EPITHELIAL TUMORS	NONEPITHELIAL TUMORS
Malignant Squamous cell carcinoma Adenocarcinoma Adenocarcinoma of the esophagogastric junction Verrucous carcinoma Carcinosarcoma Small cell carcinoma Malignant melanoma Benign Squamous papilloma Adenoma Inflammatory fibroid polyp	Malignant Lymphoma Sarcoma, including malignant GIST Metastatic carcinoma Benign GIST Leiomyoma Granular cell tumor Fibrovascular tumor Hemangioma Hamartoma Lipoma

GIST, gastrointestinal stromal cell tumor.

CARCINOMA

EPIDEMIOLOGY

A vast majority of all esophageal cancers are malignant epithelial tumors (carcinomas). The two most common types of esophageal carcinomas are squamous cell cancer and adenocarcinoma (Figs. 46-1 and 46-2). Malignant tumors of the esophagus are one of the commonest types of cancer. More than half a million patients were newly diagnosed with esophageal cancer worldwide in 2007 alone. Globally the incidence of esophageal cancer is sixth and ninth among cancers in men and women, respectively, and is the fifth and ninth leading causes of cancer deaths.¹ The American Cancer Society estimated that approximately 16,470 new esophageal cancer cases would be diagnosed in the United States in 2008 and that 14,280 patients would die from esophageal cancer.² In the United States from 2001 to 2005, the median age at diagnosis for cancer of the esophagus was 69 years. Approximately 3% of all patients with esophageal cancer were diagnosed in individuals younger than age 45; 36% between 45 and 64; 29% between 65 and 74; approximately 30% older than age 75. In 2005 the age-adjusted incidence rate of esophageal cancer in the United States for all races and both sexes was 4.3 per 100,000 and varied from 2.9 in Hispanics to 4.9 in blacks. The age-adjusted incidence rates were higher in men than women for all races (overall, 7.5 versus 1.8 per 100,000 in men and women, respectively). The highest incidence rate in the United States was in black men. Based on data from 2003 to 2005, it is estimated that 0.5% of all men and women born today in the United States will be diagnosed with cancer of the esophagus at some time during their lifetime (lifetime risk, 1 in 198). The overall five-year relative survival rates of patients with esophageal cancer by race and sex, reported for the period from 1996 to 2004 from 17 geographic areas were 16.5% for white men, 17.6% for white women, 9.2% for black men, and 12.9% for black women.³

Figure 46-1. A, Distal esophagectomy specimen. The normal white squamous epithelium on the left side of the specimen has been replaced by metaplastic Barrett’s epithelium on the right side. Note the small, irregular ulcer (arrows), which represents a focus of adenocarcinoma. B, Resected specimen of distal esophagus and proximal stomach in a patient with Barrett’s esophagus. Note the large, irregular, ulcerating adenocarcinoma, which involves a small portion of proximal stomach.

(Courtesy Edward Lee, MD, Washington, D.C.)

Figure 46-2. A, Histopathology of invasive squamous cell carcinoma. (Hematoxylin and eosin, ×40) B, Histopathology of invasive adenocarcinoma (Hematoxylin and eosin, ×40).

(Courtesy Giovanni De Petris, MD, Scottsdale, Ariz.)

Squamous cell cancer is the commonest type of esophageal carcinoma worldwide. There are marked geographic variations in the incidence of different types of squamous cell esophageal cancer, with more than 80% of these cancers occurring in developing countries. The highest incidence of esophageal cancers, with incidence rates greater than 100 per 100,000, is in the “Asian esophageal cancer belt,” extending from northern Iran through the central Asian republics to north-central China. The intermediate risk regions, with incidence rates from 20 to 50 cases per 100,000, are in parts of east and southeast Africa (e.g., eastern Kenya, Zimbabwe, and the Transkei region of South Africa), in southeastern South America (southern Brazil, Uruguay, Paraguay, northern Argentina), and in certain parts of western Europe such as northern France and Switzerland. The rest of the world including the United States is considered a low-incidence area, with rates below 10 per 100,000 of the population.¹ In high-incidence areas, there are unexplained shifts in incidence rates within countries and regions. For example, within the esophageal cancer belt, the Chinese counties with the highest cancer rates are located in the north-central provinces of Shanxi and Henan, whereas in central Asia the high-risk areas are in parts of Turkmenistan and Kazakhstan. In northern Iran there is quite a dramatic difference in the relatively small area of the Caspian littoral; the relatively dry regions east of the Caspian Sea have a high incidence with a much lower incidence in the more humid western parts.⁴

In Western countries, squamous cell cancers are more common in blacks. In low-incidence areas such as the United States, there is a male preponderance in the incidence of squamous cell cancers. However, such gender specificity is lost in areas with a high incidence of squamous cell cancers, such as China, where women are nearly equally affected. Persons with low socioeconomic status as well as unskilled manual workers are at almost two-fold higher risk of developing squamous cell cancers. Living without a life-partner increases the risk of squamous cell cancers, even after adjustment of confounding variables.⁵

Although the incidence of squamous cell esophageal cancer has decreased over the past two decades in most Western countries and in parts of Asia, including certain high-risk areas of China, there has been a disturbing upward trend in the incidence of esophageal and gastroesophageal junctional adenocarcinoma in the United States and in northern Europe including Denmark, Finland, Norway, Sweden, Scotland, and Switzerland.⁶^–⁸ In the 1960s squamous cell esophageal cancers comprised approximately 90% of all esophageal cancers. However, because of an alarming rise in the incidence of esophageal adenocarcinoma, esophageal adenocarcinoma is now the predominant type of esophageal carcinoma in the United States. This reversal pattern has also been recently noted in some European countries such as Denmark and Scotland. In a longitudinal study of annual incidence of adenocarcinoma of the esophagus reporting from 43 tumor registries in North America, Europe, and Australia since 1960, the average increase in annual incidence ranged from 15% to 42% in European countries, 23.5% in Australia, and 20.6% in the United States.⁹

ETIOLOGY AND RISK FACTORS (SQUAMOUS CELL CANCER)

Dietary and Nutritional Factors

Drinking from non–tap water has been shown to be an independent risk factor for squamous cell cancer of the esophagus in high-incidence areas of China. Exposure to polycyclic aromatic hydrocarbons commonly present in soot extract of coal-burning stoves, a domestic cooking device used in poorly ventilated kitchens throughout the esophageal cancer belt, has been implicated as a risk factor of squamous cell cancer, particularly in women who do not smoke.

An association with dietary intake of N-nitroso compounds has been implicated in the pathogenesis of squamous cell cancer, particularly in high-incidence areas. N-nitroso compounds are derived from reduced dietary nitrates, often by ubiquitous fungal toxins, and certain food material are particularly susceptible to be contaminated by N-nitroso compounds, such as smoked pickles and a bread-like food called qocho or kocho in Ethiopia.¹⁰ It has been hypothesized that in black South Africans, the rising incidence of squamous cell cancer could be partly related to a recent dietary shift to maize from sorghum.¹¹ Fusarium fungi, which grow sparsely on sorghum, grow freely on maize, producing fumonisins, which reduce nitrates to nitrites and synthesize cancer-producing nitrosamines. N-nitroso compounds are mutagenic in animal models and act by inducing alkyl adducts in deoxyribonucleic acid (DNA).¹² Chewing betel-quid with areca nut and use of gutka (pan masala, a dry powdered mixture of areca nut, catechu, lime, unspecified spices, and flavoring agents), which is very common in Southeast Asia, has been proposed to have a synergistic carcinogenic effect in association with alcohol and tobacco.¹³ In areas of the world endemic for squamous cell cancers, drinking very hot beverages has been shown to have carcinogenic attributes, probably by causing chronic esophageal damage related to repeated thermal injury.

Certain dietary factors such as selenium have been shown to be protective against squamous cell cancers. Low levels of selenium have been associated with squamous cell cancers in high-risk areas of China, and selenium supplementation has been shown to be protective in controlled trials from China.^14,¹⁵ Similarly, zinc deficiency, which potentiates the carcinogenic effects of nitrosamines as well as causes overexpression of the cyclo-oxygenase pathway in esophageal carcinogenesis, has been recognized as an independent risk factor of squamous cell cancers.¹⁶

Evidence suggests that low dietary folate intake and impaired folate metabolism due to functional polymorphisms in folate-metabolizing pathways, particularly polymorphisms in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene, play an important role in the causation of many gastrointestinal cancers, including esophageal cancer. In a recent meta-analysis of seven case-control studies, relative cancer risks for individuals in the highest compared with the lowest category of dietary folate intake were 0.66 for esophageal squamous cell carcinoma and 0.50 for esophageal adenocarcinoma.¹⁷ Also other investigators have shown that the MTHFR 677TT gene variant, which is associated with reduced enzyme activity, was associated with an increased risk of esophageal squamous cell carcinoma.¹⁸

There are clearly unknown interactions of genetic, nutritional, and environmental elements that may be synergistically important in the etiology of squamous cell esophageal cancers. For example, in northern Iran, the traditionally semi-nomadic Turkoman population has one of the highest incidences of squamous cell cancers. Intensive investigation of well-known nutritional and environmental risk factors has failed to identify a specific risk factor that could explain the very high incidence of squamous cell cancers in this population. Prevalence of cigarette smoking and alcohol consumption (discussed following), which are major risk factors for squamous cell cancers in Western populations, was on a negligible scale among men in this population and practically absent among women. Foodstuffs had very few carcinogens such as nitrosamines, aflatoxins, or polycyclic hydrocarbons. It has been postulated that a very restricted diet (low in animal protein, fruit, or fresh vegetables), along with consumption of dry, coarse bread contaminated with sharp seeds and silica fibers, frequent use of hot tea, and the regular smoking or swallowing of opium dross (“sukhtheh”), along with potential genetic predispositions, may act synergistically by an unspecified mechanism to impart a very high risk for developing squamous cell esophageal cancer in this population.

Coffee drinking and increased intake of fruit, fish, and white meat has a protective effect on squamous cell cancers. In contrast, red meat, salted meat, and meat boiled at high temperature may increase the risk of squamous cell cancers.^19,²⁰

Alcohol and Tobacco

Alcohol and tobacco use, particularly in the form of pipe, cigar, or cigarette smoking, is a dominant risk factor of squamous cell cancers in low-incidence areas, such as the United States. On the other hand, in high-incidence areas, tobacco or alcohol does not seem to play a dominant causative role, although in Asian countries, where smoking is becoming increasingly popular, particularly among men, its relative importance as a risk factor is increasing. Epidemiologic studies suggest that the amount of alcohol consumed is more important than type of alcohol consumed, and the most prevalent alcoholic beverage consumed in a particular region tends to be the one with the highest risk of squamous cell esophageal cancers in that population.²¹ Multiple epidemiological studies carried out in regions with different incidences of squamous cell cancers suggest that specific polymorphisms in genes encoding for alcohol metabolizing enzymes may determine individual susceptibility to the carcinogenic role of alcohol.^22,²³

Preexisting Diseases of the Esophagus

Several underlying esophageal diseases are known to increase risk of subsequent development of squamous cell cancers of the esophagus. There is a fairly well-established association of esophageal cancer with achalasia. In a recent epidemiologic study from Sweden involving 2896 patients with achalasia, excess risks for squamous cell carcinoma and adenocarcinoma of the esophagus were observed, predominantly in men. There was no association with esophagomyotomy.²⁴ Esophageal strictures caused by ingestion of lye, a caustic corrosive agent, are associated with a very high risk of squamous cell cancer, which develops three to five decades after the initial event. In achalasia and lye strictures, relative stasis, stagnation of food, and chronic inflammation have been implicated, but no definite carcinogenic mechanisms have been established. Tylosis, particularly the inherited form, which manifests in an autosomal dominant fashion with hyperkeratosis of palms and soles, has been associated with squamous cell cancer. For an affected family member, the estimated lifetime risk of esophageal cancer varied from 40% to 92% by the age of 70 (see Chapter 22). Although rare, the carcinogenetic events in tylosis has received recent attention in that a tylosis esophageal cancer (TOC) gene locus has been mapped to chromosome 17q25 by linkage analyses. Interestingly, loss of heterozygosity at this same locus, which contains the promoter sequence of the cytoglobin gene, has been detected in a significant number of patients with sporadic squamous cell cancers.²⁵ The association of chronic mucocutaneous candidiasis with squamous cell carcinoma of the oral cavity and esophagus has been described in patients with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED).²⁶

A rare syndrome of iron deficiency anemia, dysphagia, and postcricoid esophageal web known as Plummer-Vinson syndrome in the United States and Patterson-Kelly syndrome in the United Kingdom has been reported to have an association with squamous cell cancers (see Chapter 41). The anecdotally reported association of squamous cell cancers with partial gastrectomy has not been substantiated.

Patients with history of squamous cell cancer of the upper aero-digestive tract have an increased risk of synchronous or metachronous squamous cell carcinoma of the esophagus, most likely due to shared risk factors. In prospective controlled studies, 3% to 14% of patients with squamous cell cancers of head and neck area developed synchronous or metachronous squamous cell cancers of the esophagus.^27,²⁸ Radiation therapy following mastectomy moderately increases the risk of squamous cell esophageal cancer in the upper and middle thirds of the esophagus, starting approximately 5 years after exposure, with the risk persisting after 10 years; no similar increase in the risk of esophageal adenocarcinoma has been reported. This finding appears to be a function of the portals used for postmastectomy radiation therapy, which typically do not expose the lowest third of the esophagus, where adenocarcinoma commonly arises.²⁹

Given that human papillomavirus (HPV) has been implicated in the etiopathogenesis of squamous cell cancers of the oropharynx, its association with squamous cell cancers of the esophagus has been studied. Patients with squamous cell cancers of the esophagus from the United States, Europe, and Japan are infrequently HPV positive. On the other hand, in certain high-incidence areas, such as China and South Africa, HPV DNA can be demonstrated in a significant proportion of patients with squamous cell cancer of the esophagus. The interactive effect of genetic, environmental, and dietary risk factors in determining geographic susceptibility to the oncogenetic potential of chronic HPV infection needs further study.³⁰ There is no clear association of esophageal cancer with chronic infection with other viruses such as herpes simplex virus or Epstein-Barr virus.

ETIOLOGY AND RISK FACTORS (ADENOCARCINOMA)

Gastroesophageal Reflux Disease

Barrett’s esophagus, which is a complication of gastroesophageal reflux disease (GERD), is one of the strongest risk factors for esophageal adenocarcinoma (see Chapter 44). However, there is controversy whether GERD without Barrett’s esophagus is by itself a risk factor for esophageal adenocarcinoma. Many patients with esophageal adenocarcinoma do not report preexisting GERD symptoms and only a minority of patients with GERD develop Barrett’s esophagus. However, it is also thought that chronic mucosal inflammation in patients with recurrent GERD may predispose to esophageal adenocarcinoma. A large population-based Swedish study showed that in persons with recurrent symptoms of reflux, as compared with people without such symptoms, the odds ratio for esophageal adenocarcinoma was 7.7 and was 2 for adenocarcinoma of the cardia. The more frequent, more severe, and longer-lasting the symptoms of reflux, the greater the risk.⁴⁰ A recent Australian study suggested that obesity and GERD may play a synergistic role in the pathogenesis of esophageal adenocarcinoma.⁴¹ Overall, epidemiologic evidence suggests that chronic, severe GERD may predispose susceptible individuals to esophageal adenocarcinoma.

Barrett’s Esophagus (see also Chapter 44)

The reported prevalence of Barrett’s esophagus in the general population varies widely from 0.9% to 4.5%.^42,⁴³ Such fivefold variations in prevalence are mostly related to the type of population studied and also the definition of Barrett’s esophagus that is used. For example, experts disagree whether histopathologic demonstration of intestinal metaplasia is a requirement for diagnosing Barrett’s esophagus.^44,⁴⁵ Recent studies have suggested an increasing incidence of Barrett’s esophagus.^46,⁴⁷

The reported annual risk esophageal adenocarcinoma in patients with Barrett’s esophagus varies from 0.2% to 2% (see Chapter 44). In more recent studies with long-term follow-up of patients with histologically confirmed long-segment Barrett’s esophagus, the annual risk of developing high-grade dysplasia (HGD) or adenocarcinoma is approximately 1%.^48,⁴⁹ Although the annual incidence of cancer in those with low-grade dysplasia (LGD) was 0.6% to 1.3%, the incidence rate in patients with HGD is almost 10 times higher.^50,⁵¹ In a meta-analysis of 236 patients with Barrett’s esophagus and HGD, esophageal adenocarcinoma was reported in 69 patients over 1241 patient-years of follow-up, with a weighted incidence rate of 6.58 per 100 patient-years.⁵² In another recently published meta-analysis, the overall pooled risk for developing adenocarcinoma in all patients with Barrett’s esophagus was 6.1 per 1000 person-years and was just 4.1 per 1000 person-years when early incident cancers and HGD at baseline were excluded.⁵³ The risk of esophageal adenocarcinoma in patients with short segment Barrett’s esophagus or with specialized intestinal metaplasia of the esophagogastric junction is not known, but may be less compared with long-segment Barrett’s esophagus. However, it is important to note that these two entities are several-fold more common than long-segment Barrett’s esophagus and could account for a large number of patients with gastroesophageal junctional adenocarcinoma.

In addition to segment length and dysplasia, hiatal hernia, central obesity, and possibly smoking may be other factors favoring progression from nondysplastic Barrett’s esophagus to adenocarcinoma.^54,⁵⁵

Helicobacter pylori Infection

Epidemiologic studies show that as the prevalence of Helicobacter pylori infection has decreased in Western societies, the prevalence of GERD, Barrett’s esophagus, and distal esophageal and gastroesophageal junctional adenocarcinoma has rapidly increased. Although there are no data to suggest that H. pylori plays any role in esophageal mucosal resistance to acid-induced injury, in esophageal acid clearance, or in competence of the lower esophageal sphincter, it has been suggested that eradication of H. pylori in patients with corpus-predominant gastritis may exacerbate acid reflux. It has been postulated that the alkaline ammonia produced by H. pylori colonizing the cardiac mucosa could protect the neighboring distal esophageal squamous mucosa from damage by acidic reflux. There appears to be a negative association between H. pylori infection and GERD symptoms, although an association between successful H. pylori therapy and development of new or recurrent reflux symptoms has not been established.^56,⁵⁷ In a recent meta-analysis, patients with Barrett’s esophagus and adenocarcinoma, but not those with squamous cell esophageal cancer, were less likely to be infected with H. pylori, particularly cagA-positive strains.⁵⁸ The clinical implication of such inverse correlations is unclear and will require careful evaluation, given that H. pylori infection is considered an important etiologic factor for gastric cancer.

Diverse Preexisting Conditions

Patients with acid hypersecretory states or conditions associated with severe GERD (e.g., scleroderma) may be at increased risk for esophageal adenocarcinoma. In a population-based study from Sweden, cholecystectomy was associated with a moderately increased risk of subsequent esophageal adenocarcinoma, but not squamous cell cancer. Increased duodeno-gastroesophageal reflux and a toxic effect on bile acids and bile salts on the esophageal mucosa was thought to be the mechanism. A case control study failed to identify an association between diabetes and esophageal adenocarcinoma.⁵⁹ GERD is common in premature infants and in infants who are small for gestational age, and epidemiologic data suggest that preterm birth and low birth weight may be risk factors for development of esophageal adenocarcinoma. Down syndrome is not associated with esophageal cancer.⁶⁰

Drugs

There is conflicting evidence regarding whether long-term use of drugs that relax the lower esophageal sphincter, such as anticholinergics, β-adrenergic agonists, theophylline or aminophylline, and benzodiazepines increase risk of esophageal adenocarcinoma.⁶¹ A few epidemiologic studies and a recent meta-analysis reported a protective effect of aspirin use (and to a lesser extent nonsteroidal anti-inflammatory drug [NSAID] use) with both types of esophageal cancer, an effect that appears to be dose dependent.⁶²

FAMILY HISTORY AND GENETIC FACTORS

In areas with a high incidence of squamous cell esophageal cancer, family history is a strong risk factor for this disease. Gene expression profiling studies in these families have found consistent ribonucleic acid (RNA) expression patterns.⁶³ Furthermore, the possibility of an esophageal squamous cell cancer (ESCC) susceptibility gene has been considered based on frequent allelic loss on chromosome 13 in these patients.⁶⁴

Familial aggregation of Barrett’s esophagus, and related esophageal and junctional adenocarcinoma, has been described and a study reported that in up to 7% patients with Barrett’s esophagus, a familial aggregation can be confirmed (see Chapter 44). It has been suggested that familial Barrett’s esophagus is likely a complex genetic disorder consistent with a major mendelian autosomal dominant gene with relatively high penetrance.^65,⁶⁶

Individual variations in risk of developing esophageal cancer of any type may be partly explained by the presence of specific variant alleles (polymorphisms) of different genes that are present in a significant proportion of the population and likely play important roles in the multistep process of carcinogenesis (see Chapter 3). Such genetic polymorphisms that may increase susceptibility to esophageal cancer have been described in genes involved in alcohol metabolism, folate metabolism, carcinogen metabolism, DNA repair, cell cycle control, and oncogenes.⁶⁷

MOLECULAR BIOLOGY

Similar to other cancers, esophageal cancers of both types develop through a multistep progressive process, which at the cellular level is reflected by disorders of the control of cell proliferation, differentiation, and controlled cell death (apoptosis) (see Chapter 3). There has been increasing interest in understanding the molecular mechanisms of these carcinogenetic events, not only for understanding etiologic factors but also for potential therapeutic targeting and determining prognosis.

A simplified approach to understand the extensive recent research on the putative molecular mechanisms of esophageal carcinogenesis is to describe the known aberrations in terms of phenotypic features of cancer cells such as autonomous growth, attenuation of antiproliferative pathways, disordered apoptosis, unlimited replication, and factors promoting neoangiogenesis, invasion, and metastasis.

Autonomous Growth (Growth Factors)

Increased expression of epidermal growth factor (EGF) and transforming growth factor-α (TGF-α) has been demonstrated in esophageal adenocarcinoma and has been associated with invasive disease and possibly poorer outcome.^68,⁶⁹ Furthermore, increased concentrations of TGF-β in azygos vein blood and increased expression of connective tissue growth factor (CTGF) and endoglin, a member of the TGF-β receptor family, have been correlated with angiogenesis, angiolymphatic invasion, and metastasis in patients with esophageal cancer.⁷⁰ On the other hand, increased expression of SMAD has been associated with better survival in patients with squamous cell esophageal cancer.⁷¹ C-erbB2, a proto-oncogene coded by the HER2/neu gene and sharing a significant homology with EGF receptor, is amplified in patients with Barrett’s esophagus and adenocarcinoma, is clinically associated with a poorer outcome, and may play an early role in disease invasiveness.^72,⁷³ HER2/neu gene overexpression may promote carcinogenesis through multiple pathways, such as inhibition of apoptosis and enhanced cell proliferation, increased mitogen activated protein kinase (MAPK) activity and increased matrix metalloproteinase (MMP) activity, and by potent induction of vascular endothelial growth factor (VEGF).

The restriction point (R-point) is a critical gatekeeping checkpoint that controls G1- to S-phase transformation in the cell cycle (see Chapter 3). Cyclin D and E are proteins that are important regulators of the R-point and serve as the final step in many proliferation cascades. CCND1, the gene that encodes cyclin D1, is associated with an increased risk for esophageal adenocarcinoma.⁷⁴ Also cyclin B has been shown to be overexpressed in esophageal squamous cell cancer, with possibly with a negative prognosis.⁷⁵

Attenuation of Antiproliferative Pathways

Attenuation of antiproliferative cellular signals is a hallmark of cancer cells. Most cellular antiproliferative pathways converge on the retinoblastoma protein (Rb) pathway, which plays an important antiproliferative role by having a regulatory role on transition of cells from G0 to S phase (see Chapter 3). Loss of heterozygosity (LOH) of Rb protein and its functional repression by hypermethylation of p16, a tumor suppressor gene, has been described in patients with esophageal adenocarcinoma.^76,⁷⁷ Expression of p21, another cell cycle regulator that is activated after DNA damage by ionizing radiation, has been correlated with responsiveness of esophageal cancers to chemoradiotherapy.⁷⁸ Although mutations of the APC gene is uncommon in patients with esophageal cancer, allelic deletion of 5q where APC resides, as well as functional repression of APC by hypermethylation of the promoter region of this gene, is quite common in patients with esophageal adenocarcinoma.⁷⁹ In fact, plasma levels of hypermethylated APC DNA may be a biomarker of esophageal cancer.⁸⁰

Disordered Apoptosis

Programmed cell death, or apoptosis, is an important defense mechanism against cancer and is regulated by TP53 and bcl-2 family of genes and their proteins (see Chapter 3). Alterations in TP53 in patients with esophageal cancer are seen in up to 50% to 99% of patients and are usually associated with a more aggressive form of tumor.⁸¹ Similarly, the bcl-2 family of proteins (Bcl-2, Bcl-xl, Bax) maintains an intricate balance of pro- and antiapoptotic factors in the cellular milieu and may play an important yet unclear role in the progression of non-dysplastic Barrett’s esophagus to high-grade dysplasia and adenocarcinoma.⁸² Nuclear factor kappa B (NF-κB), an antiapopotic factor, is expressed in 60% of patients with esophageal adenocarcinoma and has prognostic significance.⁸³ The protein kinase Akt (also known as protein kinase B), a recently described serine-threonine kinase, is an important mediator of growth and antiapoptotic signals in esophageal adenocarcinoma. Increased Akt activation in the basal epithelium has been associated with metaplastic progression from squamous epithelium to nondysplastic Barrett’s esophagus, and eventual progression to high-grade dysplasia and adenocarcinoma.⁸⁴ The hormone leptin and short-term acid exposure activate Akt in esophageal adenocarcinoma cells in vitro.⁸⁵

Unlimited Replication

Telomeres are composed of several thousand repeats of short six-base-pair sequence elements and are located at the ends of chromosomes. At each cell replication the telomeres are shortened so that telomere length serves as counters of cycles of replication. After a finite number of cell replications, the telomeres are short enough to trigger the cell to exit from G1 to G0 phase, thus arresting further replication. Cancer cells, which are characterized by ability for limitless replication, achieve this ability partly by increased expression of telomerase, a ribonucleoprotein reverse transcriptase that counteracts shortening of telomeres. Increased expression of telomerase has been associated with progression of metaplastic epithelium to dysplasia to adenocarcinoma in patients with Barrett’s esophagus.⁸⁶

Factors Promoting Neoangiogenesis, Invasion, and Metastasis

The ability of cancer cells to invade and disseminate is determined by their ability to disrupt intercellular adhesion as well as by altering the delicate balance between extra cellular matrix degrading proteases, such as urokinase-type plasminogen activator (uPA) of the serine protease system, MMP, and antiproteinases, such as tissue inhibitory metalloproteinase (TIMP) (see Chapter 3). Not unexpectedly, esophageal cancer, one of the most aggressive cancers with respect to invasiveness and propensity to metastasis, is associated with molecular abnormalities related to cell-cell adhesion molecules (CAMs), such as E-cadherins, integrins, and CD44 transmembrane glycoproteins, and overexpression or altered localization of uPA, the cysteine protease, cathepsin B (CTSB) protein, MMP and TIMP. Evidence suggests that many of these may be useful prognostic markers.^87,⁸⁸

Alteration of the Cyclooxygenase Pathway

Cyclooxygenases (COX) are key enzymes in the prostaglandin metabolism. COX-2, an inducible enzyme, has been shown to be an important mediator of tumorigenesis and angiogenesis. Selective inhibition with COX-2 inhibitors induces apoptosis and reduces angiogenesis. Activation of the COX-2 pathway can inhibit apoptosis by lowering the intracellular level of arachidonic acid, a fatty acid precursor of prostaglandins, which is known to promote apoptosis. A second mechanism that can be targeted by COX-2 inhibitors is prostaglandin-E₂ (PGE₂) dependent, and appears to be mediated by increase in intracellular Bcl-2 as well as intracellular cyclic adenosine monophosphate (cAMP), both of which suppress apoptosis. The angiogenetic potential of the COX-2 pathway occurs through increased expression of VEGF, increased endothelial survival by bcl-2 and Akt signaling, induction of MMP, EGF receptor–mediated angiogenesis, and suppression of interleukin 12 (IL-12) expression. Studies have shown that patients with esophageal cancer who express a high level of COX-2 in their tumors are more likely to have metastatic disease at presentation, to have more local tumor recurrences after definitive treatment, and to have a worse survival than patients not overexpressing COX-2.^89,⁹⁰

Microsatellite Instability

Several investigators have reported microsatellite instability (MSI) in less than 20% of esophageal and gastroesophageal junctional adenocarcinomas. Early unconfirmed evidence, however, suggests that MSI may be an early event in the progression of intestinal metaplasia to esophageal adenocarcinoma.⁹¹

Chromosomal Abnormalities

Defects in mitotic checkpoint genes lead to aneuploidy, or an abnormal number of chromosomes. Although a vast majority of esophageal cancers have aneuploidy, the exact gene defects are not characterized. DNA aneuploidy detected by flow cytometry has been considered to be a marker of progression of intestinal metaplasia to esophageal adenocarcinoma.⁹² A host of specific chromosomal abnormalities have been described in patients with esophageal cancer, and recent studies based on a comparative genomic hybridization technique using different types of esophageal cancer and gastric cardiac adenocarcinoma may lead to identification of genes important for disease-specific pathogenesis.⁹³

Molecular Events in Neoplastic Progression of Barrett’s Esophagus

Research has focused on the complex molecular events that lead to development of esophageal adenocarcinoma in the setting of Barrett’s esophagus.⁹⁴ It is postulated that the initial turn-on event, which is related to chronic exposure to noxious stimuli, such as acid reflux and bile salt exposure, is the activation of the inflammatory cascade mediated by cytokines such as tumor necrosis factor-α (TNF-α) and IL-1b. This cytokine activation eventually leads to ectopic expression of CDX1 and CDX2 homeobox proteins that play a major role in the development of intestinal epithelium in the embryonic stage and in this setting cause intestinal metaplasia to develop.⁹⁵^–⁹⁷ With the development of metaplastic intestinal epithelium, multiple poorly characterized genetic (e.g, aneuploidy, loss of heterozygosity, mutation) and epigenetic events (e.g., hypermethylation) set off the metaplasia to dysplasia to adenocarcinoma sequence, which eventually leads to genetic instability with clonal expansion of cells with genetic errors. The exact sequence of this multistep process is not known, but several early events in this transition sequence have been identified.⁹⁸ Abnormalities of p16 and possibly overexpression of cyclin D1 are relatively early events that lead to loss of control of cell cycle regulatory genes. Telomerase may also play in early role. Prevalence of TP53 damage such as loss of heterozygosity and mutation increases with advancing grade of dysplasia. Similarly, progression of dysplasia is characterized by decreased expression of E-cadherin and membranous β-catenin expression. Growth signals such TNF-α and COX-2 expression also increase with progression of grades of dysplasia and warrant further evaluation as potential biomarkers.

Future Molecular Directions

Exciting developments in the diverse field of genome analysis technology, stem cell signaling pathways, microarray analysis, and proteomics will hopefully lead to clearer understanding of the pathobiology of carcinogenesis and the diverse but interrelated molecular events responsible for development and progression of dysplasia involved into the eventual development of esophageal cancers. Such developments will also likely lead to maturation of our evolving knowledge on a host of potential molecular biomarkers, prognostic indicators, and therapeutic targets for chemopreventive and chemotherapeutic strategies for incorporation into standard clinical practice.

PATHOLOGY

Squamous Cell Cancer

Esophageal squamous cell cancer typically develops by progression from premalignant (dysplastic) precursor lesions (Fig. 46-2). Many pathologists describe dysplasia using a two-tiered system: low-grade dysplasia, which includes mild and moderate dysplasia; and high-grade dysplasia, which includes severe dysplasia and cancer in situ.⁹⁹ In the World Health Organization (WHO) classification the term “intraepithelial neoplasia” is preferred over “dysplasia,” although dysplasia is by far more popular.¹⁰⁰ Dysplasia includes both cytologic and architectural abnormalities of varying severity and extent. Low-grade dysplasia often involves the basal part of the epithelium and high-grade dysplasia usually involves the entire epithelial layer and, in a small proportion of patients, dysplasia extends into the ducts of the esophageal glands, simulating stromal invasion or spread in a horizontal pagetoid pattern.¹⁰¹ Dysplasia is often multifocal, supporting a field defect hypothesis in the pathogenesis of esophageal squamous cancer. Cytologic changes are typically seen as coarse chromatin, increased nuclear to cytoplasmic ratio, nuclear hyperchromasia, nuclear pleomorphism, and mitotic figures. Architectural changes of dysplasia include disorganization, loss of polarity, overlapping nuclei, and lack of surface maturation. The presence of these features is often used to distinguish dysplasia from non-neoplastic (reactive) processes typically seen with esophageal mucosal inflammation.

Approximately 50% to 60% of squamous cell esophageal cancers occur in the middle third of the esophagus, 33% involve the distal esophagus, and 10% occur in the proximal esophagus. The gross appearance of squamous cell esophageal cancers ranges from a flat, relatively inconspicuous lesion to elevated, plaque-like, polypoid, ulcerated, exophytic, and infiltrative lesions. Superficial squamous cell esophageal cancers invade the submucosa but not the muscularis propria, whereas advanced cancers usually invade the muscularis propria and beyond, either with an infiltrative pattern of small isolated tumor nests or in an expansile pattern of a solid advancing sheet of tumor cells, often with a prominent peripheral lymphocytic infiltration. Approximately one third of squamous cell esophageal cancers are well differentiated, whereas two thirds are either moderately or poorly differentiated, without any features of keratinization.

Squamous cell cancers are aggressive and local lymph nodal metastasis occurs early, partly related to the presence of lymphatic channels in the esophageal lamina propria. Because of the prognostic importance of lymph nodal metastasis and its effect in deciding management options, early squamous cell cancer has been categorized into six subcategories based on depth of tumor infiltration. Intramucosal carcinomas are divided into three groups (m1, m2, and m3), and carcinomas invading the submucosa also are divided into three groups (sm1, sm2, and sm3) (Fig. 46-3). Data from Japan suggest that although m1 and m2 early squamous cell cancers do not usually have nodal metastasis, m3 disease has up to an 8% incidence of nodal metastasis, and this incidence progressively increases as the tumor infiltrates the submucosa, with sm1, sm2, and sm3 tumors having incidences of nodal involvement of 17%, 28%, and 49%, respectively. Similarly the incidence of vascular invasion progressively increases, with m1 tumors having none, whereas almost 90% of sm3 tumors show vascular involvement.¹⁰²

Figure 46-3. A schematic diagram of depth of invasion of a superficial esophageal neoplastic lesion, as evaluated in a resected mucosal specimen. Depths m1, m2, and m3 denote invasion limited to the epithelial layer, lamina propria, and muscularis mucosae, respectively. Similarly, sm1, sm2, and sm3 denote superficial, intermediate, and deep submucosal invasion, respectively.

Invasion of local structures, such as mediastinal pleura, the trachea, the bronchi, and the aorta as well as distant metastases to liver, lung, bone, and other sites may be present in more than a third of these patients at presentation and signifies a poor prognosis. Relatively rapid invasion of the tumor into neighboring structures in the mediastinum has been attributed to the absence of a true serosal layer in the esophageal wall.¹⁰³

Adenocarcinoma

Compared with squamous cell esophageal cancer, a larger body of information exists related to the pathobiology of dysplasia in Barrett’s esophagus and its progression to esophageal adenocarcinoma. Grossly, esophageal dysplasia in Barrett’s esophagus is usually flat and inconspicuous. Dysplasia may be described as low grade or high grade and generally follows the same patterns of cytological or architectural changes described earlier with squamous cell dysplasia. There is considerable interobserver variation in the interpretation and grading of dysplasia and adenocarcinoma among pathologists.¹⁰⁴ Furthermore, progression of dysplasia from low grade to high grade is a morphologic continuum and thus may not follow identifiable features of orderly progression for definitive categorization.¹⁰⁵ “Adenoma-like” dysplastic changes show minimal crypt distortion and mild cytological abnormalities. This is in contrast to the much less common “nonadenoma-like” dysplasia that typically shows crowded glands containing cuboidal cells with a high nuclear to cytoplasmic ratio, round nuclei with irregular contours, vesicular chromatin, and prominent nucleoli.¹⁰⁶ Goblet cells are usually depleted in dysplastic epithelium, and even the surrounding nondysplastic mucosa may show a decrease in goblet cells.¹⁰⁷

Many pathologists often use the term “indefinite for dysplasia” when true dysplasia cannot be accurately differentiated from reactive changes in the presence of esophageal inflammation. Although lack of surface maturation is normally considered a cardinal feature of dysplasia, this has been recently debated.¹⁰⁸ Adjunct immunohistochemical markers (e.g., proliferating cell nuclear antigen (PCNA) and Ki67, cyclin D1, and TP53) have been used to improve the accuracy of diagnosis of dysplasia in this setting.^109,¹¹⁰ Recent studies have reported the utility of immunostaining for alpha-methylacyl-CoA racemase (AMACR) for differentiating non-dysplastic epithelium from low-grade and high-grade dysplasia and also from adenocarcinoma.^111,¹¹² In one study, AMACR staining was negative in all cases of Barrett’s esophagus considered negative for dysplasia, whereas 38% of cases of low-grade dysplasia, 81% of cases of high-grade dysplasia, and 72% of cases of adenocarcinoma were positive.¹¹¹ Another recent study also reported a high negative predictive value for AMACR immunostaining.¹¹²

Almost all esophageal adenocarcinomas arise in the setting of Barrett’s esophagus and typically occur in the distal third of the esophagus, including the esophagogastric junction (see Chapter 44). Adenocarcinomas unrelated to Barrett’s esophagus are extremely rare and usually arise from foci of gastric heterotopia in the cervical esophagus (inlet patch; see Chapter 41). Esophageal adenocarcinoma may have a flat, inconspicuous appearance or can be polypoid, ulcerated, or infiltrative. The majority are well or moderately differentiated, usually comprising cystic or tubular glands in solid nests and irregular clusters and often in a cribriform pattern with considerable stratification. In poorly differentiated carcinomas, the tumor cells infiltrate the esophageal wall with sheets of poorly formed glands with a prominent desmoplastic stroma. Signet ring cells and bizarre pleomorphic tumor cells may be present. One of the common problems encountered by pathologists is distinguishing a tumor of the gastric cardiac from an esophageal adenocarcinoma. In these instances, correlation of the biopsy site with endoscopic anatomic landmarks is crucial.

The incidence of lymph node metastasis in esophageal adenocarcinoma is related to depth of tumor infiltration and appears to be equal or less than in squamous cell esophageal cancer. Whereas nodal disease is rare with adenocarcinomas limited to the esophageal mucosa, the rate of nodal metastases for tumors invading into the submucosa is reported to be 27% to 41% for all patients, and 67% to 78% for those with tumors infiltrating the deep submucosa.¹¹³^–¹¹⁵ Involvement of celiac and perihepatic lymph nodes is more common with esophageal adenocarcinoma than squamous cell carcinoma because of the more common occurrence of these former tumors at or near the gastroesophageal junction.

CLINICAL FEATURES

Patients with squamous cell cancer and adenocarcinoma of the esophagus present with similar symptoms. The most common is progressive dysphagia, often accompanied by disproportionate weight loss. The esophagus can distend up to a diameter of 40 mm in normal adults; solid food dysphagia can occur at luminal diameter of 25 mm, but at or below a diameter of 13 mm dysphagia is always present. Dysphagia initially can be subtle and reported by patients as a sensation of transient sticking of food. Odynophagia usually coincides with presence of an ulcerated tumor. Many patients with early esophageal cancer are asymptomatic. Some may present with iron deficiency anemia. Chest pain or pain radiating to the back is an ominous symptom, often indicating invasion into periesophageal structures. People with esophageal adenocarcinoma are almost eight times as likely to report at least weekly symptoms of reflux or regurgitation as control subjects; no association of GERD symptoms and squamous cell cancer was reported.⁴⁰ Regurgitation of undigested food material proximal to the area of obstruction and symptoms related to aspiration pneumonia are often present at advanced stages of the disease. Hoarseness can result from recurrent laryngeal nerve involvement by the tumor per se or metastatic lymph nodes. Esophagorespiratory fistula develops in approximately 5% to 15% of all patients with advanced esophageal cancer and is associated with a particularly poor prognosis. Fistula usually manifests with intractable cough and recurrent pneumonia. Uncommon sites of fistulae from esophageal carcinoma include extension to the aorta, pleura, pericardium, and mediastinum. Hematemesis can be due to local hemorrhage from an ulcerated tumor; rarely, exsanguination can occur from development of an aortoesophageal fistula. Many patients have symptoms related to metastases in the lung, liver, bone, or brain, either at presentation or during the course of the disease.

The signs of esophageal cancer are nonspecific and commonly include anemia, malnutrition, and signs of recent weight loss of varying degree. Clinical signs of aspiration pneumonia may be present. Cervical lymphadenopathy and enlargement of the liver due to presence of multiple metastatic lesions are present in a minority of these patients.

DIAGNOSIS

Laboratory Tests

Laboratory abnormalities in patients with esophageal cancer are nonspecific and most often show anemia and hypoalbuminenia. Anemia can have features of iron deficiency or anemia of chronic disease. Hypercalcemia due to osteolytic metastasis or, less commonly, as a response to circulating parathyroid hormone–related protein (in squamous cancer) may be present in up to a third of patients. Hypercalcemia is more common in patients with squamous cell cancers than adenocarcinomas and may indicate advanced disease and a poor prognosis. There are no specific serologic markers for esophageal cancer.

Imaging Tests

Chest Radiography

Chest radiographs in patients with esophageal cancer may show aspiration pneumonia, lung metastases, and pleural effusion. A dilated fluid-filled esophagus may be seen. Evidence of mediastinal widening and tracheal deviation, a thickened retrotracheal stripe, pneumomediastinum, and signs of esophagorespiratory fistula or mediastinal abscess can often be appreciated.

Contrast Esophagography

The role of contrast esophagography in diagnosis of esophageal cancer has diminished over the years with the increasing use of endoscopy for primary diagnosis. Esophagography should be performed only when this test is likely to affect decision making. Double-contrast barium radiographs often show early cancers as small polypoid lesions, plaque-like lesions, or focal irregularity of the wall. Advanced cancers commonly appear as areas of irregular luminal narrowing, ulceration, and stricture, with abrupt shoulders. Esophagogastric junctional cancers typically extend into the gastric cardia, and for this reason the fundus and cardia of the stomach should always be included in an optimal contrast radiographic study of the esophagus. To evaluate a suspected esophagorespiratory fistula, contrast radiographs are very useful for delineation of the anatomy prior to endoscopic stenting. Such contrast radiographic studies should be performed using barium instead of a hyperosmolar contrast agent such as meglumine ditrizoate because of the risk of pulmonary edema with the hyperosmolar contrast agent (Fig. 46-4).

Figure 46-4. This barium esophagogram in a patient complaining of cough and dysphagia demonstrates complete esophageal obstruction and a tracheoesophageal fistula. Note the presence of ingested barium in the airways.

Computed Tomography

Esophageal cancer typically appears on computed tomography (CT) scan as irregular thickening of the esophageal wall, with a dilated esophageal lumen proximal to the area of the malignant stricture and often as an intraluminal mass. Obliteration of the fat plane between the tumor and adjacent structures, perforation or a sinus tract into the mediastinum, fistula to the tracheobronchial tree, or enlarged mediastinal lymph nodes can be seen in patients with locally advanced tumor. The primary role of CT in esophageal cancer management is for staging, particularly to exclude distant metastatic disease to the lung and liver and to assess for mediastinal invasion.

Three-dimensional multidetector CT imaging and CT esophagography appear to be promising techniques in early reports, reproducing a contrast radiograph–like image with fairly accurate depiction of length of the tumor and its location.¹¹⁶

Endoscopy and Biopsy

During endoscopy, the location of the esophageal tumor, its relation to anatomic landmarks such as the upper esophageal sphincter and the esophagogastric junction, and the degree of luminal obstruction are typically assessed. Also endoscopic visualization combined with endoscopic biopsy provides an accurate assessment of malignant (and premalignant) lesions of the esophagus. A Paris classification has been proposed for endoscopic assessment of superficial neoplasia of the gastrointestinal tract, including the esophagus, but its clinical acceptance has been limited particularly in North America.¹¹⁷ Advanced esophageal cancers appear endoscopically as fungating, friable, often ulcerated mass lesions occupying some or all of the luminal circumference, usually with indistinct margins (Fig. 46-5). Less frequently, both types of cancers (squamous and adenocarcinoma) can present with a submucosal infiltrative pattern and may not have a prominent luminal component. If the esophagogastric junction is involved by such a tumor, the clinical presentation is often suggestive of peseudoachalasia (see Chapter 42). Typically a higher number of biopsies translates to a higher accuracy rate. Tumors with a submucosal infiltrative pattern may require an aggressive biopsy technique to obtain deeper tissue, using a bite-on-bite technique or endoscopic ultrasonography (EUS)-guided fine-needle aspiration of submucosal tissue.

Figure 46-5. Advanced squamous cell carcinoma of the esophagus that is nearly completely occluding the lumen.

Brush cytology is a useful and quick technique to increase the yield in establishing a diagnosis of esophageal cancer, particularly with the availability of advanced cytologic techniques such as fluorescence in situ hybridization (FISH).¹¹⁸

Endoscopic Detection of Dysplasia and Early Cancer

Numerous endoscopic techniques and newer imaging technologies have evolved over the past decade for endoscopic detection of early or superficial esophageal cancer.

Conventional Chromoendoscopy

Chromoendoscopy with topical application of stains or pigments has been used for improved visualization of subtle mucosal pathology. Lugol’s iodine, when sprayed on the esophageal mucosa during endoscopy, stains the glycogen-rich squamous epithelium black, dark brown, or green-brown, whereas abnormal (neoplastic or inflamed) glycogen-depleted squamous epithelium does not pick up the stain, providing good visual contrast. Lugol’s iodine increases detection of dysplasia and early squamous cell cancers compared with endoscopic visualization alone, and this method may be particularly useful in screening patients at high risk for squamous cell cancer.¹¹⁹ Lugol’s iodine may also be useful in identifying residual islands of Barrett’s epithelium after endoscopic mucosal ablative therapy and development of neosquamous epithelium. For endoscopic detection of high-grade dysplasia and early adenocarcinoma in the setting of Barrett’s esophagus, a number of chromoendoscopic techniques, based on application of vital staining with dyes such as methylene blue, toluidine blue, and cresyl violet and contrast stains such indigo carmine, have been used. The largest experience is with methylene blue–based chromoendoscopy, although the reported results of chromoendoscopy in this setting are quite variable, leading to controversy on the utility of this technique in clinical practice.¹²⁰ A meta-analysis concluded that targeted biopsies after methylene blue–based chromoendoscopy is not superior to random biopsy in detecting specialized intestinal metaplasia and dysplasia of any grade in patients with Barrett’s esophagus who are undergoing endoscopic surveillance and thus cannot be recommended for routine clinical practice.¹²¹ Chromoendoscopy using acetic acid, which dissolves the superficial mucus layer by breaking the glycoproteins’ disulfide bonds and reversibly acetylates cellular proteins, has been used to highlight the mucosal vasculature pattern in patients with Barrett’s esophagus.¹²²