The Neoplastic Esophagus

Cheryl Mather

Lisa Koch

Maria Westerhoff

Esophageal tumors arise in any of the tissues constituting its four layers: The mucosa, submucosa, muscularis propria, and adventitia. This chapter focuses on epithelial tumors, which are more likely to be malignant than benign. The majority of carcinomas arising in the esophagus are either squamous cell carcinomas (SCCs) or adenocarcinomas, which, together, are the sixth and ninth most common cause of cancer deaths in men and women worldwide, respectively (1,2). The World Health Organization (WHO) classification of epithelial tumors is shown in Table 3.1 (2). AJCC TNM staging for esophageal carcinomas is shown in Table 3.2. Mesenchymal tumors are discussed in Chapter 19. Hematologic tumors are discussed in Chapter 18. Neuroendocrine tumors are discussed in Chapter 17.

▪ SQUAMOUS PAPILLOMAS

Epidemiology

Esophageal squamous papillomas (ESPs) are rare exophytic esophageal tumors. The prevalence is generally thought to be less than 0.1%, though this varies widely with geographic location, with rates up to 0.5% in northeastern Italy (3,4,5). They are found in all age groups, but are extremely rare in children (6). ESPs are usually asymptomatic but may present with dysphagia or dyspepsia. Because the majority occur in the distal esophagus, chronic mucosal irritation has been proposed as a cause. The role of human papillomavirus (HPV) infection in these lesions is controversial, with some studies reporting no association (5,7,8) and others detecting HPV in greater than 50% of cases, most commonly types 6, 11, and 16 (9,10). Interestingly, in a Japanese study, where the prevalence of reflux disease is lower, ESPs were more likely to be located in the mid-esophagus and more likely to be associated with HPV infection, especially in younger women (9). Similarly, a study in Mexico found ESPs were predominantly located in the upper third of the esophagus, were more likely to affect young women, and had a strong association with HPV (10). Overall, these findings suggest differing etiologies for ESPs, with those in the distal esophagus being caused by chronic mucosal irritation (reflux esophagitis, alcohol, smoking, etc.) and the more proximal lesions being attributable to HPV infection. However, due to the rarity and geographic variation of this entity, it is difficult to establish this dichotomy with certainty. Though they are generally considered benign, at least one series identified a small risk of associated carcinoma, leading some authors to recommend complete removal and subsequent surveillance (7,8,11).

Gross and Microscopic Findings

Endoscopically, ESPs have a characteristic, but not pathognomonic, appearance. They are generally single, exophytic, multilobulated, soft, semipedunculated, pinkish-white lesions with smooth or slightly rough surfaces. They measure from 0.2 to 1 cm in diameter with an average size of 0.4 to 0.5 cm (5,11). Histologically, they resemble squamous papillomas in other organs, with fingerlike projections of hyperplastic squamous epithelium lining fibrovascular tissue cores (Fig. 3.1). The cells mature from the basal layer toward the surface (Fig. 3.2). The basal cells may appear prominent, but they lack significant cytologic atypia. Some may exhibit a spiked surface configuration with a prominent granular cell layer and hyperkeratosis. The squamous epithelium of distal papillomas may exhibit the characteristic features of reflux esophagitis. No histologic features have been definitively associated with HPV infection in ESPs (9,12).

▪ PAPILLOMATOSIS

Papillomatosis is the presence of multiple ESPs. It involves any part of the esophagus, but most frequently affects the distal esophagus. The lesion is extremely rare, with fewer than 20 cases reported in the literature (13,14). The papillomas
appear as multiple, small, irregular, wartlike mucosal projections. Their histology resembles that seen in isolated papillomas. In children, esophageal papillomatosis is often associated with recurrent respiratory papillomatosis, which is usually related to HPV infection (6). Esophageal papillomatosis can result from chronic inflammation from HPV infection, gastroesophageal reflux, prolonged nasogastric intubation, or the use of esophageal self-expanding metal stents. Papillomatosis is thought to have higher malignant potential than do single lesions (15,16). Papillomatosis may also be associated with SCCs at other sites (17). Florid cutaneous and mucosal papillomatosis can be seen in association with malignant acanthosis nigricans, most often due to gastric carcinoma.

TABLE 3.1 WORLD HEALTH ORGANIZATION CLASSIFICATION OF ESOPHAGEAL EPITHELIAL TUMORS

Epithelial tumors
Squamous papillomas
Intraepithelial neoplasia
	Squamous
	Glandular
		Flat
		Adenoma
Carcinomas
	Squamous cell carcinoma
	Verrucous (squamous) carcinoma
	Basaloid squamous carcinoma
	Spindle cell (squamous) carcinoma
	Adenocarcinoma
	Mucoepidermoid carcinoma
	Adenoid cystic carcinoma
	Small cell carcinoma
	Undifferentiated carcinoma
	Others
Carcinoid tumor

▪ SQUAMOUS CELL CARCINOMA

Epidemiology

Globally, esophageal carcinoma is the eighth most common cancer and the sixth most common cause of cancer death (18). As most cancer databases do not distinguish between squamous and adenocarcinoma, in-depth assessment of epidemiologic trends for each subtype is difficult. However, it is clear that the majority of esophageal carcinomas (around 80%) are SCCs, and these show a marked geographic and ethnic variation in incidence. Esophageal SCCs (ESCCs) are highly concentrated in the “esophageal cancer belt,” which runs from north-central China through the central Asian republics to northern Iran, where 90% of esophageal cancers are SCC (1,19,20). The most prominent cluster of elevated cancer rates occurs in north central China on the border of Henan, Hebei, and Shanxi provinces. Other high-risk areas include Chile, South Africa, Japan, and Brazil (21).

The incidence of ESCC increases with age and peaks in the seventh decade. ESCC is relatively uncommon in North America, Northern and Western Europe, and Oceania, where the rate of esophageal adenocarcinoma (EAC) has increased rapidly and now outpaces SCC (22). In the United States, the overall annual incidence of ESCC is 1.8 per 100,000, with the highest rates among black men (9.8 per 10,000) and male Asian or Pacific Islanders (3.0 per 10,000) (22). The incidence appears to be declining; one study found a decrease of 3.6% in ESCC incidence between 1998 and 2003 (22). Analysis of the Surveillance, Epidemiology, and End Results (SEER) 18 database showed a continued decrease in ESCC incidence from 2000 to 2011, with the most prominent change occurring among black men (23). A decrease in smoking may account for this decline (24,25).

Risk Factors

Environmental Factors

Environmental factors associated with ESCC and EACs are summarized in Table 3.3. Though not strictly dichotomous, risk factors for ESCC often fall into two groups: use of tobacco and alcohol and nutritional/dietary factors. ESCCs associated with the former tend to occur in low-incidence regions and have a heavy male preponderance. Those associated with the latter are found in high-incidence regions and tend to have a male:female ratio closer to 1.

However, many risk factors interact with one another, and their individual effects are difficult to weigh. Migrants from high-risk to low-risk countries retain their high risk through the first generation (26) but fall to the level of the host country in the second generation (27). This decline in rates may be attributed to diminished exposure to the environmental carcinogens peculiar to the country of origin. The persistence of risk in first-generation migrants, however, suggests that the anatomic changes induced by these carcinogens are not reversed in the new environment. The main risk factors include tobacco use, moderate to heavy alcohol intake, a diet lacking in raw fruits and vegetables, and low socioeconomic status. In fact, the combination of these risk factors accounted for nearly all of the ESCCs in a study of American men (28). Additionally, they were responsible for 99% of the excess incidence among black men (28). The incidence of ESCC closely correlates with low socioeconomic status whatever the level of risk in any population (29,30,31).

Alcohol and Tobacco

Alcohol and tobacco use are strong, dose-dependent risk factors for ESCC, and the risks are both independent and synergistic (32,33,34). For example, in Brittany, France, the relative risk of ESCC is 49.6 for nonsmokers with the highest alcohol intake, 7.8 for nondrinkers with the highest tobacco use, and 155.6 for men at the maximum consumption level of both substances (35). The heaviest smokers and alcohol users are also at higher risk for developing multiple ESCCs (36). As mentioned above, decreased tobacco use is thought to

underlie the decreasing prevalence of ESCC in many Western countries. Conversely, increased rates of tobacco and alcohol use in Taiwan are suspected to be the cause of that country’s recent increase in ESCC cases (37).

TABLE 3.2 TNM CLASSIFICATION OF ESOPHAGEAL CARCINOMAS

T—Primary Tumor
TX	Tumor cannot be assessed
T0	No evidence of primary tumor
Tis	High-grade dysplasia, defined as malignant cells confined to the epithelium by the basement membrane
T1	Tumor invades the lamina propria, muscularis mucosae, or submucosa
T1a	Tumor invades the lamina propria or muscularis mucosae
T1b	Tumor invades the submucosa
T2	Tumor invades the muscularis propria
T3	Tumor invades adventitia
T4	Tumor invades adjacent structures
T4a	Tumor invades the pleura, pericardium, azygos vein, diaphragm, or peritoneum
T4b	Tumor invades other adjacent structures, such as aorta, vertebral body, or airway.
N—Regional Lymph Nodes
NX	Regional lymph nodes cannot be assessed
N0	No regional lymph node metastases
N1	Metastasis in 1-2 regional lymph nodes
N2	Metastasis in 3-6 regional lymph nodes
N3	Metastasis in seven or more regional lymph nodes
M—Distant Metastases
M0	No distant metastases
M1	Distant metastases present
Stage Groupings for Squamous Cell carcinoma
When pT is…	And pN is…	And M is	And G is	And location is…	Then the stage group is…
Tis	N0	M0	N/A	Any	0
T1a	N0	M0	G1	Any	IA
T1a	N0	M0	G2-3	Any	IB
T1a	N0	M0	GX	Any	IA
T1b	N0	M0	G1-3	Any	IB
T1b	N0	M0	GX	Any	IB
T2	N0	M0	G1	Any	IB
T2	N0	M0	G2-3	Any	IIA
T2	N0	M0	GX	Any	IIA
T3	N0	M0	Any	Lower	IIA
T3	N0	M0	G1	Upper/Middle	IIA
T3	N0	M0	G2-3	Upper/Middle	IIB
T3	N0	M0	GX	Any	IIB
T3	N0	M0	Any	Location X	IIB
T1	N1	M0	Any	Any	IIB
T1	N2	M0	Any	Any	IIIA
T2	N1	M0	Any	Any	IIIA
T2	N2	M0	Any	Any	IIIB
T3	N1-2	M0	Any	Any	IIIB
T4a	N0-1	M0	Any	Any	IIIB
T4a	N2	M0	Any	Any	IVA
T4b	N0-2	M0	Any	Any	IVA
Any T	N3	M0	Any	Any	IVA
Any T	Any N	M1	Any	Any	IVB
Stage Groupings for Adenocarcinoma
When pT is…	And pN is…	And M is	And G is	Then the stage group is…
Tis	N0	M0	N/A	0
T1a	N0	M0	G1	IA
T1a	N0	M0	GX	IA
T1a	N0	M0	G2	IB
T1b	N0	M0	G1-2	IB
T1b	N0	M0	GX	IB
T1	N0	M0	G3	IC
T2	N0	M0	G1-2	IC
T2	N0	M0	G3	IIA
T2	N0	M0	GX	IIA
T1	N1	M0	Any	IIB
T3	N0	M0	Any	IIB
T1	N2	M0	Any	IIIA
T2	N1	M0	Any	IIIA
T2	N2	M0	Any	IIIB
T3	N1-2	M0	Any	IIIB
T4a	N0-1	M0	Any	IIIB
T4a	N2	M0	Any	IVA
T4b	N0-2	M0	Any	IVA
Any T	N3	M0	Any	IVA
Any T	Any N	M1	Any	IVB
Reprinted from Esophagus and Esophagogastric Junction. In: Amin MB, Edge SB, Greene FL et al: AJCC Cancer Staging Manual, 8th ed. New York: Springer, 2017, with permission.

FIG. 3.1 Esophageal papilloma composed of vascular connective tissue cores covered by hyperplastic squamous epithelium with surface koilocytes. (Courtesy of Dr. Barbara Winkler, New York, NY.)

One of the best-studied classes of tobacco-associated carcinogens is nitrosamines, which are potent alkylating agents that can produce various alkyl DNA adducts. These adducts particularly involve O₆-methylguanine, which can preferentially mispair with thymine rather than cytosine, causing GC to AT mutations (38). O₆-methylguanine-DNA methyl transferase (MGMT) is a primary defense against alkylaseinduced carcinogenesis, and, interestingly, abnormal methylation of the MGMT promoter may be a risk factor for ESCC (39). Tobacco-specific nitrosamines are strongly associated with SCC of the upper aerodigestive tract (UADT) (40), and therefore persons at high risk for ESCC due to alcohol and tobacco consumption are vulnerable to field cancerization of the entire UADT (41). One report found that 6.7% of ESCC patients had synchronous or metachronous head and neck cancers (42). Similarly, a second series found that 7.1% of ESCC patients had secondary cancers, and the most common synchronous or antecedent head and neck cancer was in the hypopharynx. Patients with multiple cancers were younger, more likely to drink alcohol, and more likely to be male than those with a single primary; multiple cancers imparted a worse prognosis (43).

FIG. 3.2 Squamous papilloma in an adult with multiple lesions involving the upper respiratory tract due to human papilloma virus types 6 and 11. Cytopathic epithelial changes consist of koilocytosis and minimal nuclear atypia.

TABLE 3.3 ENVIRONMENTAL RISK FACTORS FOR ESOPHAGEAL CARCINOMA

	Squamous Cell Cancer	Adenocarcinoma
Alcohol intake	Yes	No
Tobacco use	Yes	Yes
HPV infection	Maybe	No
Inadequate intake of fruits and vegetables	Yes	Yes
High intake of nitrate and nitroso compounds	Yes	No
Thermal injury	Yes	No
Caustic injury	Yes	No
Achalasia	Yes	No
Barrett esophagus	Rarely	Yes
Obesity	No	Yes
Prior radiotherapy	Yes	Yes
Low socioeconomic status	Yes	No
HPV, human papilloma virus.

Dietary Factors

A diet lacking in fruits and vegetables has long been considered a risk factor for ESCC. Observational studies find increased intake of fruits and vegetables to be a significant protective factor in many populations (44,45), including low-incidence regions (46). Specific protection has been noted for citrus fruit (47), raw vegetables (48), and cruciferous vegetables (45). In fact, the vegetable-rich Mediterranean diet appears to lower the risk of ESCC, even when associated with moderate to high alcohol consumption (35).

Deficiencies of various micronutrients are often seen in high ESCC incidence regions, and this has been thought to contribute to carcinogenesis. Selenium and/or zinc deficiencies were found to be associated with the ESCC belt in eastern Africa (49) and China (50), and decreased calcium and zinc were implicated in Iran (51). There is also evidence for vitamin C (52), vitamin D₃, and beta-carotene (53), among others. Multiple possible mechanisms have been postulated. Mineral deficiencies in the soil lead to increased fungal invasion and mycotoxin food contamination (see below). Calcium, riboflavin, vitamin A, and vitamin C play a role in maintaining mucosal integrity and epithelial differentiation, and deficiencies in these substances may render the esophageal mucosa vulnerable to carcinogens in foods, such as mycotoxins (54) and N-nitroso compounds (55). However, a 20-year follow-up of a randomized controlled trial of dietary supplements (26 vitamins and minerals taken for 6 years) found no effect on ESCC cancer risk in a high-risk, poorly
nourished Chinese population (56). Moreover, a large metaanalysis found no benefit for supplementation with vitamin A, vitamin C, vitamin E, beta-carotene, riboflavin, zinc, or selenium, alone or in various combinations (57). Therefore, a causal role for micronutrient deficiency in ESCC has not been definitively established.

Nitrosamines, one of the major categories of carcinogens associated with tobacco, are also found in fermented, moldy, and pickled foods. As these foods are daily staples in many high-risk ESCC areas of China, they have long been postulated to play a role in carcinogenesis (58). While in vitro studies showed some evidence for mutagenicity of pickled foods (59), case-control and cohort studies failed to consistently support a causal role. A more recent meta-analysis found a weak association between pickled food consumption in ESCC that did not reach significance in prospective studies or in the high-incidence region of Linxian, and the authors concluded that the link remains strongly suggested but not proven (60).

Fungi frequently contaminate the grains and foodstuffs consumed in high-risk geographic areas. Fusarium and Aspergillus species produce fumonisins, mycotoxins that can be found on maize (corn), rice, and other cultivated grains. Increased consumption of fumonisin has been associated with ESCC in high-incidence regions of China (61,62,63). In fact, in South Africa, the switch from sorghum to a maizebased diet, and the Fusarium that grows along with it, has been postulated as the cause of the high rates of ESCC now afflicting that country (64). While observational, these associations suggest a link between fumonisin-contaminated food and ESCC. Aflatoxin, another mycotoxin produced by Aspergillus species, is well known to cause hepatocellular carcinoma and may also be associated with ESCC (65).

Drinking high-temperature beverages, including coffee, tea, and maté (a South American herbal infusion), is a common practice in many high-incidence ESCC regions. Drinkers of very hot beverages have higher ESCC rates, which is thought to be due to recurrent thermal injury. Moreover, while the amount of tea and coffee consumed (and therefore the compounds they contain) does not increase, and may even decrease risk, consumption of maté is independently associated with increased ESCC risk. Most studies also find increased risk for people who eat foods at high temperatures (66).

Another habit associated with ESCC is areca nut, a component of betel quid that is commonly used in Asian communities. Chewing areca releases nitrosamines in the saliva, and chewing areca nut is a significant risk factor for ESCC, both independently and synergistically with tobacco use (67,68).

Occupational Factors

Certain occupations are associated with an increased risk for ESCC. A Spanish study found increased risk among miners, shotfirers, stone cutters and carvers, as well as waiters and bartenders (69). In Kashmir, India, a high-incidence area, long-term daily close contact with animals was associated with increased ESCC risk, even when adjusted for socioeconomic factors (70). A similar study found that this risk was specifically related to contact with ruminants (71).

Radiation Exposure

Risk of ESCC is increased in patients treated with radiation therapy for various malignancies, including Hodgkin disease (72) and breast cancer. The risk following treatment for breast cancer increases starting 5 years after exposure (73). The risk is dose dependent (74) and therefore may be decreasing as radiotherapy protocols are revised (75). Most radiation-induced cancers arise in the upper and mid-esophagus (in the radiation field), and the tumors may be multifocal in nature.

HPV Infection

The detection of HPV in ESCC varies widely across studies and with geography, with detection rates in recent studies ranging from 12% to close to 40% (76). HPV type 16 is most commonly detected (76). The presence of HPV infection may be suspected in cytology preparations, as shown in Figure 3.3. HPV DNA may be found in invasive SCC, areas of carcinoma in situ, the hyperplastic epithelium surrounding cancers, and histologically normal cells near these cancers (77). The highest rates are seen in Asia, with lower rates in Europe, North America, and Australia. These differences have been shown to be due to the geographic variation in HPV rates, rather than differences in HPV detection methods, which are notoriously variable. This finding has led to the proposal that ESCC has different etiologies in low- vs. high-incidence regions, with HPV infection playing a role only in the latter (78).

Other Predisposing Conditions

Any of the many causes of chronic esophagitis (discussed in Chapter 2) can increase the risk of ESCC. The ESCC associated with caustic burns (usually from an alkaline
substance) emerges on average 30 years after the initial injury, usually near the site of tracheal bifurcation. These so-called corrosion carcinomas may have a better prognosis than does routine ESCC, possibly due to the younger age of the patients and the presence of disease-limiting scar tissue (79). Postprandial food retention causes esophagitis and a subsequent increased risk of ESCC in patients with diverticula (such as Zenker) (80) and motility disorders, including achalasia (81) and systemic sclerosis (82). The esophagitis that accompanies Plummer-Vinson syndrome is also associated with an increased risk of SCC in the hypopharynx and upper esophagus (83). Celiac disease, which may cause iron deficiency anemia leading to Plummer-Vinson syndrome, has also been associated (83). Somewhat surprisingly, atrophic gastritis is associated with a twofold increase in ESCC (84). This is thought to be due to achlorhydria, which may allow proliferation of bacteria and increased production of acetaldehyde and N-nitroso compounds. However, the extent of atrophy does not correlate with the risk of ESCC, and some authors have proposed that the association is not causal but due to mutual association with smoking (85). Interestingly, Helicobacter pylori infection has been associated with an increased risk of ESCC in Western populations (86) but may be protective in Asian populations (87,88). The reasons for this dichotomy are not clear, but may be related to dietary and lifestyle factors as well as genetic differences.

FIG. 3.3 Cytologic features of a squamous cell showing a koilocytic perinuclear halo.

Environmental and Genetic Interactions

Genetic polymorphisms in enzymes that metabolize alcohol and tobacco render some individuals more susceptible to their deleterious effects. Acetaldehyde, the genotoxic first metabolite of alcohol, is broken down by aldehyde dehydrogenases (ALD). The ALDH2^*2 variant allele encodes an inactive enzyme that is found in up to 30% of east-Asian populations. Heterozygous carriers have decreased enzyme activity and accumulate acetaldehyde upon alcohol consumption, causing an unpleasant flushing reaction that tends to prevent alcoholism. However, alcoholics with the mutant allele develop tolerance to this reaction, and the presence of this less active allele increases their risk of ESCC (89). In addition, even light drinkers with the variant allele have higher relative risks of alcohol-related esophageal cancers compared with individuals with the common alleles (90).

Aromatic hydrocarbons in tobacco smoke require metabolic activation by phase I enzymes (CYP450s) and then detoxification by phase II enzymes (GSTM1). Patients, and especially heavy smokers, with the Val/Val CYP1A1 genotype are at increased risk of ESCC that is enhanced when associated with GSTM1^– (91). In addition, polymorphisms are common in the gene encoding 5,10-methylenetetrahydrofolate reductase (MTHFR), an enzyme that plays a central role in folate metabolism, and those that result in reduced enzymatic activity significantly associate with increased ESCC risk, especially in smokers (92,93).

Inherited Risk Factors

The autosomal dominant familial syndrome tylosis esophageal cancer (TOC), also called type A tylosis, is characterized by palmoplantar keratoderma, oral and esophageal leukoplakia, follicular keratosis, and a strong susceptibility to ESCC. In one large TOC family, members had a 95% risk of developing esophageal cancer by age 65 (94). The mean age of onset for esophageal malignancies in these patients is 61 years, which is not different from classic ESCC. The neoplastic squamous cell lesions that develop resemble those arising in the absence of tylosis.

The causative mutation was recently found in the catalytically inactive rhomboid protease RHBDF2, which is normally concentrated at the keratinocyte membrane but is found in the cytoplasm in tylotic patients (95). Interestingly, RHBDF2 may be involved in EGFR signaling, which has been implicated in sporadic ESCC (96). Furthermore, ESCCs frequently have loss of the TOC locus (97) and show cytoplasmic staining for RHBDF2 (95), implicating this pathway as a major mechanism for carcinogenesis.

Pathobiology

Dysplasia

Esophageal dysplasia (intraepithelial neoplasia) was traditionally classified into mild, moderate, and severe degrees. However, since interobserver agreement in distinguishing the three grades is generally poor, most now favor a two-tier system of low-grade dysplasia (encompassing mild and moderate dysplasia) and high-grade dysplasia (HGD) (including severe dysplasia and carcinoma in situ). ESCC necessarily progresses through a sequence of low-grade dysplasia, HGD, and invasive carcinoma. In a 13.5-year study, the only histological lesion associated with an increased risk of invasive carcinoma was dysplasia, and the risk increased with the grade of dysplasia, indicating that grading is clinically meaningful (98)

Multiple lines of evidence support the multistep progression of ESCC. There is a sequential acquisition of molecular abnormalities as the lesions progress from low- to high-grade dysplasia to invasive carcinoma (2). Those that are thought to be important are shown in Figure 3.4. A biopsy study from Chinese patients found that loss of heterozygosity increased with increasing grades of dysplasia (99). Another Chinese biopsy series found increasing frequency of MSI with increasing grade of dysplasia (100). p53 mutations may also be found in areas of transition from esophagitis to dysplasia and are among the earliest changes seen in the development of ESCC (2). A significantly greater frequency of p53 expression occurs in HGD versus low-grade dysplasia and in low-grade dysplasia versus normal esophageal mucosa (101). Moreover, a Japanese study of field carcinogenesis found different p53 mutations in synchronous multicentric ESCCs, but the identical p53 mutations were found in the dysplastic epithelium adjacent to each invasive cancer (102,103). The natural history of squamous dysplasia has not been studied extensively,
but studies from a high-risk Chinese population found that the risk of progression to ESCC after 3.5 years was 5%, 27%, and 65% for mild, moderate, and severe dysplasia (104). This risk increased to 24%, 50%, and 74% after 13.5 years (98).

FIG. 3.4 Diagram of the progressive acquisition of molecular abnormalities as the epithelium progresses from normal to invasive cancer.

These data indicate that early detection of squamous dysplasia might decrease mortality from ESCC. However, squamous dysplasia is generally asymptomatic, and early detection would require population-based screening. Because endoscopy with biopsy is an expensive and invasive test, investigators have evaluated balloon cytology, an easier and more economical screening test, for screening in high-risk areas. The technique uses an inflatable balloon at the end of a soft tube and collects cells throughout the esophagus for cytologic evaluation. The results of these screening programs have been mixed, with some studies finding unacceptably low sensitivities and others determining it to be a cost-effective screening method (105,106,107). Population-based screening programs for ESCC are not beneficial for low-risk areas, such as North America or Europe. However, endoscopic screening of patients with head and neck SCC, who are therefore at high risk for ESCC, is recommended, as early detection of ESCC in these patients improves prognosis (108).

Dysplasia has several endoscopic appearances including a friable, irregular erosion and a raised polypoid lesion, with or without erosions or a hyperemic roughening that bleeds easily. Grossly visible areas of dysplasia vary in size from 0.5 to 5 cm in diameter. The dysplasia may be scanty in type with welldefined margins, extensive, or multifocal. Extensive lesions have ill-defined margins. The gross changes may be very subtle, showing only a slight mucosal depression, but mucosal staining with Lugol facilitates the detection of dysplasia since the normal mucosa is stained but the dysplastic mucosa is not (2). Dysplasia may merge with or be separate from an invasive cancer. Dysplasia is more likely to be identified in small or early cancers than in large or advanced neoplasms, since large cancers are more likely to overgrow their precursors.

Histologically, dysplasia is characterized by both architectural and cytologic abnormalities. It is defined by a disorderly proliferation of immature cells with hyperchromatic nuclei, abnormally clumped chromatin, and pleomorphic nuclei (Fig. 3.5). The cells have an increased nuclear:cytoplasmic ratio and may demonstrate loss of polarity. The nuclei are commonly overlapping, and mitoses are frequent and often abnormal. The dysplasia is considered to be low grade when the abnormal cells are limited to the basal and middle thirds of the mucosa and high grade when they extend to the upper third of the epithelium. High-grade dysplasia shows a greater degree of cytologic atypia than do low-grade lesions. In carcinoma in situ (the high end of the spectrum of HGD), atypical cells extend through the full thickness of the epithelium without evidence of surface maturation. Dysplastic cells may also extend into the underlying submucosal glands and ducts. While ductal extension predisposes to deeper penetration (109), this finding by itself does not constitute invasion. Dysplastic squamous cells may also spread in a pagetoid manner into the adjacent normal esophageal mucosa.

There are several diagnostic pitfalls with respect to squamous dysplasia, most importantly regenerative/reactive changes and pseudoepitheliomatous hyperplasia. Herpes esophagitis, chemotherapy, or radiotherapy and areas of regeneration adjacent to ulcers may induce histologic changes that may be mistaken for squamous neoplasia. The differences between regenerative and neoplastic changes are summarized in Table 3.4. Inflammation or ulceration, if extensive, may help identify the epithelial changes as regenerative in nature. However, caution must be exercised because dysplastic epithelium can be ulcerated or inflamed. Both radiation and/or chemotherapy, particularly in the setting of neoadjuvant therapy, may induce mucosal changes that mimic dysplasia. Paclitaxel treatment may result in cells containing enlarged, irregular, hyperchromatic nuclei
as well as abnormal mitotic figures, including ring mitoses. Typically, radiation change is associated with a maintained (low) nuclear:cytoplasmic ratio. If one is unable to distinguish between dysplastic and regenerative changes, one can use the term “indefinite for dysplasia” to describe the changes that are present. Subsequent biopsies, particularly those obtained once the inflammation has been treated, often help clarify the nature of the underlying process. Immunostaining for p53 may also help distinguish dysplasia from reactive changes. While this test is by no means specific, the presence of large numbers of p53 immunoreactive cells (as opposed to only isolated positive cells) is much more likely to occur in areas of dysplasia than in reactive lesions.

FIG. 3.5 Squamous dysplasia. A: Low-grade dysplasia. The changes are more severe on the right-hand side of the photograph. Note the beginning of irregular budding to the left of the arrows and the disorderly arrangement of the epithelium. B: Low-grade (mild) dysplasia. Disorderly atypical squamous epithelial cells localize to the basal epithelium. C: Low-grade (moderate) dysplasia. Dyskeratotic cells and cells with enlarged nuclear-to-cytoplasmic ratios and prominent nucleoli are present. D: High-grade (severe) dysplasia. The atypical cells extend almost to the free surface.

TABLE 3.4 FEATURES USEFUL IN DISTINGUISHING REACTIVE FROM NEOPLASTIC SQUAMOUS EPITHELIUM

Reactive Changes	Neoplastic Changes
Basal cell hyperplasia	Highly atypical cells
Glycogen depletion	Keratinizing epithelium
Vesicular hyperchromatic nuclei	Bizarre cell shapes
Normal or increased N:C ratio	Increased N:C ratios
Prominent nucleoli	Prominent heterochromatin
Increased mitotic activity	Eosinophilic nucleoli
Basophilic cytoplasm	Irregular nuclear outlines
Presence of inflammation
Presence of causative agent (i.e., HSV, etc.)
Nonkeratinizing epithelium
Epithelial edema
Vascular congestion
HSV, herpes simplex virus; N:C, nuclear:cytoplasmic.

Early Esophageal Cancers

Japanese and Western pathologists differ in their diagnostic criteria for esophageal squamous neoplasms. Invasion is the most important criterion for a diagnosis of carcinoma for Western pathologists, whereas nuclear and structural features are more important for Japanese and Chinese
pathologists. These pathologists use the term early esophageal cancer to designate a neoplastic process that is confined to the mucosa or submucosa. Therefore, in Japan, ESCCs can include cases judged to be noninvasive, low-grade dysplasia in the West. This difference may contribute to widely variant incidence rates and predictions of prognosis. In an effort to address these differences, the Vienna Classification was developed (Table 3.5) (110), although it has not been widely adopted.

TABLE 3.5 VIENNA CLASSIFICATION

Category 1:	Negative for dysplasia/neoplasia
Category 2:	Indefinite for dysplasia/neoplasia
Category 3:	Noninvasive neoplasia: Low grade (low-grade dysplasia) Low-grade dysplasia or adenoma includes mild and moderate dysplasia
Category 4:	Noninvasive neoplasia: High grade (HGD) High-grade adenoma/dysplasia (severe dysplasia) Noninvasive carcinoma (carcinoma in situ) Suspicious for invasive malignancy
Category 5:	Invasive neoplasia Intramucosal carcinoma: Invades the lamina propria Invasion into the submucosa or beyond

A more discriminating assessment of early cancers is achieved by dividing them into three levels of mucosal and submucosal penetration (Fig. 3.6) (111). The deeper the penetration, the greater the probability is of lymph node metastases, as shown by Araki et al. (112), who found nodal spread in 35.7% of sm3 cancers, compared with 8.3% of sm1 lesions. Additional risk factors for lymph node involvement include neural and lymphovascular invasion and lack of a dense lymphocytic infiltrate (113). Predicting lymph node status is crucial, as node-negative superficial cancers can be treated by endoscopic mucosal resection (EMR), which incurs less morbidity and a smaller risk of mortality than does esophagectomy. If metastases or lymphovascular invasion are found in a patient with HGD, an undetected invasive cancer is likely to be present. Resection specimens should be extensively sampled to find the invasive focus. If none is found, an invasive focus may remain in the patient.

FIG. 3.6 Diagram of the system of staging mucosal and submucosal invasion.

FIG. 3.7 Carcinoma in situ and early squamous cell carcinoma. The intraepithelial neoplasia sends short fingerlike extensions into the underlying lamina propria. A marked lymphocytic infiltrate accompanies the lesion. There is a small patch of nearly normal epithelium (arrows). (Case courtesy of Masaki Mori, Department of Surgical Oncology, Medical Institute of Bioregulation, Kyushu University, Beppu, Japan.)

Identifying superficially invasive cancers in resection specimens is usually not a diagnostic problem. The earliest invasive lesions appear to drop off the base of the mucosa. The overlying mucosa may or may not be involved by fullthickness replacement by intraepithelial neoplasia (Fig. 3.7). Progression from noninvasive to invasive disease is associated with an increased lymphocytic reaction (Fig. 3.7). The interpretation of small endoscopic biopsies may be challenging. The distinction of neoplasia from regenerating squamous epithelium in the setting of esophagitis poses the greatest difficulty. Regenerating squamous cells generally do not show abnormal mitoses or loss of polarity.

Multivariate analysis indicates that factors that increase the relative risk of recurrence with submucosal cancer are intramural metastases, vascular invasion, and nodal metastases (114). The postresection 5-year survival rates of patients with submucosal SCC vary from 44% to 96%, with the most favorable prognosis occurring in patients without vascular invasion, intramural metastases, or nodal involvement. Patients with all three of these have the least favorable prognosis (114).

Invasive Squamous Cell Carcinoma

Clinical Features

ESCC usually grows slowly. The patients may remain asymptomatic with invasive disease because the esophagus is highly distensible and tumors can grow to a considerable size before the lumen becomes sufficiently narrowed to produce symptoms. Symptomatic ESCC presents with dysphagia,
odynophagia, weight loss, coughing, choking, pain, and dehydration (115). Frequently, patients do not complain of dysphagia but make subtle changes in their eating habits without realizing it. Other symptoms include fever, anemia, hematemesis, melena, hoarseness, or the sensation of food “becoming stuck in the throat.” A persistent hiccup may indicate the presence of laryngeal nerve paralysis, a sign of advanced disease. Local tumor extension beyond the esophagus often leads to substernal or high back pain. Aortic erosion results in rapid exsanguination. Aspiration of esophageal contents through a tracheoesophageal fistula is a common cause of death in patients with advanced ESCC. Palpable lymph nodes in the cervical or supraclavicular regions may be noted.

As with other squamous neoplasms, paraneoplastic hypercalcemia may be seen and is associated with a poor prognosis (116). A hypertrophic osteoarthropathy affects some patients with ESCC (117), but this may result from concomitant chronic obstructive lung disease, which shares an association with heavy tobacco consumption.

Pathologic Features

The AJCC divides the esophagus into three compartments (118). The cervical esophagus extends from the pharyngoesophageal junction to the thoracic inlet, approximately 18 cm from the incisors. The middle esophagus extends from the thoracic inlet to a point 10 cm above the GEJ, approximately 31 cm from the incisors and at the level of the lower edge of the eighth thoracic vertebra. The lower esophagus extends from this point to the GEJ, or approximately 40 cm from the incisors. SCCs may develop in both the hypopharynx and cervical esophagus in heavy consumers of alcohol and tobacco. Cancers that appear after radiation therapy usually develop in the upper and mid-esophagus. Most ESCCs in high-risk populations develop in the middle and lower thirds of the esophagus.

FIG. 3.8 Gross features of squamous cell carcinoma. A: Large fungating and polypoid excrescences of the midthoracic esophagus. B: Neoplastic oval ulcer of the lower thoracic esophagus. The wall of the esophagus is infiltrated and thickened. C: Ulcerating carcinoma of the lower thoracic esophagus with extension to the cardia. D: Stenosing ulcerated carcinoma with dilation proximal to the tumor.

Grossly, ESCCs appear as fungating, ulcerating, infiltrating, or stenotic lesions. Mixed gross growth patterns also occur. Advanced tumors may measure up to 10 cm in length. Fungating cancers present either as large, intraluminal, variably ulcerated masses with raised, everted margins or less commonly as polypoid, irregular, bulky tumor masses (Fig. 3.8). The lesions may have sharply defined borders, and intramural submucosal extension may be grossly inapparent. The extent of tumor infiltration at the tumor base varies and does not necessarily reflect the size of the protruding mass. Infiltrating carcinomas cause esophageal wall
thickening. Rarely, the pattern resembles the linitis plastica pattern seen in gastric carcinoma.

FIG. 3.9 Well-differentiated keratinizing squamous cell carcinoma. A: Note the infiltrating nests with prominent central keratinization. B: The nuclear-to-cytoplasmic ratio is increased relative to normal.

Biopsies cannot determine the extent of invasion, but they yield a positive diagnosis in 81% to 100% of cases, depending on the number of biopsies obtained. Histologically, typical SCCs show varying grades of differentiation ranging from well-differentiated keratinizing carcinomas containing well-formed squamous cell nests and keratin pearls to undifferentiated tumors without recognizable keratin; they are classified into well-, moderately, and poorly differentiated lesions based on how closely they resemble mature nonneoplastic squamous epithelium (Figs. 3.9, 3.10 and 3.11). Most tumors are well- to moderately differentiated lesions. These tumors contain squamous cell nests, dyskeratotic cells, and keratin pearls. As the lesions become less mature, they show progressive degrees of nuclear pleomorphism and cytologic atypia with loss of keratinization and intercellular bridges, although one occasionally sees marked keratinization of highly atypical cells. Less well-differentiated tumors consist of cellular masses containing polygonal, round, or fusiform, nonkeratinizing cells. Poorly differentiated carcinomas typically contain an abundance of basaloid cells, and the degree of differentiation often varies throughout the tumor. They generally appear as invasive sheets of cells with prominent areas of central necrosis. Occasionally, areas of individual cell necrosis in poorly differentiated tumors produce a pseudoacinar pattern, but mucicarmine stains are negative. Most poorly differentiated SCCs contain at least focal areas of identifiable squamous differentiation, such as dyskeratotic epithelial nests, keratin pearls, or intercellular bridges.

FIG. 3.10 Moderately differentiated invasive squamous cell carcinoma. Note the absence of marked atypia, keratinization, and pearl formation.

FIG. 3.11 Poorly differentiated invasive squamous cell carcinoma. Note the high degree of atypia and the brisk mitotic index.

FIG. 3.12 Moderately differentiated squamous cell carcinoma involving the regional lymphatics and lymph node. A: The lymph node has become secondarily involved with a moderately to poorly differentiated tumor. The nerve outside of the lymph node is also surrounded by tumor (arrow). B: Tumor within lymphatic spaces.

As the tumor cells infiltrate the esophageal wall, they may form sheetlike nests with rounded margins or they may have an asteroid shape with spiculated margins. Tumors with an asteroid configuration are more likely to show deep penetration, lymphatic permeation, nodal metastases, and desmoplasia and have a worse prognosis than those with rounded borders (119). Tumors with downward penetration are more likely to show vascular and lymphatic invasion (Fig. 3.12).

FIG. 3.13 Esophagus following radiotherapy. A: Low-power magnification showing the presence of a recurrent tumor (arrows) deep in the wall of the esophagus. The superficial tissues have become markedly sclerotic. The overlying epithelium is hyperplastic but nonneoplastic. B: Higher magnification shows the presence of the dense, sclerotic, submucosal tissues with atypical stellate-shaped radiation fibroblasts.

Patients treated preoperatively with chemotherapy or chemoradiation may show a spectrum of treatment responses from complete ablation to unaltered tumor (Figs. 3.13 and 3.14). The tumor may completely disappear, creating a partially re-epithelialized ulcer containing granulation tissue heavily infiltrated by lymphocytes. Calcification may be present. Fibrosis in the muscularis propria causes shrinkage of the muscle bundles. Tumor regression can be graded (120), although this is not commonly done.

FIG. 3.14 Squamous cell carcinoma (SCC) following radiotherapy. A: Most of the tumor appears viable, although the cytoplasm is vacuolated and some nuclei appear pyknotic. B: Biopsy of a stenotic area in a patient several years after radiotherapy for SCC. The tissue fragments contain squamous epithelial cells and a highly cellular stroma. C: Higher magnification of the epithelial component of the tumor shows marked cytologic atypia and a disorderly architecture. D: The stroma contains infiltrating squamous cell nests as well as atypical stromal cells secondary to the radiation.

Cytologic Features

Cytologic evaluation of the esophagus may be important for screening of high-risk populations, as mentioned above. Exfoliated malignant cells from intraepithelial SCCs may be obtained by means of esophageal washings or balloon cytology. The cells resemble those of squamous neoplasia of the cervix. Abundant cell samples are usually obtained from SCCs. Paradoxically, large fungating growths are frequently associated with inadequate material; false-positive results are rare in this setting. Well-differentiated carcinomas shed highly atypical and partly keratinized cells with bizarre shapes, anisocytosis, and hyperchromatic nuclei (Fig. 3.15). Malignant pearl formations may be observed. Moderately and poorly differentiated SCCs exfoliate single or clustered immature atypical cells with increased nuclear:cytoplasmic ratios and either pale nucleoli or dark angulated nuclei containing large amounts of heterochromatin (Fig. 3.16).

Tumor Spread

ESCC spreads within the esophageal wall, invading the muscularis propria and extending into the periesophageal tissues. Mediastinitis, pleural fistulas, and empyema may develop. Depending on tumor location, invasion into the trachea, bronchi, aorta, pleural cavity, lung, thyroid, lymph nodes, pericardium, major vessels, and/or nerves occur. Malignant tracheoesophageal fistulas develop in up 5% of patients, often as a result of treatment, and portend a very poor prognosis (121). Hematogenous metastases occur late in the disease, usually following nodal metastases.

Intramural intralymphatic vascular spread is common; lymphatic extension produces submucosal nodules distant from the main tumor in up to 26% of ESCCs (122). In rare cases, intramural metastases can be found in the stomach (123). Because the esophageal lymphatics are located in the lamina propria, lymph node involvement occurs early.

In Western populations, up to 61% of patients show local extension and nodal involvement at the time of diagnosis (124). Previous staging guidelines emphasized the location of involved nodes, but data suggest that the number of involved lymph nodes is the more important prognostic factor. Many authors have reported a high rate (30% to 40%) of lymph node micrometastases (detected by immunohistochemistry) in ESCCs originally classified as node negative by routine histopathologic examination (125,126,127,128). In most studies, micrometastases were associated with decreased survival or time to recurrence.

FIG. 3.15 Well-differentiated squamous cell carcinoma of the esophagus. A-D: Variably shaped cells are found singly and in small groups.

FIG. 3.16 Moderately to poorly differentiated squamous cell carcinoma of the esophagus. A: Two large hyperchromatic cells: one has ingested an erythrocyte. B: Cluster of hyperchromatic cells (May-Grunwald-Giemsa). C: Poorly differentiated squamous cell carcinoma.

FIG. 3.17 Prognostic markers. A: Squamous cell carcinoma (SCC) stained for the epidermal growth factor receptor (EGFR). The tumor is strongly positive, especially at the tumor-stromal junction. B: EGFR immunoreactivity of a poorly differentiated SCC present within vessels. C: p53 immunostain showing numerous immunoreactive cells. D: Fluorescence in situ hybridization for cyclin D showing the presence of multiple copies of the gene in the neoplastic cells. The nuclei are stained with propidium iodide and appear red. The cyclin D is labeled with a fluorescent probe and appears yellow. More than two copies (yellow spots) are seen in many cells.

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