Clinical Features

Esophageal squamous papilloma is the most common benign type of epithelial tumor of the esophagus. Studies suggest a prevalence rate of as much as 1%. These lesions may affect patients of all ages and both sexes. Most are asymptomatic, but large lesions may cause epigastric pain, dysphagia, or symptoms related to luminal obstruction.

Pathogenesis

The pathogenesis of esophageal squamous papilloma is controversial. Whereas several studies have shown a high association (as much as 86%) with human papillomavirus (HPV) infection, other studies have failed to show a strong association with HPV. When detected, both low-risk and high-risk subtypes (e.g., types 6/11 and 16, respectively) have been reported. Variation in the prevalence of HPV among studies may result from differences in the techniques used to detect viral antigens or DNA and the possibility that as yet unidentified subtypes of HPV may be involved. Others have proposed that these lesions develop as a result of chronic mucosal irritation, perhaps secondary to gastroesophageal reflux disease (GERD).

Pathologic Features

Grossly, esophageal squamous papillomas are usually small, discrete, sessile, soft, tan lesions that range in size from 0.5 to 3 cm; they occur most commonly in the distal or middle esophagus but may develop anywhere in the esophagus ( Fig. 24.1 ). As much as 20% of cases are multiple, and rare cases of diffuse papillomatosis have also been reported. Microscopically, three distinct histopathologic types have been recognized: exophytic, endophytic, and spiked (verrucoid) ( Fig. 24.2 ). The exophytic type, which is the most common, is composed of finger-like papillary fronds. The endophytic type shows a smooth, round surface contour and an inverted papillomatous proliferation. Least common is the spiked or verrucoid type, which has a spiked surface contour, a prominent granular cell layer, and marked hyperkeratosis.

Endoscopic photograph of an exophytic squamous papilloma of the esophagus showing a well-circumscribed, broad-based nodule with a verrucoid irregular surface.

A, Exophytic squamous papilloma of the esophagus. This lesion shows finger-like projections of acanthotic squamous epithelium covering fibrovascular lamina propria pegs. B, Endophytic-type squamous papilloma showing an inverted papillomatous surface contour. C, Spiked-type squamous papilloma showing prominent spikes of acanthotic epithelium with marked hyperkeratosis and hypergranulosis. D, Medium-power photomicrograph of a case of diffuse papillomatosis. Notice the superficial keratinocytes with koilocytosis. E, The deep portion of the same papilloma as in D shows basal zone hyperplasia.

All types are characterized by the presence of a branched fibrovascular core of lamina propria with a variable degree of acute and chronic inflammation and vascular congestion. The overlying squamous epithelium in all types is acanthotic, often reactive, showing a prominent basal cell zone and complete surface maturation (see Fig. 24.2, E ). Features that are variably present include koilocytosis, parakeratosis, binucleation, dyskeratosis, and a prominent granular cell layer. Mitoses may be present in the basal and suprabasal epithelial layers, particularly in cases with active inflammation.

Differential Diagnosis

A papilloma that is large, is oriented poorly, or shows marked reactive changes may, on occasion, be difficult to distinguish from a well-differentiated squamous cell carcinoma or a verrucous carcinoma. However, esophageal squamous papillomas lack cytologic atypia, mitoses in the middle and upper levels of the squamous epithelium, atypical mitoses, and an infiltrative growth pattern characteristic of carcinoma. Furthermore, their gross (endoscopic) appearance is distinctive. In contrast to carcinoma, papillomas are well localized and well demarcated, smooth, discrete polyps without necrosis, stricture formation, or heaped-up borders. They lack the central keratinous crater characteristic of verrucous carcinoma ( Table 24.1 ).

Papillomas may also be confused with pseudoepitheliomatous hyperplasia occurring adjacent to a healing ulcer or overlying a granular cell tumor. However, the latter type of lesion lacks a fibrovascular core and other features of HPV infection such as koilocytosis. Unlike esophageal squamous papillomas, pseudoepitheliomatous hyperplasia often shows abundant inflammation and surface erosion.

Prognosis

Squamous cell papillomas are benign lesions with little or no malignant potential. However, rare cases associated with squamous dysplasia, or even squamous cell carcinoma, have been reported, often in association with extensive esophageal papillomatosis.

Submucosal Gland/Duct Adenoma

Adenomas that develop from the submucosal glands are rare. They are usually histologically similar to those that arise from the minor salivary glands. This is not surprising because, embryologically, the esophageal submucosal glands are considered a continuation of the minor salivary glands of the oropharynx. They are usually submucosal and develop as well-circumscribed lesions that resemble pleomorphic adenomas or, more rarely, pancreatic or ovary-like serous cystadenomas.

Microscopically, adenomas that develop from the submucosal gland ducts show a mixture of tubal, cystic, and papillary growth patterns similar to intraductal papillomas of the breast or sialadenoma papilliferum of the salivary glands. The epithelium typically contains two cell layers (similar to the normal submucosal gland ducts) with only mild to moderate cytologic atypia and infrequent mitoses ( Fig. 24.3, A ). Other adenomas may resemble salivary gland Warthin tumors (see Fig. 24.3, B ). The immunophenotype of the tumor cells is also similar to that of the normal esophageal gland ducts. A mixed inflammatory infiltrate may be present as well. Most of these tumors behave in a benign fashion, although rare carcinomas have been reported.

Benign gland/duct adenoma of the esophagus. A, This lesion is composed of a proliferation of irregular glands lined by flattened, cuboidal to low columnar epithelium focally showing two cell layers. No mitosis or significant atypia is noted. B, Another gland/duct-associated lesion has the morphology of a Warthin tumor, with eosinophilic cuboidal epithelium and a lymphoid stroma. A normal esophageal submucosal gland is visible at the left.

Polypoid Dysplasia in Barrett’s Esophagus

Adenoma-like polypoid dysplastic lesions may develop in BE (see Chapter 14 ). Endoscopically, these lesions usually appear as well-defined sessile or pedunculated polyps that range in size from 0.5 to 1.5 cm and usually occur in the middle or distal esophagus within areas of BE ( Fig. 24.4 ). Histologically, these polyps are composed of a tubular or tubulovillous proliferation of low- or high-grade dysplastic epithelium, similar in appearance to colonic adenomas. The polyp epithelium is usually of the intestinal type, similar to the surrounding BE, but it may also show a gastric (foveolar) phenotype or mixed features of both.

Polypoid dysplasia in Barrett’s esophagus. A, Gross image of two well-circumscribed pedunculated polyps situated just above the gastroesophageal junction and arising on a background of Barrett’s mucosa. The squamous mucosa of the normal esophagus is seen just above the polyps. B, Low-power photomicrograph of the circumscribed polypoid area of dysplasia in another example. Notice that the polyp is formed of tightly packed, convoluted, dysplastic glands and is arising from columnar mucosa with intestinal metaplasia. C, The polyp is composed of high-grade dysplastic columnar epithelium.

In one study, these lesions showed proliferative and molecular abnormalities (loss of heterozygosity of APC and TP53 ) similar to those of flat dysplasia and probably should be treated in a similar fashion. In fact, of the 10 cases reported, 9 were associated with adenocarcinoma, illustrating their high malignant potential. Because of the high association with flat dysplasia in the nonpolypoid Barrett’s mucosa, treatment by polypectomy is not considered adequate. Affected patients should be treated according to standard protocols for flat Barrett’s dysplasia, taking into account the extent, location, and grade of dysplasia in the esophagus as a whole.

Developmental Cysts and Duplications

Congenital cystic lesions and duplications may occur in the esophagus and mimic a malignant tumor because of their mass effect. These lesions, which are discussed more thoroughly in Chapter 8 , are categorized by their site of origin, their embryologic derivation, and the histologic appearance of their lining epithelium. Clinically, they may be asymptomatic, or they may cause symptomatic compression of nearby respiratory or alimentary tract structures.

Bronchogenic cysts result from anomalous budding of bronchial structures derived from the embryonic foregut. They are typically located in the mediastinum or in the wall of the esophagus. Grossly, these cysts are usually unilocular and do not normally communicate with the esophageal lumen. Microscopically, they are lined by ciliated columnar epithelium and frequently contain cartilage, smooth muscle, and mucous glands in the surrounding cyst-lining tissue ( Fig. 24.5 ).

Bronchogenic cyst. The epithelial lining consists of ciliated columnar epithelium overlying a wall of fibromuscular tissue.

Intramural cysts most likely develop as a result of abnormal recanalization of the esophageal lumen during embryogenesis. They may produce extrinsic compression and obstruction of the esophageal lumen or trachea, and they have also been associated with hemoptysis. Histologically, unilocular cysts may be lined by respiratory, gastric, oxyntic, squamous, or simple cuboidal epithelium, often with smooth muscle and ganglia in the cyst wall. A lymphoepithelial cyst of the cervical esophagus has also been reported. This lesion is characterized by a cyst lined most often by squamous or cuboidal epithelium and surrounded, uniformly, by a dense mononuclear inflammatory infiltrate.

Dorsal enteric (neurenteric) cysts occur primarily in the posterior mediastinum of infants and are thought to arise from incomplete closure of the notochordal remnant. These cysts may be associated with additional congenital defects, including spina bifida and vertebral anomalies. Microscopically, they are lined by gastric, intestinal, squamous, or respiratory epithelium and are usually surrounded by all the normal tissue layers of the bowel wall.

Other rare congenital anomalies include esophageal duplications, which may be asymptomatic but more often cause dysphagia or respiratory symptoms. They are usually isolated but may also be associated with other congenital foregut lesions such as pulmonary cystic malformations. Histologically, these cysts may be lined by squamous, gastric, ciliated columnar, or even pancreatic epithelium. The wall consists of admixed fibrous tissue and smooth muscle but does not contain organized layers of muscularis or cartilage.

Developmental cysts and duplications are benign. However, they may become infected as a result of rupture. Extremely rarely, adenocarcinoma or squamous cell carcinoma may develop from these lesions.

Among acquired cystic lesions, mucoceles are not uncommon. They may even develop in excluded segments of esophagus created after surgery for esophageal atresia or rupture. In large or chronic cases, the cystic lining may not be apparent microscopically, revealing only inflammation and fibrous tissue.

Heterotopias

Gastric, thyroid, parathyroid, pancreatic, or even sebaceous tissue may be present as heterotopias in the esophagus. These deposits are presumed to be congenital in origin, although, as discussed later, some possible relationships with clinical conditions such as GERD and BE have been proposed.

Gastric heterotopia (“inlet patch”) is by far the most common type, being present in an estimated 2% to 11% of the general population. These lesions are usually located in the upper third of the esophagus. Although they are often asymptomatic, they may give rise to symptoms that result from complications of acid secretion, such as heartburn, dysphagia, active esophagitis, ulceration, bleeding, stricture, and perforation. Patients with Helicobacter pylori gastritis frequently show concurrent colonization of the heterotopic mucosa. The diagnosis is established by finding gastric glandular and surface epithelium (usually with parietal cells) in the esophagus in patients without intervening BE ( Fig. 24.6, A ). Some investigators have found a positive correlation with the presence of BE, although the basis for this association, if any, is unknown. Rarely, adenocarcinoma may develop in gastric heterotopia (see Fig. 24.6, B ), and an intraductal papillary mucinous neoplasm arising from a pancreatic heterotopia has been reported.

A, Gastric heterotopia. Gastric surface epithelium and oxyntic glands from a heterotopia in the upper esophagus. B, Poorly differentiated adenocarcinoma (bottom) is arising in a focus of gastric heterotopia.

Heterotopic sebaceous glands are the second most common form of heterotopia in the esophagus. They may occur at any level of the esophagus, are frequently multiple, and usually appear as slightly elevated, yellowish lesions, 1 to 2 mm in diameter. Microscopically, these lesions show sebaceous cells within the epithelium or in the lamina propria ( Fig. 24.7 ). Sebaceous cells are microvesicular and contain vacuolated cytoplasm filled with lipid substances. An excretory duct, with or without a connection to the surface epithelium, may be present as well. One study suggested that sebaceous glands may represent a metaplastic process because of their frequent association with reflux esophagitis and expression of cytokeratin 14 (CK14), which has been demonstrated in cell lines to represent the progeny of dormant stem cells.

Sebaceous heterotopia of the esophagus. Associated with the squamous epithelium is a proliferation of vacuolated sebaceous cells mixed with keratin debris.

Pseudoepitheliomatous Hyperplasia

Pseudoepitheliomatous hyperplasia is a morphologic pattern of reactive squamous epithelium that most commonly occurs adjacent to healing ulcers. It is characterized by parallel, elongated, and typically evenly spaced and uniform columns (pegs) of highly reactive squamous cells with prominent nucleoli and mitoses, which may extend deep into the lamina propria ( Fig. 24.8 ). Inflammation, both acute and chronic, is usually present, and this assists in recognizing the reactive nature of the cell proliferation. Lack of surface maturation (nucleated cells at surface) and parakeratosis may be present as well. Its appearance may simulate invasive squamous cell carcinoma, although the lack of either cytologic atypia or deeply infiltrative growth supports its benign nature. Furthermore, the squamous cells in reactive hyperplasia usually retain their polarity with respect to each other (absence of overlapping nuclei) and with respect to the basement membrane. Nevertheless, if the columns (pegs) of squamous epithelium are irregular and nonuniform, particularly in areas immediately adjacent to ulcers, and this feature is present in abundance, suspicion for a malignant process should be higher.

A, Pseudoepitheliomatous hyperplasia of the esophagus. This marked reactive change is characterized by a proliferation of irregular pegs of squamous epithelium that extend into the underlying lamina propria with a moderate amount of chronic inflammation. B, High-power view shows that the epithelium is composed of hyperchromatic cells with a slightly increased nucleus-to-cytoplasm ratio and visible nucleoli. However, no atypical mitoses or significant overlapping of the cells and their nuclei is observed. In addition, no significant loss of polarity is seen.

On occasion, this pseudoepitheliomatous reaction may be endoscopically visible and polypoid; some authors refer to these lesions as “hyperplastic” or “inflammatory” polyps. In addition, polypoid foci of pseudoepitheliomatous hyperplasia may be confused with the endophytic type of squamous papilloma. However, the latter lesions usually lack the significant inflammation and epithelial damage associated with hyperplasia.

Clinical Features

Squamous cell carcinoma is the most common malignant tumor of the esophagus worldwide. However, in the United States and Western Europe, the incidence of this type of esophageal cancer has been declining over the past 20 years, both in absolute terms and relative to esophageal adenocarcinoma (see later discussion). In 2005, the overall incidence of squamous cell carcinoma in the United States was approximately 2.0 per 100,000 person-years. It affects predominantly men (two to three times more often than women) with a peak incidence in the seventh decade of life. There is a marked geographic and ethnic variation in incidence: the highest rates (as many as 161 per 100,000) occur in China, Iran, South America, and South Africa. In the United States, the disease is approximately four times more common in black men than in white men. Common presenting symptoms include dysphagia and weight loss. In addition, as much as 3% of patients with esophageal squamous cell carcinoma have concurrent head and neck squamous cell carcinoma.

Pathogenesis

The pathogenesis of squamous cell carcinoma is multifactorial and varies significantly among different regions of the world. Many cases develop without an identifiable cause or predisposing condition. Known risk factors in high-prevalence areas such as China and Iran include consumption of food or water rich in nitrates and nitrosamines, which results in the development of chronic esophagitis. Additional risk factors, common to both Western and developing countries, include tobacco smoke, alcohol, and various vitamin deficiencies. Other predisposing conditions are achalasia, Plummer-Vinson syndrome, strictures resulting from acid or lye ingestion, and the rare autosomal dominant condition tylosis palmaris et plantaris. Individuals related to affected family members are also at increased risk for esophageal carcinoma.

HPV infection has been implicated in tumorigenesis in many squamous epithelia. However, its precise role in esophageal carcinoma is controversial. HPV DNA has been isolated from esophageal tumors at prevalence rates of 0% to 66%. Viral types most commonly identified include HPV types 16 and 18. Varying rates of HPV positivity among studies may be attributed to differences in the techniques used to detect HPV and to different populations of patients studied (e.g., isolation rates are highest in high-risk areas such as China and Iran). Therefore, HPV is most likely a causative factor in only a small fraction of squamous cell carcinomas, and, when present, this agent is typically found in high-risk areas.

Molecular Features

At the molecular level, the most common alterations are overexpression of cell cycle regulatory proteins (e.g., cyclin D1 in 50% of tumors) and inactivation or loss of tumor suppressor proteins (e.g. p16 [CDKN2A] in as much as 80% of cases). Environmental risk factors such as tobacco, alcohol, and diet appear to produce mutations through the production of reactive oxygen species and DNA adducts. Polymorphisms in the ALDH2 and ALDH1B1 genes, which encode enzymes involved in alcohol metabolism, and in CYP1A1, a detoxification enzyme for xenobiotics, are associated with elevated risk for squamous cell carcinoma. Most of these tumors also express high levels of the epidermal growth factor receptor (EGFR), seen in 29% to 92% of the cases in some studies. Some of these alterations, such as inactivating mutations of TP53 and increased cell proliferation, appear to occur early in neoplastic progression and are frequently detectable in squamous dysplastic precursor lesions as well. For more information on molecular features, refer to Chapter 23 .

Clinical Features

Esophageal squamous cell carcinoma, similar to its counterparts in the skin or cervix, is believed to develop through a progression of premalignant or dysplastic precursor lesions. Dysplasia is defined as the presence of unequivocal neoplastic cells confined to the epithelium. Squamous dysplasia is more common in patients at high risk for squamous cell carcinoma and is adjacent to squamous cell carcinomas in 60% to 90% of cases. In addition, dysplasia is frequently multifocal, and carcinomas associated with dysplasia are more likely to be multifocal in origin. Dysplasia is currently classified as low-grade or high-grade, based on the proportion of the thickness of the epithelium involved by dysplasia. In this two-tiered system, low-grade dysplasia roughly corresponds to the previously used terms mild and moderate dysplasia, and high-grade dysplasia includes severe dysplasia and carcinoma in situ (see later discussion).

Pathologic Features

Microscopic Pathology

Dysplastic squamous epithelium is characterized by a combination of architectural and cytologic abnormalities that vary in extent and severity, and this is reflected in the grade ( Fig. 24.9 ). The epithelium is usually hypertrophic but may be atrophic in rare circumstances. Dysplasia may involve the basal layer only or the full thickness of the epithelium. In 20% of cases, dysplastic epithelium spreads into esophageal mucosal gland ducts and simulates stromal invasion. Low-grade dysplasia reveals involvement of the basal third to half of the squamous epithelium with neoplastic cells, whereas high-grade lesions show complete or almost complete involvement of the native squamous epithelium. Dysplastic cells may occasionally grow as isolated cells in a horizontal pagetoid fashion, although this pattern must be distinguished from pagetoid involvement of the squamous epithelium by adenocarcinoma.

Squamous dysplasia of the esophagus. A, Low-grade squamous dysplasia is characterized by a proliferation of neoplastic cells involving about one third to one half of the thickness of the epithelium. B, High-grade dysplasia. In contrast to A, dysplastic cells extend to the surface of the epithelium and are associated with a significant loss of surface maturation. C, In this high-power image, dysplastic cells are shown to have an increased nucleus-to-cytoplasm ratio, marked hyperchromatic nuclei, significant loss of polarity, and overlapping of the cells and their nuclei. D, This unusual morphologic appearance of squamous dysplasia is characterized by disorganized large cells with open nuclei. E, High-power photomicrograph of the dysplastic cells seen in D .

Cytologic changes include nuclear hyperchromasia, pleomorphism, increased nucleus-to-cytoplasm (N : C) ratio, and increased mitotic rate. The chromatin of dysplastic cells is usually coarse and may be associated with thickening of the nuclear membrane. Nucleoli may be present but are not a consistent feature and are not specific because they are also frequently present in reactive squamous epithelium (discussed later). When present, nucleoli may be unusually large in size and irregular in shape. Architecturally, dysplastic cells display disorganization, loss of polarity, overlapping nuclei, and lack of surface maturation, which are key features in helping to distinguish true dysplasia from non-neoplastic (reactive) processes (see Fig. 24.9, C ). Mitotic figures are usually increased in number and may be found at any level of the epithelium (base, midepithelium, or surface). Abnormal (tripolar or disorganized) mitotic figures may be present as well, particularly in high-grade lesions.

Rarely, precursor dysplastic lesions may reveal a proliferation of disorganized large cells (with a normal or even low N : C ratio) with open irregular nuclei, prominent enlarged and irregular single or multiple nucleoli, peripheral condensation of chromatin, and multinucleation (see Fig. 24.9, D and E ). In these cases, the border between the epithelium and the lamina propria is often highly irregular, showing sharp, budding, or bulbous expansions of epithelium protruding deep into the lamina propria. This type of dysplastic epithelium is often associated with inflammation and surface maturation, although the latter to a much lesser degree than in either normal or reactive squamous epithelium. In these cases, distinguishing dysplastic epithelium from either markedly reactive squamous epithelium or very well-differentiated squamous cell carcinoma may be extremely difficult. Often, repeat biopsies from deeper portions of the lesion and close correlation with the gross endoscopic appearance are necessary to help establish a final diagnosis. In these cases, invasion should not be diagnosed unless there is unequivocal evidence of irregular clusters of neoplastic cells within the deep lamina propria that are clearly disconnected from the overlying surface epithelium (on deeper levels of tissue sectioning) and associated with a peritumoral stromal desmoplastic response.

Differential Diagnosis (Reactive versus Neoplastic)

Squamous dysplasia must be distinguished from reactive epithelial changes associated with esophagitis. Although regenerating squamous cells may show mild nuclear enlargement, hyperchromasia, and expansion of the basal cell layers, they lack significant nuclear pleomorphism, overlapping nuclei, and nuclear crowding and do not display abnormal mitoses (see Fig. 24.9 ). Unlike in dysplasia, the chromatin is typically fine and homogeneous, and nucleoli, when present, are small and regular in shape. Architecturally, reactive squamous epithelium often displays some degree of surface maturation. Essential to the benign, non-neoplastic diagnosis is the fact that the basal and suprabasal layers maintain their polarity and orderly spacing in reactive lesions. Mucosal inflammation frequently accompanies reactive squamous epithelium, and in the presence of inflammation, a diagnosis of dysplasia should be rendered with caution. In biopsy specimens in which the epithelial changes appear sufficiently marked to suggest dysplasia but a reactive process cannot be excluded because of inflammation, a diagnosis of “indefinite for dysplasia” is appropriate. In such cases, follow-up biopsies after treatment of the underlying esophagitis frequently help resolve the diagnostic uncertainty. The results of ancillary stains, such as strong nuclear staining for TP53 (indicative of inactivating mutations) and extensive, suprabasal cell proliferation highlighted by the proliferation marker Ki67, may also support a diagnosis of dysplasia in problematic cases. Histologic features useful in the differential diagnosis of squamous dysplasia are summarized in Table 24.2 .

In biopsy specimens from patients who have received chemotherapy or radiotherapy, the squamous epithelium may contain markedly atypical cells with enlarged hyperchromatic nuclei that raise the possibility of dysplasia. However, in contrast to dysplasia, these cells do not have an increased N : C ratio and often contain distinctive vacuolization in their cytoplasm. Furthermore, unlike in dysplasia, mesenchymal cells showing similar changes may also be present in the lamina propria, as well as other characteristic stromal changes of chemotherapy or radiotherapy ( Fig. 24.10, A ). Therefore, awareness of the patient’s clinical history is critical.

A, Reactive squamous epithelium with nuclear atypia from a patient who received chemoradiotherapy. Nuclear changes are present in both epithelial and stromal cells. B, Reactive epithelial giant cell changes are seen in the basal portion of the epithelium adjacent to a healing ulcer. C, High-power image of another multinucleated epithelial giant cell shows increased nuclear size and prominent nucleoli but a low nucleus-to-cytoplasm ratio. These cells are usually located in the basal portion of the epithelium, as here.

Biopsy specimens from patients with esophagitis caused by GERD or other causes such as drug effects occasionally contain multinucleated epithelial giant cells, raising the possibility of dysplasia (see Fig. 24.10, B and C ). In these cases, no other cytologic or architectural features of dysplasia are present, and results of special studies for viral inclusions are negative. In inflammation-induced multinucleation, the nucleated squamous cells are typically basal or suprabasal in location and may be increased in number adjacent to areas of ulceration. In contrast, multinucleated virally infected cells (e.g., herpes simplex) are common in the surface epithelium and adjacent to sloughing epithelium.

Prognosis and Treatment

Squamous dysplasia frequently occurs adjacent to invasive carcinoma. For example, 30% of patients with a biopsy diagnosis of high-grade dysplasia show invasive squamous cell carcinoma in subsequent endoscopic resections. In addition, patients with squamous dysplasia are at increased risk for squamous cell carcinoma on follow-up. In a 13-year follow-up study of patients from China, 106 with low-grade dysplasia and 23 with high-grade dysplasia, those with low-grade dysplasia had a threefold to eightfold increased risk, and patients with high-grade dysplasia had a 28- to 34-fold increased risk for invasive carcinoma. In another study, 15% of patients with low-grade dysplasia progressed to high-grade dysplasia, whereas invasive carcinoma developed in 30% of patients with high-grade dysplasia during an 8-year follow-up period. However, dysplasia may also regress or disappear, although sampling error certainly may account for a normal finding on follow-up biopsy in a patient with dysplasia in a prior biopsy specimen. Therefore, patients with a diagnosis of squamous dysplasia require thorough endoscopic examination with biopsies, first to exclude synchronous invasive squamous cell carcinoma (particularly if associated with a visible mass lesion or ulceration) and second to detect the development of early invasive tumor on follow-up. Any grade of squamous dysplasia associated with a mass lesion should be considered carcinoma and treated accordingly. Low-grade dysplasia without a mass or associated carcinoma may be managed with repeated biopsies and continued surveillance in most instances. Some endoscopically subtle invasive carcinomas have been reported that apparently arose from low-grade dysplasia, further emphasizing the need for careful endoscopic scrutiny and adequate sampling in patients with any grade of squamous dysplasia.

Endoscopic mucosal resection or endoscopic submucosal dissection, which permits removal of dysplastic lesions or even early superficial cancers, aids in the diagnosis of early invasive tumors and is performed increasingly in some highly specialized centers. In one study of 87 patients with high-grade dysplasia and 213 patients with early (intramucosal) carcinoma treated with these two techniques, a total of 19 patients (6%) developed recurrences over an 85-month follow-up period. Endoscopic submucosal dissection gave superior results, with no nodal or distant metastases during a 36-month follow-up period.

Pathologic Features

Gross Pathology

Squamous cell carcinomas occur in the middle third of the esophagus in 50% to 60% of cases, the distal third in 30%, and the proximal third in 10% to 20%. Superficial tumors most commonly appear as mucosal plaques or slightly elevated flat lesions but may also be ulcerated, polypoid, or even grossly inconspicuous. Superficially invasive tumors are more commonly multicentric (as much as 20% of cases) when compared with advanced tumors. This finding may reflect either the presence of synchronous primary tumors occurring in a background of dysplasia or the presence of satellite tumor nodules resulting from intramural metastasis.

The gross appearance of advanced tumors may be classified as exophytic or fungating (60% of cases), ulcerating (25% of cases), or infiltrative (15% of cases) ( Fig. 24.11 ). However, this feature is not a significant prognostic factor. In patients treated with preoperative irradiation or chemotherapy, the tumor may be invisible or perhaps replaced by a shallow surface erosion.

A, Gross appearance of a superficial squamous cell carcinoma of the esophagus ( right lower corner ). B, Exophytic and ulcerating advanced squamous cell carcinoma of the esophagus is seen in the midportion of the organ.

Microscopic Pathology

Superficially invasive tumors consist of irregular, elongated projections of dysplastic epithelium that extend into the lamina propria, muscularis mucosae, or submucosa as isolated cells or clusters of cells with a minimal desmoplastic response. Invasion of mucosal and submucosal lymphatics is not uncommon and is likely to account for the occasional instances of intramural metastasis. Advanced carcinomas spread through the esophageal wall, either with an infiltrative pattern composed of individual small nests of tumor cells or with an expansile (pushing) growth pattern composed of a solid mass of tumor cells with a smooth advancing edge. A prominent lymphocytic infiltrate occasionally surrounds the tumor.

Squamous cell carcinomas show a range of differentiation from well to poor ( Fig. 24.12 ). Well-differentiated tumors show variably sized nests of polygonal epithelioid cells with ample eosinophilic cytoplasm, easily recognizable intercellular bridges, and abundant keratinization (squamous pearls), with relatively few compact basaloid cells. Moderately differentiated tumors account for approximately two thirds of squamous cell carcinomas. They contain a higher proportion of primitive basaloid cells than well-differentiated tumors, and they are typically arranged in irregular nests and trabeculae with only focal keratinization. Poorly differentiated tumors show no evidence of keratinization, grow in solid sheets or as single cells, and may contain large, bizarre pleomorphic cells. Squamous cell carcinomas commonly show varying degrees of differentiation within a single tumor. Focal glandular or mucinous differentiation occurs in as much as 20% of cases. If the glandular and squamous components of the tumor are comparable in proportion but intimately mixed, it qualifies as an adenosquamous carcinoma (see Carcinoma with Mixed Squamous and Glandular Elements ). Focal neuroendocrine or small cell differentiation has also been reported.

A, Well-differentiated squamous cell carcinoma characterized by a proliferation of atypical squamous epithelium forming irregular pegs that extend into the underlying lamina propria. This is associated with a mild desmoplastic reaction and chronic inflammation. B, Moderately differentiated squamous cell carcinoma. In this image, the tumor shows a mixture of keratinizing and basaloid epithelial elements. C, Poorly differentiated squamous cell carcinoma characterized by marked nuclear pleomorphism. However, focal areas of cellular keratinization are present.

Special studies are rarely required to establish a diagnosis of conventional squamous cell carcinoma but may be useful in small biopsy specimens or when rare tumor cells are present, such as for patients who have received neoadjuvant chemoradiotherapy. By immunohistochemistry, squamous cell carcinoma cells are positive for broad-spectrum anticytokeratins and for cytokeratins 13, 14, 18, and 19. CK7 reactivity is present in as much as 29% of cases, but most cases are negative for both CK7 and CK20. In addition, most tumors express the nuclear antigen TP63, similar to squamous cell carcinomas that arise in other sites of the human body. Mucin stains may show focal positivity in a high proportion of cases, but this finding alone should not imply that the tumor is an adenosquamous carcinoma. Focal positivity for neuroendocrine markers, such as chromogranin and synaptophysin, also does not exclude a diagnosis of squamous cell carcinoma if it is present in a minority of the tumor cells and if the tumor is otherwise morphologically typical of a squamous cell carcinoma and does not show areas of small cell carcinoma.

Differential Diagnosis

In small, poorly oriented biopsy specimens, distinguishing between in situ neoplasia (dysplasia) and invasive squamous cell carcinoma may be difficult. Squamous dysplasia, unlike invasive carcinoma, displays smooth-edged papillations with a continuous basement membrane and a connection to the surface epithelium and lacks single-cell infiltration, the presence of irregular discontinuous nests of cells, and desmoplastic stroma. However, the diagnostic criteria for squamous cell carcinoma differ between Western and Japanese pathologists, and many lesions that would be considered “high-grade dysplasia” by Western pathologists are diagnosed as “carcinoma” by Japanese pathologists solely on the basis of nuclear features.

Invasive squamous cell carcinoma must also be distinguished from non-neoplastic lesions such as pseudo­epitheliomatous hyperplasia and pseudodiverticulosis. Pseudoepitheliomatous hyperplasia, similar to other reactive squamous proliferations, does not show significant nuclear pleomorphism, loss of polarity, or overlapping of nuclei and always reveals a connection to the surface epithelium (see Fig. 24.8 ). Reactive lesions do not show desmoplasia. Pseudodiverticulosis is a rare condition that produces numerous islands of reactive squamous epithelium in the mucosa and submucosa, some of which may be irregular in shape, simulating a carcinoma ( Fig. 24.13 ). This condition is caused by extensive squamous metaplasia of the esophageal ducts and glands, which may occur in association with strictures or motility disturbances. On radiologic examination, pseudodiverticulosis may mimic carcinoma by showing irregular stricture formation. Identifying characteristic diverticula with a barium swallow procedure helps separate this condition from carcinoma radiologically. Pathologically, these lesions are distinguished from invasive carcinoma by the lack of an infiltrative growth pattern, absence of histologic features of dysplastic squamous epithelium, and the presence of smooth, often rounded, islands of reactive squamous epithelium associated with, or replacing, the submucosal glands and ducts with a prominent inflammatory infiltrate.

Pseudodiverticulosis of the esophagus. Low-power image shows a reactive proliferation of squamous epithelium extending into the submucosal gland ducts and associated with a marked chronic inflammatory infiltrate. In contrast to carcinoma, the borders of the squamous proliferation are smooth and do not show atypia or other features of malignancy, such as desmoplasia.

Biopsy or resection specimens from patients who have been treated with neoadjuvant chemoradiotherapy may contain only scattered atypical cells, which can occasionally make it difficult to distinguish residual carcinoma from reactive mesenchymal cells. Carcinoma cells may be identified by positive immunostaining for cytokeratins and an increased N : C ratio; reactive mesenchymal cells are typically cytokeratin negative and have expanded, often bubbly or “wispy” cytoplasm. Typically, the N : C ratio of these cells is maintained.

Poorly differentiated tumors may be difficult to recognize as squamous in phenotype, and melanoma or even lymphoma may be suspected on morphologic grounds. Positivity for cytokeratins and negativity for melanocytic and lymphoid markers may help eliminate these alternative diagnoses. In some patients, pulmonary squamous cell carcinoma involves the esophageal wall by metastasis or direct extension (see later discussion) and may be confused with a primary esophageal tumor. Adjacent squamous dysplasia provides strong evidence for an esophageal origin of the tumor. In addition, approximately 10% to 20% of lung squamous cell carcinomas show nuclear immunostaining for thyroid transcription factor 1 (TTF-1), which is not expressed in esophageal epithelium or in tumors derived from it.

Prognosis and Treatment

Squamous cell carcinomas may spread horizontally, but more typically they invade vertically through the esophageal wall and in this manner spread to involve contiguous organs such as the trachea, aorta, and pericardium. Intramural metastasis was detected in as much as 7% of resection specimens in one study. Regional lymph node metastasis is present in approximately 60% of patients at the time of diagnosis, and the lymph node positivity rate correlates with depth of invasion (<5% for intramucosal carcinomas and as much as 45% for submucosal carcinomas). Carcinomas originating in the upper thoracic esophagus are more likely to metastasize to cervical or upper mediastinal nodes, whereas tumors from the middle and lower thirds of the esophagus metastasize to lower mediastinal or perigastric nodes. However, skip nodal metastases are not uncommon in esophageal cancers. Distant metastasis, which most frequently involves the lung or liver, is present in as much as 60% of patients at autopsy.

Overall, the 5-year survival rate for patients with squamous cell carcinoma is only 10%, but it approaches 30% to 40% for patients treated with esophagectomy. The most significant prognostic factor is tumor stage, which is based on the American Joint Committee on Cancer (AJCC) tumor-node-metastasis (TNM) classification system ( Table 24.3 ). Patients with tumors that penetrate into the submucosa have 5-year survival rates in the range of 60% to 75%, compared with 40% to 60% and 25% to 30% for patients with tumors that extend into the muscularis propria and the adventitia, respectively. The presence of lymph node metastasis and a greater number of positive lymph nodes are also correlated with worse prognosis. In patients who have received neoadjuvant chemoradiotherapy, the presence of residual tumor is correlated with reduced survival. In one study of 175 patients, 55 (31%) had complete histologic tumor response; their median survival time was 125 months, compared with 21 months for those who had residual tumor. Some authors have also found that poor tumor differentiation is an independent prognostic factor, and tumor differentiation as well as tumor location are now incorporated into the AJCC staging for this tumor type (see Table 24.3 ). Intramural metastases and lymphovascular invasion have also been found to be predictive of regional lymph node metastasis and poor survival in some studies, but these findings need to be tested in a prospective manner.

Table 24.3

AJCC TNM Classification of Esophageal Carcinomas

Primary Tumor (T)
TX	Primary tumor cannot be assessed
T0	No evidence of primary tumor
Tis	High-grade dysplasia
T1	Tumor invades lamina propria, muscularis mucosae, or submucosa
T1a	Tumor invades lamina propria or muscularis mucosae
T1b	Tumor invades sumucosa
T2	Tumor invades muscularis propria
T3	Tumor invades adventitia
T4	Tumor invades adjacent structures
T4a	Resectable tumor invading pleura, pericardium, or diaphragm.
T4b	Unresectable tumor invading other adjacent structures such as aorta, vertebral body, trachea, etc.
Regional Lymph Nodes (N)
NX	Regional lymph nodes cannot be assessed
N0	No regional lymph node metastasis
N1	Regional lymph node metastasis involving 1 to 2 nodes
N2	Regional lymph node metastasis involving 3 to 6 nodes
N3	Regional lymph node metastasis involving 7 or more nodes
Distant Metastasis (M)
MX	Distant metastasis cannot be assessed
M0	No distant metastasis
M1	Distant metastasis

 

Stage Grouping (Squamous Cell Carcinoma)
	T	N	M	Grade	Location *	5-Yr Survival (%)
Stage 0	Tis	N0	M0	1, X	Any	75
Stage IA	T1	N0	M0	1, X	Any	75
Stage IB	T1	N0	M0	2-3	Any	60
	T2-3	N0	M0	1, X	Lower, X
Stage IIA	T2-3	N0	M0	1, X	Upper, middle	53
	T2-3	N0	M0	2-3	Lower, X
Stage IIB	T2-3	N0	M0	2-3	Upper, middle	41
	T1-2	N1	M0	Any	Any
Stage IIIA	T1-2	N2	M0	Any	Any	25
	T3	N1	M0	Any	Any
	T4a	N0	M0	Any	Any
Stage IIIB	T3	N2	M0	Any	Any	17
Stage IIIC	T4a	N1-2	M0	Any	Any	14
	T4b	Any	M0	Any	Any
	Any	N3	M0	Any	Any
Stage IV	Any	Any	M1	Any	Any	<5
Stage Grouping (Adenocarcinoma)
	T	N	M	Grade		5-Yr Survival (%)
Stage 0	Tis	N0	M0	1, X		82
Stage IA	T1	N0	M0	1-2, X		78
Stage IB	T1	N0	M0	3		63
	T2	N0	M0	1-2, X
Stage IIA	T2	N0	M0	3		50
Stage IIB	T3	N0	M0	Any		40
	T1-2	N1	M0	Any
Stage IIIA	T1-2	N2	M0	Any		25
	T3	N1	M0	Any
	T4a	N0	M0	Any
Stage IIIB	T3	N2	M0	Any		17
Stage IIIC	T4a	N1-2	M0	Any		14
	T4b	Any	M0	Any
	Any	N3	M0	Any
Stage IV	Any	Any	M1	Any		<5

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