brittany, the relative risk is 49.6 for nonsmokers with the highest alcohol intake, 7.8 for nondrinkers with the highest tobacco use, and 155.6 for men at the maximum consumption level of both substances (23). Persons at high risk for SCC due to alcohol and tobacco consumption and poor nutrition may be vulnerable to field cancerization of
the entire upper aerodigestive tract (UADT), including the esophagus (24). The frequency of developing a second UADT SCC in the 10 years following treatment of an index cancer is estimated to be from 5% to 40% (25). A prospective family study found the 10-year standardized incidence rates for esophageal cancer to be elevated after the diagnosis of an index cancer in the UADT (8.24) and lung (2.0) (26). Half of the multicentric cancers are synchronous. Most metachronous cancers develop within 3 years.

Patients with esophageal SCC can be divided into two overlapping risk groups: Those who smoke and consume large amounts of alcohol and those whose diets lack green, leafy vegetables, citrus fruits, micronutrients, and trace elements (27). The missing trace elements include molybdenum, manganese, zinc, iron, silicon, barium, titanium, and magnesium. Mineral deficiencies in the soil lead to increased fungal invasion and mycotoxin food contamination. Calcium, riboflavin, vitamin A, and vitamin C deficiencies may also play a role in esophageal carcinogenesis, since these vitamins play a role in maintaining mucosal integrity and normal epithelial differentiation. Deficiencies in these substances render the esophageal mucosa vulnerable to carcinogens in foods, such as mycotoxins in the Transkei (28) and N-nitroso compounds in China (29).

The influence of dietary supplements on SCC cancer risk has been studied among high-risk Chinese communities. These micronutrients have included β-carotene, vitamin E, selenium, zinc, molybdenum, retinol, riboflavin, and vitamin C. Overall, the evidence shows that these supplements cause a small, or borderline, reduction in the SCC risk (27). Since exposure to dietary carcinogens begins in childhood, it is not surprising that micronutrient supplements show only modest protection from this cancer in the adults in high-risk populations.

Thermal injury from hot drinks including hot tea in East Asia and maté consumption in South America has long been identified as a risk factor for SCC (27,30). It is difficult to separate the effects of thermal injury from the constituents of tea and maté, but the many studies strongly suggest that hot drinks do impose a risk of developing SCC (27).

The nitrosamine content of foods varies widely in high- and low-risk areas of China. Fermented, moldy, pickled food that contains high levels of nitroso compounds is a dietary staple in high-risk areas (27). The low molybdenum content of the soil in these high-risk areas yields crops with a high nitrate content that may be converted to potentially carcinogenic nitroso compounds. Nitrosamines are potent alkylating agents that can produce various alkyl DNA adducts, particularly involving O⁶-methylguanine, which can preferentially mispair with thymine rather than cytosine, causing GC to AT mutations (31). O⁶-methylguanine-DNA methyl transferase (MGMT) is a primary defense against alkylase-induced carcinogenesis. Some SCC patients have MGMT inactivation via aberrant promoter methylation (32). Vitamin C inhibits this conversion.

The dietary factors that increase or decrease the SCC risk vary from culture to culture. Thus, heavy chili consumption is an independent risk factor for SCC in India (33). Capsaicin, the active component of chili and its metabolites, may be a proximate carcinogen/mutagen. In contrast, a Mediterranean diet would appear to lower the risk of SCC, even when associated with moderate to high alcohol consumption (34).

Genetic polymorphisms in enzymes that metabolize alcohol render some individuals vulnerable to its deleterious effects. Acetaldehyde, the first metabolite of alcohol, is eliminated by aldehyde dehydrogenase-2 (ALDH2) (35). ALDH2 polymorphisms influence blood acetaldehyde concentrations after drinking (36). An inactive mutant allele, ALDH2*2, is common in Orientals and is associated with increased circulating acetaldehyde levels, inducing painful facial flushing among occasional alcohol consumers (37). Alcoholics with this mutant allele develop tolerance to this reaction and the presence of this less active genotype in alcoholics enhances their SCC risk (38). The influence of alcohol on SCC risk may also be modified by an XRCCI polymorphism at codon 399. The XRCCI protein facilitates base excision repair or single-strand break repair. The odds ratio (OR) for SCC among alcoholics with the Arg/Arg XRCCI genotype compared to the Arg/Gln or Gln/Gln genotypes is 2.78 (1.15 to 6.67) (39). Recent data suggest that individuals with low selenium intake and ALDH2 Lys/Lys and XRCC1 399 Gln/Gln genotypes associate with an increased risk of developing SCC, especially in the presence of exposure to tobacco and alcohol (40).

Aromatic hydrocarbons in tobacco smoke require metabolic activation by phase I enzymes (CYP450s), and are then subject to detoxification by phase II enzymes (GSTM1) (41). Patients with the Val/Val CYP1A1 genotype are at increased risk of SCC (OR = 6.63, 95% confidence interval [CI], 1.86 to 23.7); this risk is enhanced when associated with GSTM1^– (OR = 12.7, CI 95%, 1.97 to 81.8) (47). The cyclin D1 G870A polymorphism also influences the SCC risk in smokers (42). A study of North Chinese patients found that smokers with the G/G cyclin D1 phenotype have a lower risk of SCC than those with the G/A or A/A phenotypes.

Low folate and impaired folate metabolism have also been implicated in the development of gastrointestinal cancers. Genetic polymorphisms in 5,10-methylenetetrahydrofolate reductase (MTHFR) plays a central role in folate metabolism. This gene is polymorphic and the MTHFR 677TT genotype, which is associated with reduced enzymatic activity, significantly associates with increased esophageal SCC risk (43).

Certain occupations associate with an increased risk for SCC. These include warehouse workers and workers in miscellaneous food industries as well as those with occupational
exposure to asbestos, metal dusts, vulcanization products, asphalt, petrochemicals, and combustion products (44). Persons engaged in the production and distribution of alcoholic beverages also have an increased SCC risk as seen in the Calvados region of France (45).

Radiation therapy increases esophageal SCC in patients treated for various malignancies. As an example, the risk following treatment for breast cancer increases starting 5 years after exposure (46). Most radiation-induced cancers arise in the upper and midesophagus and the tumors may be multifocal in nature.

HPV DNA may be found in invasive SCC, areas of carcinoma in situ, the hyperplastic epithelium surrounding cancers, and histologically normal cells near these cancers (47). The areas with the highest incidence of HPV infections include China, Japan, and parts of South Africa. Although HPV types 6, 7, 9, 11, 13, 16, 18, 24, 30, 33, 51, 52, 57, and 73 have all been identified, HPV 16 is the most common (47). A p53 codon 72 polymorphism significantly (p = 0.001) associates with HPV-related esophageal cancers in northern China (48). Fifty-three percent of patients with HPV positive were Arg/Arg carriers, compared to 26% of HPV-negative cancers and 23% of controls. The presence of HPV infection may be suspected in cytology preparations, as shown in Figure 3.3.

Fungi frequently contaminate the grains and foodstuffs consumed in high-risk geographic areas. The fungi belong to many genera, but Fusarium and Aspergillus are the two most common and their respective mycotoxins, fumonisin B1 and aflatoxin, act as carcinogens. They are found on maize (corn), millet, and other cultivated grains in Linxian and on pickled vegetables. The fungi reduce nitrates to nitrites and promote the formation of nitrosamines (22).

Chronic Chagas disease, resulting from infection by Trypanosoma cruzi, causes achalasia and associates with SCC development (49). Since the infection is frequently acquired in early childhood, the resulting carcinoma may appear as early as the 3rd decade of life.

The autosomal dominant familial syndrome palmoplantar keratoderma (PPK) (tylosis) predisposes patients to the development of esophageal SCC. PPK results in defective mucosal keratinization (50) and altered mucosal integrity, increasing susceptibility to environmental mutagens. The mean age of onset for esophageal malignancies in these patients is 61 years. Members of PPK families have a 50% risk of developing esophageal cancer by age 50 and a 90% to 95% risk of developing esophageal cancer by age 65 (50). These patients also have an increased risk of melanoma, breast and lung cancer, leukemia, hepatomas, malignant lymphomas, and colorectal adenomas (50,51). The presence of multiple carcinomas involving the oral cavity, tongue, oropharynx, and stomach suggests that exposure to a common environmental agent contributes to the genesis of all of the tumors. PPK patients who smoke are particularly likely to develop SCC (51). PPK results from a mutation in the tylosis in esophageal cancer (TOC) region of chromosome 17q25 (52). Loss of heterozygosity (LOH) of polymorphic microsatellite markers located near the TOC locus also occurs in sporadic esophageal cancers (52,53). PPK patients develop chronic esophagitis, followed by dysplasia, carcinoma in situ, and invasive carcinoma. Other histologic changes include abnormal keratinocyte maturation, the presence of basophilic inclusions, and surface keratinization (54). The neoplastic squamous cell lesions that develop resemble those arising in the absence of tylosis.

The recessive form of dystrophic epidermolysis bullosa due to a type VII collagen mutation is a less common source of inherited esophageal SCC (55). This condition is most common among people of Northern European origin.

Esophageal SCC usually grows slowly. The patients may remain asymptomatic with invasive disease because the esophagus is highly distensible and tumors can grow to a considerable size before the lumen becomes sufficiently narrowed to produce symptoms. Symptomatic esophageal SCC presents with dysphagia, odynophagia, weight loss, coughing, choking, pain, and dehydration (88). 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 or aspiration, ominous signs 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 SCC. Palpable lymph nodes in the cervical or supraclavicular regions may be noted.

Patients may also develop various paraneoplastic syndromes. Tumor-induced hypercalcemia is common (89). It results from the release of calcium from the bones due to tumor production of parathyroid hormone–related protein (PTHrP) (90). The presence of hypercalcemia is a poor prognostic sign (91). A hypertrophic osteoarthropathy affects some patients with esophageal SCC (92), but this may result from concomitant chronic obstructive lung disease, which shares an association with heavy tobacco consumption. An acute vasculitis developed in a patient with stage II SCC, a phenomenon attributed to circulating immune complexes or tumor-associated antigens (93). The vasculitis went into remission after tumor resection.

The AJCC divides the esophagus into three compartments (79). The cervical esophagus extends from the pharyngoesophageal junction to the thoracic inlet, approximately 18 cm from the incisors. The middle esophagus extends from the thoracic inlet to a point 10 cm above the GEJ, approximately 31 cm from the incisors and at the level of the lower edge of the eighth thoracic vertebra. The lower esophagus extends from this point to the GEJ, or approximately 40 cm from the incisors. Carcinomas may develop in both the hypopharynx and cervical esophagus in men who are heavy consumers of alcohol and tobacco. SCCs complicating the Plummer-Vinson syndrome arise in the area of the cricopharyngeus muscle in women (male:femal ratio = 1:10) with a median age of 45 to 50 years. Cancers that appear after radiation therapy for breast cancer usually develop in the upper and midesophagus. Most SCCs in high-risk populations develop in the middle and lower thirds of the esophagus.

Esophageal SCCs appear as fungating, ulcerating, infiltrating, or stenotic lesions. Mixed gross growth patterns also occur. Advanced tumors may measure up to 10 cm in length. Fungating cancers present either as large, intraluminal, variably ulcerated masses with raised, everted margins or less commonly as polypoid, irregular, bulky tumor masses (Fig. 3.9).
The lesions may have sharply defined borders; intramural submucosal extension may be grossly inapparent. The extent of tumor infiltration at the tumor base varies and does not necessarily reflect the size of the protruding mass. Ulcerating cancers have irregular, noninverted, and sometimes serpiginous edges, and a shaggy, hemorrhagic central crater. The ulcers lie along the longitudinal esophageal axis and the tumors may extend into the surrounding viscera. Infiltrating carcinomas cause esophageal wall thickening. The esophagus appears rigid with slitlike areas of stenosis. The proximal esophagus dilates. Rarely, the pattern resembles the linitis plastica pattern seen in gastric carcinoma. Papillary or verrucous lesions usually develop in the proximal esophagus. Their differential diagnosis includes a papilloma, sarcomatoid carcinoma, and verrucous carcinoma.

Biopsies cannot determine the extent of invasion, but they yield a positive diagnosis in 81% to 100% of cases, depending on the number of biopsies obtained. Endoscopic ultrasonography (EUS) may identify tumor penetration to the submucosa or muscularis propria in up to 80% of early cases (94). EUS is most useful in identifying the superficial lesions that are best treated by surgery alone. Detection of nodal involvement is more accurate with EUS than with tomography (95). Fine needle aspirations enhance the ability of EUS to detect nodal disease, yielding an accuracy of more than 90% (96).

SCCs arise from areas of pre-existing dysplasia and invade through the basement membrane into the lamina propria or deeper tissues. Histologically, ordinary SCCs show varying grades of differentiation ranging from a well-differentiated keratinizing carcinoma containing well-formed squamous cell nests and keratin pearls to undifferentiated tumors without recognizable keratin or prickle cells. The tumors are classified into well-, moderately, and poorly differentiated lesions based on how closely they resemble mature nonneoplastic squamous cells (Figs. 3.10, 3.11, and 3.12). As the lesions become less mature, they show progressive degrees of pleomorphism and loss of keratinization and intercellular bridges. The degree of keratinization and the prominence of intercellular bridges inversely correlate with the degree of cytologic atypia and nuclear pleomorphism, although one occasionally sees marked keratinization of highly atypical cells. Most tumors are well- to moderately differentiated lesions. Well-differentiated keratinizing carcinomas have a high proportion of large differentiated squamous cells (Fig. 3.10) and a low proportion of small basal-type cells, which are typically located at the periphery of the tumor cell nests. The tumors contain squamous cell nests, dyskeratotic cells, and keratin pearls. Less well-differentiated tumors consist of cellular masses containing
polygonal, round, fusiform, or, rarely, small nonkeratinizing cells. Poorly differentiated carcinomas typically contain an abundance of basaloid cells and the degree of differentiation often varies throughout the tumor. Most poorly differentiated SCCs contain some foci of squamous differentiation such as dyskeratotic epithelial nests, keratin pearls, or intercellular bridges. They generally appear as invasive sheets of cells with prominent areas of central necrosis. Occasionally, areas of individual cell necrosis in poorly differentiated tumors produce a pseudoacinar pattern, but mucicarmine stains are negative. Typically the degree of differentiation varies throughout the tumor. In undifferentiated lesions, one may not recognize keratin or prickle cells, and one has difficulty identifying the tumor as squamous in nature. Most tumors contain at least focal histologically identifiable squamous differentiation with evidence of epithelial nests, pearls, or intercellular bridges. Cytokeratin 14 immunostains may help identify a tumor as being squamous cell in origin (97).

As the tumor cells infiltrate the esophageal wall, they may form sheetlike nests with rounded margins or they may have an asteroid shape with spiculated margins. Tumors with an asteroid configuration are more likely to show deep penetration, lymphatic permeation, nodal metastases, and desmoplasia and have a worse prognosis than those with rounded borders (98). Tumors with downward penetration are more likely to show vascular and lymphatic invasion (Fig. 3.13).

Patients treated preoperatively with chemotherapy or chemoradiation may show complete tumor ablation, partial regression with a reduced tumor:stroma ratio, or residual unaltered tumor cells, sometimes resulting in a stricture (Figs. 3.14 and 3.15). Tissues examined within 3 to 6 days of preoperative treatment show pronounced apoptotic changes, with or without necrosis. Most tumor cells appear extensively degenerated. The tumor may completely disappear, creating a
partially re-epithelialized ulcer containing granulation tissue heavily infiltrated by lymphocytes. Calcification may be present. Fibrosis in the muscularis propria causes shrinkage of the muscle bundles. Tumor regression can be graded (99), although this is not commonly done.

Cytologic evaluation of the esophagus is important as noted above. Exfoliated malignant cells from intraepithelial squamous cell carcinomas may be obtained by means of esophageal washings. These cells resemble those of carcinoma in situ of the cervix without evidence of keratinization. Abundant cell samples are usually obtained from SCCs. Paradoxically, large fungating growths frequently associate with inadequate material; false-positive results are rare in this setting. Well-differentiated carcinomas shed highly atypical and partly keratinized cells with bizarre shapes, anisocytosis, and hyperchromatic nuclei (Fig. 3.16). Malignant pearl formations may be observed. Moderately and poorly differentiated squamous cell carcinomas exfoliate single or clustered immature atypical cells with increased nuclear:cytoplasmic ratios and either pale nucleoli or dark angulated nuclei containing large amounts of heterochromatin (Fig. 3.17).

SCC spreads within the esophageal wall, invading the muscularis propria and extending into the periesophageal tissues. Mediastinitis, pleural fistulas, and empyema may develop. Depending on tumor location, invasion into the trachea, bronchi, aorta, pleural cavity, lung, thyroid, lymph nodes, pericardium, major vessels, and/or nerves occur. Malignant tracheoesophageal fistulas develop in up to 28% of patients (100). Eventually the tumors become fixed to surrounding structures, including the diaphragm, mainstem bronchi, aortic arch, or the great veins of the neck. At this point, the lesion is unresectable.

Intramural intralymphatic vascular spread is common; lymphatic extension produces submucosal nodules distant from the main tumor in up to 16% of esophageal carcinomas (85). The esophageal lymphatics drain into the mediastinal lymphatics leading to regional spread early in the disease. In Western populations, up to 61% of patients show local extension and nodal involvement at the time of diagnosis (101). Cervical nodes become involved in 19% to 60% of cases, mediastinal nodes in 21% to 64%, and abdominal nodes in 47%. Tumors of the cervical region metastasize to infraclavicular, peritracheal, supraclavicular, paraesophageal, and posterior mediastinal lymph nodes. Tumors of the upper and midesophagus commonly involve the paraesophageal, posterior, and tracheobronchial nodes. Lower esophageal tumors disseminate to paraesophageal, celiac, and splenic and hepatic artery lymph nodes. However, the distribution of nodal metastases does not always reflect the site of the primary tumor, since 40% of cervical esophageal tumors metastasize to abdominal nodes; 38% of lower esophageal carcinomas metastasize to cervical nodes (101). Extrathoracic nodal metastases represent distant metastases. The number of positive nodes is higher in distal cancers than in upper or midesophageal cancers. Simultaneous metastases to lymph nodes in the neck, mediastinum, and abdomen occur far more commonly in lower esophageal cancers than in upper and midesophageal cancers. In some cases, the appearance of a supraclavicular, cervical, or abdominal metastasis may precede detection of the primary tumor.

Hematogenous metastases occur late in the disease, usually following nodal metastases. The most common metastatic sites include liver (35% to 72%), lungs (20% to 60%), adrenals (35%), kidneys (25% to 26%), bones (9% to 20%), adrenal gland (5%), peritoneum (2%), and, rarely, the central nervous system (2%) (101).

SCC induction and progression result from genetic and epigenetic changes in genes controlling cell cycling, cell growth, DNA repair, and tumor dissemination (see Fig. 3.18). A brief summary of immunostains that may be useful in the diagnosis of dysplasia and in determining the prognosis of esophageal SCC follows. Abnormalities in p53 expression are common in esophageal SCCs occurring early in tumor development (102). A significantly greater frequency of p53 expression occurs in high-grade dysplasia versus low-grade dysplasia and in low-grade versus normal esophageal mucosa (103). p53 expression had no influence on survival in one study (104), was a marker for radioresistance in another study (105), and in another had no predictive value in patients receiving either chemoradiation therapy or radiation alone (106). Cyclin D overproduction or production at the wrong time may stimulate
inappropriate cell division. Tumors showing cyclin amplification tend to invade deeply (107). Cyclin D overexpression increases in frequency from 22% in well-differentiated cancers to 54% in poorly differentiated tumors (107), but is not a useful prognostic marker. Cyclin B1 expression, however, associates with poor prognosis in both univariate and multivariate analyses (108).

Expression of epithelial growth factor receptor (EGFR), c-erbB2, Int-2, transforming growth factor-alpha (TGF-α), and human stomach cancer transforming factor (HST-1) has prognostic significance for SCC. EGFR overexpression occurs in 40.65% to 71% of esophageal SCC (109) (Fig. 3.18) and correlates with nodal metastases and depth of invasion. Immunoreactivity for TGF-α in esophageal SCC ranges from 35% to 78% (109,110) and associates with lower survival than seen in TGF-α–negative cancers (p <0.01). Survival is poorest with cancers that overexpress both EGFR and TGF-α (111). Amplification of HST-1 affects approximately 50% of SCCs, associating with hematogenous spread (112). Expression of vascular endothelial growth factor (VEGF), a selective mitogen for endothelial cells, correlates with microvessel density adjacent to the tumor. Shortened survival has been observed in VEGF-positive esophageal SCCs in most studies (113), but not all (114).