11: Pathology of Esophageal Cancer

Esophageal cancer is a gastrointestinal malignancy that encompasses a range of pathologic entities. Squamous cell carcinomas constitute at least 90% of all cancers worldwide.¹ Adenocarcinoma is the second most common type of cancer. Other types, such as small cell carcinoma and malignant melanoma are rare. The incidence of esophageal adenocarcinoma has increased in the United States from 0.5 to 0.9/100,000 in the 1970s to 3.2 to 4.0/100,000 in the 1980s and 1990s. Although esophageal adenocarcinoma accounted for about 16% of all esophageal cancers among White men in the United States in the mid-1970s, by the late 1990s, this number approached 50%. This increase has been seen across all socioeconomic groups² but has been most pronounced in affluent populations.^3-7 Over the same period of time, there has been a decline in both esophageal squamous cell carcinomas and adenocarcinomas of the distal stomach.^8,9 Barrett esophagus is a metaplastic condition in which normal squamous mucosa of the distal esophagus is transformed into intestinalized columnar epithelium. Barrett esophagus is the established precursor lesion for nearly all esophageal adenocarcinomas.

Squamous cell carcinoma 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

Pathology

Precancerous Lesions

Chronic esophagitis is common in populations with a high incidence of esophageal carcinoma, and usually involves the middle and lower thirds of the esophagus. “White” patches are seen at endoscopy, which corresponds to acanthosis and swollen clear squamous cells. Squamous dysplasia is a precursor of esophageal squamous cell carcinoma. Dysplasia may appear endoscopically as areas of friable or erythematous mucosa, erosions, plaques, or nodules. Ill-defined irregularities of the mucosal surface, or white patches, also may be present. In a very small proportion of cases, foci of dysplasia, or cancer, may appear endoscopically normal.⁵⁵ The age distribution of dysplasia and carcinoma suggested a continuous progression from mild to severe dysplasia and carcinoma in situ. Further evidence of the role of dysplasia as a precancerous lesion comes from its frequent occurrence in areas adjacent to, or distant from, invasive squamous carcinoma when esophagectomy specimens have been studied in detail.^56-59 Prevalence of dysplasia at the margins of invasive carcinoma is reported to be inversely related to the depth of invasion of the main lesion. This suggests that dysplasia represents a precursor lesion rather than cancerization of overlying benign epithelium by the invasive carcinoma.⁶⁰ Multicentric tumors may be present in 15% to 30% of squamous cell carcinomas further supporting the idea of a “field effect” in carcinogenesis.^61,62

The histological criteria for dysplasia include architectural and cytological abnormalities. Two classifications have been used. The original classification defined dysplasia as mild when <25% of the epithelium was involved, moderate when 25% to 50% of the epithelium was involved, and severe when more than 50% of the mucosa was involved. A two-tiered system, where low-grade dysplasia is defined as <50% and high-grade dysplasia as >50% involvement of the epithelium with neoplastic cells, is preferred (Fig. 11-1A,B). Cytological features of dysplasia include high nuclear-cytoplasmic ratio, nuclear hyperchromasia and pleomorphism, and increased mitotic activity. Dysplasia also may spread in a pagetoid fashion or into underlying esophageal gland ducts.^63,64 In some cases, the presence of koilocytotic change may reflect an underlying HPV infection.^65,66

In the presence of significant inflammation, a diagnosis of dysplasia should be made with caution because regenerative changes secondary to inflammation, radiation, or chemotherapy may mimic dysplasia. Unlike dysplasia, regenerative epithelium shows surface maturation and does not show significant nuclear crowding and loss of polarity, and atypical mitoses are typically absent. Vesicular chromatin, with prominent nucleoli, is often present in regenerating epithelium. In cases of uncertainty, a diagnosis of “indefinite for dysplasia” should be rendered.

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

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

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 cells^77,81 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 component^82,83 whereas others have reported negative reactions to keratin and variable positivity for desmin, smooth muscle actin, vimentin, alpha-1-antichymotrypsin, and alpha-1-antitrypsin.^79,84,85 Although hematogenous spread is more common in carcinosarcomas than pure squamous cell carcinoma, the overall 5-year survival rate has been shown to be similar.^77,86

Basaloid Squamous Cell Carcinomas comprise about 2% to 11% of all squamous cell carcinomas^87,88 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

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 esophagus^64,97,98 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

Clinical Features

Barrett esophagus is a metaplastic precancerous lesion involving the distal esophagus that occurs in patients with chronic gastroesophageal reflux disease and is present in the majority of patients with esophageal adenocarcinoma. The distal third of the esophagus is the most common location for esophageal adenocarcinoma. The overall incidence of esophageal adenocarcinoma has increased from 3.6 per million in 1973 to 25.6 per million in 2006.^2,8,108 The incidence of adenocarcinoma has also risen among Black males and women during this period, but the rates have remained at much lower levels. Increasing rates of esophageal adenocarcinoma have also been reported from the United Kingdom, Scandinavia, France, Switzerland, Australia, and New Zealand.^109-114 Interestingly, recent incidence trend analysis for esophageal adenocarcinoma using the SEER database shows that the increase in incidence of esophageal adenocarcinoma may have slowed down and possibly reached a plateau. The rising trend appears to have slowed down from an annual 8.2% increase prior to 1996 to 1.3% in subsequent years. This is largely due to changes in incidence of early stage disease, which has changed from a 10% annual increase prior to 1999, to a 1.6% decline subsequently.¹¹⁵

Etiology and Associations

The underlying risk factors for adenocarcinoma of the distal esophagus and the gastroesophageal junction are significantly different from those of esophageal squamous cell carcinoma. Gastroesophageal adenocarcinomas show an association with reflux disease, obesity, dietary factors, smoking, and alcohol consumption, and are inversely associated with gastric colonization by Helicobacter pylori. Obesity and overweight have been consistently shown to be associated with esophageal adenocarcinoma, but not to squamous cell carcinoma.^116,117 This may be related to increased abdominal pressure predisposing to gastroesophageal reflux disease and increasing likelihood of developing Barrett esophagus.^118,119 The impact of smoking on risk of esophageal adenocarcinoma is weak compared to squamous cell carcinoma. There is a two- to threefold increased risk in smokers, but unlike squamous cell carcinoma, the risk of esophageal adenocarcinoma does not decrease substantially after cessation of smoking.^120-122 Alcohol consumption has not been consistently related to an increased risk for esophageal adenocarcinoma. The use of aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs) may reduce the risk of esophageal cancer. A 35% decrease in the risk of esophageal cancer among NSAID users compared with nonusers was shown in a recent meta-analysis.^123-127 Single nucleotide polymorphisms (SNPs) involving Caspase-7 and Caspase-9 genes are reported to be significantly associated with an increased risk of esophageal adenocarcinoma. SNP in the PR (progesterone receptor) gene among women carrying the variant G allele may exert a protective effect.¹²⁸

Pathologic Features

Gross Pathology of Adenocarcinoma

The majority of esophageal adenocarcinomas involve the distal third of the esophagus and present as ulcerating, infiltrative lesions (40%–50%), frequently associated with stenosis of the esophageal lumen. Others are fungating (20%–25%), flat (10%–15%), or polypoid (5%–10%) in appearance.^129,130 A diffusely infiltrative growth pattern resembling linitis plastica in the stomach is seen in rare instances.¹³¹ Early cancers detected during surveillance of patients with Barrett esophagus may be invisible on endoscopy or appear as small depressed or elevated lesions.¹³² Multicentric tumors have also been described.^130,133 Barrett esophagus is often apparent in the background, although in large tumors this may be obliterated completely by the tumor mass. Patients in whom esophagectomy is performed after neoadjuvant chemoradiation therapy may not show any residual lesion upon gross examination. Only a flat ulcerated lesion or an indurated scar may be present at the primary tumor site.¹³⁴

Microscopic Pathology of Adenocarcinoma

Histologically, these tumors show a similar spectrum of changes as adenocarcinomas that develop in the stomach. High-grade dysplasia is commonly seen in adjacent columnar epithelium.129,135 The majority of tumors show a tubular or papillary growth pattern with variable grades of differentiation. Well-differentiated tumors show >95% gland formation, with columnar to cuboidal cells, hyperchromatic or vesicular nuclei, and a variable amount of eosinophilic or clear cytoplasm. Moderately differentiated tumors show gland formation in 50% to 95% of the tumor and poorly differentiated tumors show <50% glandular differentiation (Fig. 11-6A,B). The degree of nuclear pleomorphism parallels the grade of differentiation. Large, bizarre pleomorphic nuclei are more commonly seen in poorly differentiated tumors. About 5% to 10% tumors are of the mucinous (colloid) type and show prominent pools of extracellular mucin with floating clusters of tumor cells (Fig. 11-7). Signet ring cell carcinoma is less common (5% of cases) than in the stomach. Foci of squamous, neuroendocrine, and Paneth cell differentiation have been described in esophageal adenocarcinomas and represent multidirectional differentiation in the tumor.¹³⁶ Pagetoid spread into overlying squamous epithelium occurs, at times, in poorly differentiated adenocarcinomas.¹³⁷ The presence of a double muscularis mucosa in patients with Barrett esophagus may lead to errors in staging of early adenocarcinomas. The deep layer of muscularis mucosae is often thick and may be mistaken for muscularis propria138-140 in an endoscopic mucosal resection specimen which may lead to over staging of invasive carcinomas in about 7% cases.¹³⁹ Carcinomas that invade between the two layers of muscularis mucosae are associated lymphovascular invasion in about 10% of cases.139,140

In esophagectomies performed after neoadjuvant therapy, residual tumor is often present in small, isolated clusters in association with dense fibrosis or pools of acellular mucin. Tumor cells may appear more pleomorphic and show neuroendocrine differentiation as a consequence of treatment. Large pools of mucin without any viable tumor cells, with or without calcific deposits, may be present and should not be reported as residual tumor¹⁴¹ since these are not associated with an increased risk of recurrence or distant metastasis. The amount of residual carcinoma (0%, 1%–50%, and >50%) seen in resections performed after preoperative chemoradiation has been shown to be a reproducible predictor of survival in some studies.¹⁴²

Ancillary Studies

Isolated tumor cells in postneoadjuvant therapy resection specimens may be difficult to distinguish from reactive mesenchymal cells. Immunostains for keratins can be helpful in these cases. Keratin stains may also help determine the deepest extent of tumor invasion for accurate staging when the residual tumor is present predominantly as single cells. In small biopsy specimens, distinction of primary esophageal adenocarcinoma from secondary tumors may be an issue. Esophageal spread from gastric, pulmonary, or breast carcinoma is the most common consideration in the differential diagnosis. Immunoreactivity for TTF-1 and estrogen receptor is useful in distinguishing esophageal tumors from pulmonary and breast primaries, respectively. Distinguishing gastric carcinomas with extension into the esophagus from primary esophageal adenocarcinoma is virtually impossible using immunohistochemical studies. The presence of Barrett esophagus with dysplasia adjacent to the carcinoma is the only truly reliable form of evidence in favor of an esophageal primary.

Molecular Findings

Esophageal adenocarcinoma arises from Barrett esophagus through a progressive, step-wise accumulation of genetic abnormalities. Aneuploidy and tetraploidy, on flow cytometric analysis of mucosal biopsies, are strong predictors of risk of progression to adenocarcinoma in patients with Barrett esophagus. Common alterations in adenocarcinomas include inactivation of p16, p27, and p53 through mutation or transcriptional silencing, and overexpression of cyclin D1.^143-145 Cyclin D1 overexpression has been reported in up to 64% of adenocarcinomas. TP53 mutations in esophageal adenocarcinoma are predominantly G:C to A:T transitions at CpG dinucleotide sites and loss of heterozygosity of the 17p locus of the gene is associated with increased risk for aneuploidy and tetraploidy, as well as high-grade dysplasia. CDKN2 A inactivation occurs through promoter hypermethylation or 9p loss of heterozygosity and may be a critical early event in Barrett esophagus–associated neoplasia. Amplification of EGFR and HER2 also occur in 15% to 30% of cases.^146,147 Upregulation of miR-196a has been shown in esophageal adenocarcinoma and is believed to target annexin-A1 leading to suppression of apoptosis and enhance cell survival.¹⁴⁸

Adenocarcinoma Variants

Non–Barrett-Associated Adenocarcinomas

Occasional reports have described adenocarcinomas arising in heterotopic gastric mucosa in the cervical esophagus.^149-153 Salivary gland type adenocarcinomas may rarely occur in the middle third of the esophagus, which presumably arise from the submucosal gland/ducts.

Carcinomas with Mixed Squamous and Glandular Differentiation

These are uncommon aggressive tumors in which the tumor shows bidirectional differentiation. They have been termed as adenosquamous or mucoepidermoid carcinoma in literature depending on whether the two components are discrete (adenosquamous) or intimately associated with each other (mucoepidermoid). Adenosquamous carcinomas also show a greater degree of nuclear pleomorphism in the squamous component compared to mucoepidermoid carcinoma. A background of Barrett esophagus is often present.^{130,154–156} The prognosis of patients with these tumors remains uncertain due to their rarity.

Adenoid Cystic Carcinoma

True adenoid cystic carcinomas of the esophagus are extremely rare.^89,90,157 They show a biphasic phenotype with predominance of basal/myoepithelial cells and interspersed ductal structures. The growth pattern is solid, cribriform, or tubular and abundant basement membrane like myxohyaline stroma is present. Marked nuclear pleomorphism, brisk mitotic activity, and necrosis are not features of adenoid cystic carcinoma and should alert the pathologist to the possibility of a basaloid squamous cell carcinoma with which these tumors have been confused in the past. The ductal cells stain with keratin and the basal/myoepithelial cells with S100 and actin. Adenoid cystic carcinomas are slow growing tumors that rarely metastasize, and have a much better prognosis than basaloid squamous cell carcinomas.

Choriocarcinoma

Choriocarcinoma of the esophagus is a rare tumor that has been reported in both adult men and women.^158-161 They are large, exophytic, fungating tumors with extensive hemorrhage and necrosis. Foci of typical squamous cell carcinoma or Barrett esophagus–associated adenocarcinoma coexist in many cases. An admixture of syncytiotrophoblast and cytotrophoblast is present on histological examination. Tumors with yolk-sac like differentiation have also been described.¹⁶⁰ The possibility of contiguous spread from a mediastinal germ cell tumor should be excluded. Most patients have widespread metastatic disease at presentation. The overall prognosis is extremely poor.

Natural History and Prognosis of Adenocarcinoma

Tumor stage remains the best prognostic indicator in esophageal adenocarcinoma. Survival rates between 80% and 100% are reported for tumors confined to the mucosa or submucosa but decline significantly to about 10% to 20% for those that invade deep into the muscularis propria.^162-164 Nodal metastasis to periesophageal and perigastric lymph nodes occurs in 50% to 60% of patients and appears to be closely related to the depth of tumor infiltration. Risk of nodal metastasis is <5% for intramucosal cancers and rises to over 30% for tumors with submucosal invasion. The number of positive lymph nodes is also of prognostic value^165-167 and this is reflected in the recently updated TNM classification which is summarized in Table 11-1. Histological type is not considered an independent prognostic factor, but mucinous and signet ring cell carcinomas have been shown to be associated with poor survival on multivariate analysis in some studies.¹⁶⁸ Absence of residual tumor (complete pathologic response) in resections performed after neoadjuvant therapy is associated with a good outcome whereas persistent nodal disease is a strong adverse prognostic indicator.^169-171

Neuroendocrine Tumors

Carcinoid tumors are now designated as well-differentiated neuroendocrine tumors in the new WHO classification. Initially described in 1969, esophageal carcinoids are the rarest of all GI carcinoid tumors. In a meta-analysis of 8305 carcinoids of various sites, only three were located in the esophagus.¹⁷² The patients show a male predominance (6:1) of variable ages. The majority of tumors occur in the distal third of the esophagus or at the gastroesophageal junction. Carcinoids of the esophagus occur in two clinical scenarios: as solitary, circumscribed, polypoid lesions, or in association with Barrett esophagus. Increased numbers of endocrine cells have been described in some cases of Barrett esophagus^173,174 and this may contribute to the development of esophageal carcinoids. The morphology is similar to carcinoid tumors seen elsewhere in the gastrointestinal tract. The tumors show nested or trabecular architecture and the cells are monomorphic with a characteristic salt and pepper nuclear chromatin pattern (Fig. 11-8). Immunohistochemical markers of neuroendocrine differentiation, such as chromogranin and synaptophysin are invariably positive. Esophageal carcinoids were initially thought to be associated with a poor prognosis. More recent data suggests that cases previously reported as esophageal carcinoids with an adverse outcome may have been examples of small cell carcinoma because there was evidence of high mitotic activity and necrosis in the tumors.^175-177 Hoang et al.¹⁷⁸ described four new cases in 2002 and reviewed the outcome of other reported cases in literature. All 11 patients with primary esophageal carcinoids were alive and disease free after 1 to 23 years of follow-up. This suggests that the prognosis of esophageal carcinoids is favorable. Neuroendocrine tumors of the gastrointestinal tract are now graded on the basis of the mitotic activity and proliferative index on a Ki67 immunostain.¹⁷⁵ The prognostic value of this scheme for esophageal carcinoids remains uncertain given the rarity of these tumors. A brief summary of the current grading scheme is provided in Table 11-2.

Small Cell Carcinomas constitute 1% to 2.4% of all esophageal carcinomas.^{175,179–182} In the majority of cases, these tumors are large, protuberant, and arise in the middle and lower thirds of the esophagus. On histological examination, small, fusiform, or polygonal-shaped cells with little cytoplasm, hyperchromatic nuclei, and inconspicuous nucleoli are present, arranged in sheets or anastomosing cords and ribbons (Fig. 11-9). Crush artifact of the tumor cells is common, particularly in biopsy material and rosette formation may be present. Squamous differentiation has been described, as well as foci of glandular differentiation, particularly in resection specimens.¹⁸³ About a third of cases may shows areas of squamous cell carcinoma in situ.¹⁸⁴ Carcinoid-like areas within an otherwise typical small cell carcinoma have also been reported occasionally.¹⁸¹ Confirmation that the tumor is a primary small cell carcinoma and not an undifferentiated squamous cell carcinoma depends on demonstration of neuroendocrine differentiation by chromogranin and synaptophysin immunostains or the finding of neurosecretory granules on ultrastructural examination. Poorly differentiated squamous cell carcinomas and adenocarcinomas stain positively with p63 and CDX2, respectively, and are helpful in arriving at the correct diagnosis. The prognosis of these tumors is poor with a median survival between 3 and 12 months,¹⁸⁰ although occasional long-term survivors have been reported.^185-187

Malignant Melanoma

It is now well recognized that melanocytes may be identified in normal esophageal mucosa in about 4% to 8% of normal individuals.^188-191 Benign appearing melanocytosis and atypical junctional lesions, similar to those seen in the skin, have also been described in association with primary esophageal malignant melanomas. Melanocytosis has been reported in about 25% of primary melanomas of the esophagus.¹⁹² Metastatic malignant melanoma involves the esophagus in about 4% of patients with disseminated disease.¹⁹³ Therefore, a melanoma presenting in the esophagus is still much more likely to represent a metastasis rather than a primary tumor. In a recent analysis using the SEER database, the age-adjusted rates of cutaneous, anorectal, and esophageal malignant melanoma were 70.1, 0.27, and 0.03 per million, respectively.¹⁹⁴ The diagnostic criteria for primary esophageal melanoma require demonstration of melanocytes in adjacent epithelium with melanocytosis or junctional changes.¹⁹⁵ The majority of primary esophageal melanomas is melanotic and show pigmentation upon gross and microscopic examination, although primary amelanotic melanomas of the esophagus have also been reported.¹⁹⁶ Primary malignant melanomas have been reported mostly in elderly people in the sixth to seventh decade of life. They are twice as common in men and most often involve the middle or lower third of the esophagus. Most lesions appear as large, polypoid, and friable lesions that bulge into the lumen upon endoscopy. Satellite lesions, melanocytosis, or atypical junctional lesions are often present.^197-201 Histologically, spindle and/or epithelioid tumor cells are present which contain melanin pigment (Fig. 11-10) and are positive for S100, Melan-A, and HMB45 immunostains.²⁰²

Both primary and secondary malignant melanomas involving the esophagus have a poor prognosis. The mean survival after diagnosis is only about 13 months.²⁰³

Gastrointestinal Stromal Tumor

Symptomatic gastrointestinal stromal tumors (GISTs) are uncommon in the esophagus. However, a significant number of esophageal GISTs are detected incidentally during examination of esophagectomies performed for another type of malignancy. In a series of 150 esophagectomies performed for esophageal or gastroesophageal junction adenocarcinomas, incidental GISTs were detected in 10% of cases.²⁰⁴ Most tumors occur in the lower third of the esophagus.²⁰⁵ The histological and immunophenotypic features of esophageal GISTs are similar to their counterparts in the stomach (Fig. 11-11). Both spindle and epithelioid cell types have been described. The tumor cells stain consistently with KIT and CD34.^206,207 KIT positivity is also seen in malignant melanoma and is a potential pitfall in diagnosis because primary or metastatic amelanotic melanoma involving the esophagus may be mistaken for a GIST.²⁰⁸ Melanocytic markers Melan-A and HMB45 are helpful in arriving at the correct diagnosis. Miettinen et al.²⁰⁵ reported a series of 17 GISTs in which nine patients died of disease. However, all fatal cases were more than 10 cm in size and one had more than five mitoses per 50 high power fields. The incidentally detected tumors in esophagectomy specimens are invariably associated with an excellent outcome.

Miscellaneous

Primary sarcomas of the esophagus have also been reported.^209-216 It is important to sample a tumor extensively to exclude the possibility of sarcomatous differentiation in a spindle cell carcinoma before a diagnosis of primary esophageal sarcoma can be established with certainty. Secondary tumors in the esophagus are rare but may cause obstruction and mimic a primary tumor. They may be the result of direct spread from adjacent organs, or of spread by lymphatics or bloodstream. Direct spread occurs most commonly from carcinoma of the stomach into the lower end of the esophagus, less commonly from the bronchus or thyroid.^217-218 Immunohistochemical analysis with TTF-1 may be particularly helpful in these latter instances to exclude an esophageal primary. Lymphatic spread has been described from carcinomas of the breast,^217,219,220 and bloodstream metastasis has been reported from primary tumors of the testis, prostate,^221,222 kidney,²²³ endometrium,²²⁴ and pancreas.²¹⁷

With the incidence of esophageal carcinoma increasing worldwide, the importance of differentiating histologic subtypes and staging classifications is paramount. The authors explain the histologic and pathologic differences with an emphasis on light microscopic findings. In addition, the recent identification of genetic variants that encode for specific pathologic changes as well as familial and pathogenic predisposition are reviewed. The importance of understanding the discrete differences between squamous carcinoma and adenocarcinoma, as well as the grade of the tumor, are apparent with the new AJCC staging strategy (7th edition). Likewise, the correlation between the depth of penetration and prevalence of lymph node metastasis is increasingly important as the new staging system includes the number of lymph nodes involved.