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 adenomas⁹ or, more rarely, pancreatic or ovary-like serous cystadenomas.¹⁰

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.¹¹ 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.¹² A mixed inflammatory infiltrate may be present as well. Most of these tumors behave in a benign fashion,¹³ although rare carcinomas have been reported.¹⁴

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.¹⁵

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.¹⁶ In fact, of the 10 cases reported, 9 were associated with adenocarcinoma, illustrating their high malignant potential.¹⁶ 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.

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.^27–29 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.³⁰ 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.^27,29 Rarely, adenocarcinoma may develop in gastric heterotopia (see Fig. 24.6, B),^31,32 and an intraductal papillary mucinous neoplasm arising from a pancreatic heterotopia has been reported.³³

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.³⁴ 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.³⁵

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.³⁶ 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.

On occasion, this pseudoepitheliomatous reaction may be endoscopically visible and polypoid; some authors refer to these lesions as “hyperplastic” or “inflammatory” polyps.³⁷ 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.

Dysplastic epithelium appears erythematous, friable, and irregular in more than 80% of cases.⁵⁰ Erosions, plaques, and nodules may also be present. However, dysplasia may appear completely normal endoscopically. Mucosal staining with Lugol iodine may be helpful to highlight dysplastic mucosa and has been advocated as a means of improving the sensitivity of endoscopic biopsy surveillance in high-risk populations.⁵³ When available, enhanced endoscopic visualization techniques such as narrow-band imaging are also helpful in highlighting dysplastic mucosa that is otherwise grossly nondescript.⁵⁴ Dysplastic cells may also be harvested by exfoliative balloon cytology, a technique that is often used for screening in high-risk areas such as China (see Chapter 3).⁵⁵

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.⁵⁶ 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.^57,58

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.⁴⁹ 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.

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).⁵⁹ 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.⁶⁰ 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.⁶¹ 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.⁶² 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.⁶³

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.⁶⁰

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%.^39,64 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.^52,65

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).³⁹ 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.

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.⁶⁶

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.^67,68 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.⁶⁹

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.^70,71 CK7 reactivity is present in as much as 29% of cases, but most cases are negative for both CK7 and CK20.⁷² In addition, most tumors express the nuclear antigen TP63, similar to squamous cell carcinomas that arise in other sites of the human body.⁴⁹ 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.⁷³

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.⁷⁴

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).⁷⁵ 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.

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.⁷⁶

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.⁷⁷ 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).^64,78 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.^39,64 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.⁷⁹

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.^39,80,81 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).^81,82 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.^81,83 The presence of lymph node metastasis and a greater number of positive lymph nodes are also correlated with worse prognosis.⁸⁴ 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.⁸⁵ Some authors have also found that poor tumor differentiation is an independent prognostic factor,^80,86 and tumor differentiation as well as tumor location are now incorporated into the AJCC staging for this tumor type (see Table 24.3). Intramural metastases⁷⁷ and lymphovascular invasion⁸⁷ 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.

The mainstay of treatment for esophageal squamous cell carcinoma is surgical resection, most commonly transthoracic esophagectomy. As mentioned previously, early (intramucosal or submucosal) carcinomas in selected patients have been managed with endoscopic resection, with low rates of tumor recurrence or metastasis in specialized centers.⁶⁰ For those with more advanced but potentially resectable (stage II and III) tumors, neoadjuvant chemoradiotherapy followed by surgery induces tumor regression and improves survival in a subset of patients.^85,88

Pathologic Features

Grossly, basaloid squamous carcinomas are large, bulky, fungating tumors that frequently ulcerate and form strictures. They most commonly arise in the middle and distal esophagus.

Microscopically, the basaloid component comprises anywhere from 5% to 90% of the tumor and shows a variety of morphologies such as solid, cribriform, trabecular, and ductal growth patterns.⁸⁹ The characteristic basaloid tumor cells are oval to round, large, and somewhat pleomorphic with an open pale chromatin pattern, small nucleoli, and scant cytoplasm; cells are arranged in solid or cribriform lobules, often showing central necrosis and peripheral palisading (Fig. 24.14). Mitoses are usually easily identifiable. An in situ or invasive squamous cell carcinoma component is often present, at least focally. For example, in one study of 18 basaloid carcinomas, 72% of cases showed areas of squamous cell carcinoma, 50% of which also had in situ squamous cell carcinoma.⁹⁰ In addition, other lines of differentiation, including adenocarcinoma, small cell carcinoma, or even spindle cell carcinoma may coexist with the basaloid component.⁹¹ On the basis of these findings, basaloid carcinoma has been proposed to arise from a multipotential stem cell, or basal cell, in the native squamous epithelium.

Special Studies

A mucoid matrix that stains positive for periodic acid–Schiff (PAS) and Alcian blue may be present in the cribriform spaces of some tumor cell nests. By immunohistochemistry, basaloid carcinomas typically show weak staining for broad-spectrum keratins (in a membrane-type pattern) and for TP63 and absence of staining for the neuroendocrine markers neuron-specific enolase (NSE) and S100. The basal cells stain strongly for CK14 and CK19.^89,91–93 Some tumors show focal actin and vimentin positivity in the basaloid cells and carcinoembryonic antigen (CEA) positivity in the pseudoglandular spaces. At the molecular level, basaloid carcinomas are similar to conventional squamous cell carcinomas, particularly with regard to the frequency of alterations of cyclin D1, and the TP53 and retinoblastoma (RB) tumor suppressor genes.^91,94 However, these tumors are consistently negative for HPV.⁹¹

Differential Diagnosis

The differential diagnosis of basaloid carcinoma includes conventional (pure) squamous cell carcinoma, adenoid cystic carcinoma, and neuroendocrine carcinoma (NEC). Cases with a prominent basaloid mucoid matrix (Alcian blue positive, PAS positive) or extensive necrosis can adopt a pseudoacinar or cribriform pattern that may be mistaken for adenoid cystic carcinoma (see Fig. 24.14, D and E). This is an important distinction, because true adenoid cystic carcinomas of the esophagus are less aggressive than basaloid carcinomas (see Adenoid Cystic Carcinoma). Unlike basaloid carcinomas, adenoid cystic carcinomas form true epithelial lumina, do not coexist with conventional squamous cell carcinoma or squamous dysplasia, and lack significant pleomorphism, mitoses, and necrosis (see Fig. 24.25). The basal cells of adenoid cystic carcinoma are smaller and more hyperchromatic and regular in size compared with basaloid carcinoma, and they stain strongly for S100 and actin, whereas the basal cells of basaloid carcinoma are typically positive for CK14 and CK19.^92,93 In conventional squamous cell carcinomas, a significant proportion of tumor cells have eosinophilic cytoplasm, grow in irregular infiltrative clusters rather than in rounded nests, and show focal keratinization. However, the distinction between basaloid and squamous carcinoma may be arbitrary and of little prognostic value. The differential diagnosis of basaloid carcinoma, adenoid cystic carcinoma, and NEC is summarized in Table 24.4.

Differentiation of basaloid carcinoma from NEC is usually easily and best performed by immunohistochemical staining with chromogranin, synaptophysin, Leu-7, or CD56. Basaloid carcinomas may show focal and rare weak staining with endocrine markers, but this contrasts greatly with diffuse strong staining in most NECs. Although small cell carcinoma may show only weak or focal staining, these tumors are characterized by the presence of small hyperchromatic cells without nucleoli and with prominent nuclear molding. This contrasts with basaloid carcinomas, which have larger nuclei, lack molding, and have prominent nucleoli.

Prognosis

Basaloid squamous carcinoma is a highly aggressive tumor that carries a prognosis similar to that of pure squamous cell carcinoma. Although prognostic information is limited because of the relative rarity of this tumor type, the available studies show no difference in overall survival between these two tumor types.⁹⁰

Carcinosarcoma, also known as polypoid carcinoma, spindle cell carcinoma, and sarcomatoid carcinoma, was first described by Virchow in 1865; it represents approximately 2% of esophageal carcinomas. Similar to squamous cell carcinoma, it predominantly affects men (80%) in middle to late adult life (40 to 90 years).⁹⁵ Because of the typical exophytic intraluminal growth pattern of these tumors, presenting symptoms are commonly related to esophageal obstruction.

Pathologic Features

Grossly, these tumors may grow to large sizes (1 to 25 cm) and show a predilection for the middle and distal segments of the esophagus. Eighty percent of lesions are polypoid and have an exophytic growth pattern (Fig. 24.15), whereas only 10% of cases show an infiltrative growth pattern.

Microscopically, the tumor is characterized by a combination of epithelial and spindle cell (or other mesenchymal) elements (Fig. 24.16). The epithelial element is typically moderately to well-differentiated squamous cell carcinoma. In some cases, only in situ carcinoma is present.⁹⁵ In fact, some cases show only a small amount of the epithelial component, and this is usually either at the base of the polyp or at the periphery of the invasive tumor. The sarcomatous component is commonly a high-grade spindle cell sarcoma. However, osteosarcomatous, rhabdomyosarcomatous, or chondrosarcomatous differentiation may be present as well.

Immunohistochemically, the epithelial component is typically keratin positive, whereas the sarcomatous component usually stains with vimentin. However, keratin or vimentin may be seen occasionally in either component of the tumor.

By electron microscopy, a mixture of cell types has been identified, ranging from pure epithelial cells, to cells that show a combination of epithelial and sarcomatous features, to cells with pure sarcomatous differentiation.⁹⁶ It is these ultrastructural findings, combined with the histologic finding in most cases of areas of transition between epithelial and sarcomatous differentiation, that have led to the prevailing theory that these tumors are derived from diverse differentiation (metaplasia) of the carcinomatous element. In addition, molecular studies have found shared chromosome losses and mutations in both the carcinomatous and sarcomatous elements, with additional changes found only in the sarcomatous areas, further supporting this theory of histogenesis.⁹⁷ In another study of 20 cases, the sarcomatous and carcinomatous areas showed similar Ki67 proliferation indices.⁹⁸

Verrucous carcinoma of the esophagus is an extremely rare low-grade malignant neoplasm, first described in the oral cavity by Ackerman in 1948, with approximately 20 cases reported. Affected patients range from 36 to 76 years of age, and the disease has a male predilection. These tumors may grow very large before the onset of symptoms, with a resultant long delay in diagnosis. Presenting complaints are usually dysphagia, weight loss, coughing, and hematemesis. The pathogenesis has been related to various causes of chronic mucosal irritation such as caustic injury (lye), achalasia, lichen planus, diverticular disease, and GERD.^100,101 A circumstantial association with esophageal HPV infection was reported in one patient.¹⁰²

Pathologic Features

Pathologically, verrucous carcinomas have an exophytic papillary growth pattern and often occupy most, or even the entire, circumference of the esophageal lumen. These tumors show characteristic luminal stricturing and erosion, with necrotic and keratinaceous surface debris. Microscopically, the characteristic features are those of a very well-differentiated verrucoid, or papillomatous, proliferation of squamous cells with mild cytologic atypia, prominent acanthosis, hyperkeratosis, swollen rete pegs, and inflammation (Fig. 24.17). Invasion is usually difficult to assess because it is typically in the form of broad pushing margins. Classic tumors show a central “crater” of keratin with heaped up edges due to acanthotic squamous epithelium. Mitoses may be limited to the basal layers of the tumor or, rarely, scattered in the mid layers as well. Although the degree of cytologic atypia is considered “mild,” often the cells are larger in size than their benign counterparts and show enlarged nuclei with irregular nuclear contours, prominent nucleoli, and slight pleomorphism with loss of polarity. These features may extend several layers above the basal layer of the squamous epithelium. Furthermore, some areas of these tumors may show lack of surface maturation. A mild inflammatory response at the tumor–stroma interface is common.

Lymphoepithelioma-Like Carcinoma

A small number of esophageal carcinomas display an undifferentiated phenotype and are associated with a prominent lymphoid infiltrate, similar to lymphoepitheliomas of the nasopharynx. Most cases have been reported from Japan and have clinically resembled conventional squamous cell carcinomas.^66,106 These tumors are histologically identical to their counterpart in the nasopharynx, showing syncytia of primitive-appearing epithelioid cells surrounded by a dense inflammatory infiltrate including lymphocytes and plasma cells (Fig. 24.18). By analogy with the tumors in these other organs, Epstein-Barr virus has been suggested as an etiologic agent. However, the virus has been detected in only a minority of esophageal tumors by various methods, including in situ hybridization, immunohistochemistry, and DNA amplification.^107,108 Although the clinical behavior of these tumors is incompletely understood because of their rarity, some authors have suggested that they have a slightly better prognosis than ordinary squamous cell carcinomas.¹⁰⁶

Esophageal Carcinoma Cuniculatum

Carcinoma cuniculatum is an unusual, extremely well-differentiated variant of squamous cell carcinoma that has been reported in approximately 9 patients.¹⁰⁹ The tumor is more common in men (male-to-female ratio, 7 : 2), with a mean age of 57 years, who present with a distal esophageal mass (mean size, 4 cm). Grossly, this tumor type is notable for the presence of prominent surface furrows or sinuses (Fig. 24.19). Microscopically, the furrows correspond to keratin-filled cysts or cavities surrounded by acanthotic, hyperkeratotic squamous epithelium with only mild atypia. Squamous dysplasia was not identified in the surrounding mucosa in any of the published cases, and studies for HPV were consistently negative. None of the reported patients showed lymph node metastasis, and none died of disease after surgical resection. Distinction of this tumor type from verrucous carcinoma is difficult and may, in fact, be arbitrary. Indeed, some reported cases of verrucous carcinoma have histologic features that overlap with those of carcinoma cuniculatum.¹¹⁰ Both subtypes of squamous carcinoma are associated with an excellent prognosis if surgical resection is complete and successful.

Clinical Features

The incidence of adenocarcinoma of the esophagus has increased dramatically in the last two to 3 decades. This tumor now constitutes more than 50% of all esophageal carcinomas diagnosed in the United States, and it is the most common tumor in the distal esophagus.^1,2,38 In 2010, the overall incidence of esophageal adenocarcinoma in the United States was estimated at 2.5 per 100,000 population.¹¹¹

The demographic characteristics of patients with adenocarcinoma are similar to those of patients with BE. BE-associated adenocarcinoma affects predominantly older men (mean age, 60 years; male-to-female ratio, 3 : 1 to 7 : 1), and more than 80% of patients are white.^2,38,111 Depending on the size and location of the tumor, patients may present with dysphagia, odynophagia, or obstruction. Progressive dysphagia and weight loss are ominous signs that are usually associated with advanced disease.

Pathogenesis and Risk Factors

The most significant risk factor for adenocarcinoma is BE, currently defined in the United States by the presence of columnar epithelium (with goblet cells) anywhere in the tubular esophagus; BE develops in approximately 6% to 12% of patients with GERD.^112,113 Obesity, most likely through its association with GERD and BE, is associated with an approximately fourfold increased risk of developing adenocarcinoma compared with a normal body mass index.¹¹⁴ Tobacco use confers an elevated risk for developing adenocarcinoma both in the general population and in BE patients, although the magnitude of risk (approximately 1.5- to 2-fold) does not approach the levels observed for esophageal squamous cell carcinoma.¹¹⁵ No consistent association between alcohol use and adenocarcinoma has been found in recent epidemiologic studies.¹¹⁶

The overall prevalence of adenocarcinoma in patients with BE was estimated to be between 5% and 28% in early studies.¹¹⁷ However, many of the early studies of adenocarcinoma in patients with BE were retrospective and overestimated the magnitude of risk.¹¹⁸ More recent studies suggest that patients with BE have an approximately 11-fold increased risk for the development of adenocarcinoma compared with the general population.¹¹⁹ Indeed, only a small percentage of patients with BE (1% to 5%, or 0.1% to 0.5% per year) develop adenocarcinoma when followed prospectively.^120–126 Factors that increase the risk for adenocarcinoma include the presence, grade, and extent of dysplasia in BE^{120,123,127,128}; the presence of DNA aneuploidy in BE¹²⁷; greater lengths of BE^120,129; and the presence of a hiatus hernia.^129,130 As noted earlier, tobacco use also contributes to the risk of malignant progression in BE patients.¹¹⁵

Intestinal (Goblet Cell) versus Nonintestinal (Nongoblet) Columnar Metaplasia

One current area of controversy concerns the magnitude of risk for adenocarcinoma in patients with metaplastic esophageal columnar mucosa without intestinal metaplasia (goblet cells). Although intestinal (goblet cell) metaplasia has traditionally been used to define BE, biopsy specimens from columnar-lined esophageal segments may contain large areas devoid of goblet cells, and these nonintestinalized areas have been found to harbor genetic alterations associated with neoplastic progression.^131–133 A retrospective study of 712 BE patients found that the risk for adenocarcinoma was similar whether the index esophageal biopsy samples had glandular mucosa with intestinal metaplasia or nonintestinalized glandular mucosa (4.5% and 3.6%, respectively, after a 12-year follow-up period).¹³⁴ Furthermore, in a series of 141 BE-associated “early” adenocarcinomas, 57% occurred within nongoblet columnar mucosa.¹³⁵ Although additional population-based and preferably prospective studies are needed to more precisely define the relative importance of nonintestinal mucosa as a precursor to adenocarcinoma, current evidence suggests that this pathway accounts for a definite, albeit small, percentage of malignant esophageal tumors.

Molecular Features

The molecular genetic alterations that underlie the development of BE-associated adenocarcinoma have been the subject of extensive study.^48,136 Similar to most epithelial malignancies, esophageal adenocarcinomas show alterations in multiple genetic loci (genomic instability), which are acquired in a stepwise fashion during the progression of dysplasia to carcinoma. Among the most common are inactivation (through mutation or transcriptional silencing) of the tumor suppressor proteins p16, p27, p53 and of the adenomatous polyposis coli (APC) gene (75% to 92% of tumors) and overexpression or amplification of cyclin D1 (22% to 64% of cases).^137,138 Amplification of the genes for the growth factor receptor EGFR (13% to 30%), ERBB2/HER2 (15% to 25%), and MET (2%), although present in only a minority of adenocarcinomas, have significant therapeutic implications.^139–141 Downregulation of p16, mutation of p53, and upregulation of cyclin D1 are early abnormalities that occur even before the onset of morphologic dysplasia. For example, methylation, loss of heterozygosity (LOH), or mutations in p16 have been observed in as much as 80% of BE patients before the onset of dysplasia or carcinoma.¹³⁸

Widespread genomic instability is the molecular hallmark of progression to malignancy, and it is believed to be the cause, not the consequence, of carcinogenesis in BE.¹³⁶ Most, if not all, chromosomes are affected in this process, either by increased number or by alteration of content (e.g., additions, deletions). In fact, alterations in DNA content (aneuploidy) in nondysplastic BE is a strong predictor of progression to high-grade dysplasia and adenocarcinoma.^127,142 By contrast, DNA mismatch repair defects resulting in microsatellite instability occur infrequently (5% to 10%) in BE-associated adenocarcinomas.¹⁴³ Abnormalities in DNA content can be measured in a variety of ways, including fluorescence in situ hybridization (FISH), chromosomal karyotyping, comparative genomic hybridization, flow cytometry, and, more recently, image cytometry. Some of these techniques are currently being investigated and have been proposed as potentially providing prognostic markers in BE patients.^{127,130,133,142} However, at present, no specific biomarkers or biomarker panel has been recommended for routine clinical use to help manage BE by potentially altering the frequency of surveillance endoscopies.¹⁴⁴

BE-associated adenocarcinomas are located almost exclusively in the distal third of the esophagus in areas of involvement with BE. Distal tumors frequently show extension into the proximal stomach. They may be classified as polypoid (protruding) (5% to 10%), flat (10% to 15%), fungating (20% to 25%), or infiltrative (40% to 50%) (Fig. 24.20, A and B).^39,145 Early carcinomas may be undetectable or may appear only as slightly irregular, depressed or elevated lesions.¹⁴⁶ Diffusely infiltrative tumors are uncommon. Large tumors may obliterate the underlying or adjacent Barrett’s mucosa, particularly those that arise in the distal esophagus at or near the level of the GEJ. In such instances, it may occasionally be difficult to determine whether an adenocarcinoma located near or at the GEJ is, in fact, esophageal (BE-related) or gastric in origin. Also, patients who have been treated with preoperative chemotherapy or radiation therapy may have little or no gross residual tumor left in their resection specimen. In fact, as much as 50% of patients treated with neoadjuvant therapy show either no, or only minimal, microscopic residual tumor after surgery.^147,148

Microscopic Pathology

These tumors, like squamous cell carcinomas, typically spread vertically through the esophageal wall and metastasize to regional lymph nodes. Adenocarcinomas are graded as well, moderately, or poorly differentiated. The AJCC grading system classifies tumors by the proportion of tumor that is composed of glands.⁸¹ However, most tumors are moderately or well differentiated.^39,145 Some tumors show variations in grade within the same tumor, and the highest grade is usually recorded for prognostic purposes.

Well-differentiated carcinomas (i.e., >95% of tumor composed of glands) are made almost entirely of irregularly shaped or cystic glandular and tubular profiles that infiltrate the mucosa, submucosa, and muscularis (see Fig. 24.20, C). The tumor cells are cuboidal to columnar in shape and contain irregular nuclei with coarse or vesicular chromatin, prominent nucleoli, and a variable amount of eosinophilic or clear cytoplasm. In moderately differentiated carcinomas (50% to 95% of tumor composed of glands), tumor cells are arranged in solid nests and irregular clusters as well as glands (see Fig. 24.20, D). In these tumors, the cells within the glandular profiles may adopt a cribriform pattern and show considerable stratification. Poorly differentiated carcinomas (5% to 49% of tumor composed of glands) often infiltrate the esophageal wall in a diffuse manner and usually with a prominent desmoplastic stroma. The tumor cells are arranged in sheets and in poorly formed glandular lumina; signet ring cells and bizarre pleomorphic tumor cells may be present. Interestingly, a subset of poorly differentiated adenocarcinomas involve the surface squamous epithelium in the form of single cells that grow in a pagetoid fashion.⁵⁸ Other intestinal cell types, such as Paneth cells and endocrine cells,¹⁴⁹ are present focally in as much as 20% of adenocarcinomas.

Approximately 5% to 10% of adenocarcinomas contain areas of mucinous (colloid) histology, characterized by tumor cell clusters floating in pools of mucin. Another 5% contain areas of infiltrating signet ring cells (see Fig. 24.20, E), and occasional cases show clear cell morphology (see Fig. 24.20, F).^145,150 Occasional tumors may show multidirectional differentiation, with coincident areas of glandular, squamous, or neuroendocrine differentiation (see later discussion).

In patients treated with preoperative chemoradiotherapy, residual tumor cells may be present merely as individual cells or as small, isolated clusters of cells, in association with ulceration, dense fibrosis, or pools of mucin.^147,148 These cells are frequently pleomorphic, showing extreme nuclear irregularity and enlargement; on occasion, they may be difficult to distinguish from reactive mesenchymal cells. Immunohistochemistry for keratins often helps in this situation, being generally positive in the tumor cells and negative in the mesenchymal cells. Clusters of residual keratin-positive endocrine cells may be present in the deep lamina propria of treated areas, but these should not be mistaken for residual carcinoma.¹⁵¹ Sometimes, the only sign of a treated tumor is acellular pools of mucin dissecting through the layers of the esophageal wall (Fig. 24.21). However, acellular mucin pools do not result in an increased risk of recurrence or metastasis.¹⁴⁵

Differential Diagnosis

Most of the difficulties related to diagnosing adenocarcinomas occur in the evaluation of endoscopic biopsy specimens, in which the distinction between high-grade dysplasia and intramucosal or invasive carcinoma may be uncertain. Architectural features such as single cell infiltration of the lamina propria, sharply angulated glands, small glands in a back-to-back pattern, confluent glands or a sheetlike growth pattern, and glandular intraluminal necrosis support a diagnosis of adenocarcinoma (Fig. 24.22).¹⁵⁵ It is not uncommon for dysplastic glands to be situated within the fibers of the muscularis mucosae, which in BE is often duplicated and fragmented. This finding should not be overinterpreted as representing “invasive” tumor unless other features mentioned earlier are also present.

For patients treated with preoperative chemoradiotherapy, cytokeratin immunostaining may be necessary to distinguish rare residual tumor cells from mesenchymal cells with treatment effect.

In some patients, it may be necessary to exclude the possibility of metastasis or spread to the esophagus from another primary site such as the stomach, lung, or breast. The presence of BE and dysplastic epithelium adjacent to the carcinoma is normally considered convincing evidence that the tumor has arisen from the esophagus. In addition, primary esophageal adenocarcinomas do not stain for TTF-1 or estrogen receptor,¹⁵⁶ markers of lung and breast tumors, respectively.

Distinguishing an esophageal adenocarcinoma from a proximal gastric tumor can be difficult, particularly if the tumor has obliterated adjacent or underlying Barrett’s epithelium (see Table 24.6). Distal gastric adenocarcinomas often arise in a background of intestinal metaplasia of the gastric mucosa and are positive for CK20 in as many as 90% of cases, compared with esophageal adenocarcinomas, which less commonly stain for this antigen.^152,156,157 However, esophageal and gastric cardia adenocarcinomas have very similar CK7 and CK20 staining patterns in most studies, which makes distinction of these tumors difficult on the basis of immunohistochemistry alone.^158,159 In some investigators’ view, differentiation between esophageal and GEJ or cardia adenocarcinomas has no epidemiologic or biologic basis, and all tumors that arise in this region should be considered “esophageal” adenocarcinomas secondary to GERD.¹⁶⁰ However, recent evidence indicates that a subset of GEJ carcinomas arise in a background of nonintestinalized gastric mucosa and may reflect a different carcinogenesis pathway that is less highly associated with GERD.^135,161 Additional study is needed to determine whether GEJ carcinomas of this type should be regarded as a separate biological entity with a natural history distinct from BE-associated adenocarcinomas.

Adenoid Cystic Carcinoma

True adenoid cystic carcinomas of the esophagus are extremely rare.¹⁸⁶ They are histologically and immunophenotypically identical to the salivary gland type of adenoid cystic carcinoma. Most of the cases previously termed “adenoid cystic carcinoma” were most likely basaloid squamous carcinomas with adenoid cystic carcinoma–like features.⁹³ True adenoid cystic carcinomas are more common in women, are typically present in middle age, and show no histologic association with squamous cell carcinoma (i.e., are derived from the submucosal glands).

Grossly, these tumors form well-circumscribed, solid nodules in the submucosa. Adenoid cystic carcinoma is composed of two distinct populations of cells: ductal epithelium and basaloid cells. The basaloid cells are small and hyperchromatic, show no or only minimal pleomorphism, and demonstrate infrequent mitoses and no necrosis (Fig. 24.25). The ductal cells form solid nests or cribriform spaces, often associated with abundant basement membrane material. The overlying squamous epithelium does not exhibit dysplasia. Immunohistochemically, adenoid cystic carcinomas show strong keratin and CEA staining in the ductal-type epithelium and weak keratin plus strong S100, actin, and vimentin positivity in the basaloid cells.^92,94 The principal diagnostic challenge is to differentiate adenoid cystic carcinoma from basaloid squamous carcinoma, as discussed earlier (see Table 24.4).

So few true adenoid cystic carcinomas have been reported that clinical follow-up data are scarce. However, these tumors seem to have a better prognosis than typical squamous or basaloid carcinomas. They are slow-growing tumors that rarely metastasize and therefore are associated with excellent overall survival.¹⁸⁷

Well-Differentiated Neuroendocrine Tumor (Grades 1 and 2)

Well-differentiated neuroendocrine tumors (also termed carcinoid tumors) of the esophagus are extremely rare and have been reported either as isolated polypoid tumors or as incidental findings in esophagectomies for adenocarcinoma.¹⁹⁷ They are histologically similar to those that occur in other parts of the gastrointestinal tract. Although they have not been well studied because of their rarity, all reported examples appear to have behaved in a relatively benign fashion (see Chapter 29 for additional discussion). Grade 2 esophageal neuroendocrine tumors are poorly defined in the literature because of varying nomenclature and histologic criteria; therefore, their behavior is poorly understood, but it probably lies intermediate between well differentiated (grade 1) lesions and poorly differentiated tumors. Indeed, many tumors referred to in prior case reports as “carcinoids” probably represent poorly differentiated NECs.

Large Cell Neuroendocrine Carcinoma (Grade 3)

Overall, esophageal NECs are more common than low-grade neuroendocrine tumors, but they still account for only approximately 1% of all esophageal malignant neoplasms.³⁹ Approximately 70% of NECs are of the large cell type. These tumors arise most commonly in the distal esophagus of elderly patients (mean age, 61 years), with a strong (8 : 1) male predilection.⁷³ Patients are seen with symptoms of dysphagia or obstruction. The tumor comprises cells with a moderate amount of cytoplasm, conspicuous nucleoli, and coarse chromatin, growing in nests and acinar structures with focal necrosis (Fig 24.27, A through C). These tumors were sometimes referred to as “atypical carcinoid” or “malignant carcinoid” in the older literature.¹⁹⁸ They may be confused with poorly differentiated squamous cell carcinoma or adenocarcinoma. However, these two latter tumor types should be negative, or show only focal immunoreactivity, for neuroendocrine immunomarkers.

Small Cell Neuroendocrine Carcinoma (Grade 3)

NECs of the small cell type are more frequently encountered in Asian patients and are most common in middle-aged to older adults (median age, 60 years; range, 40 to 90 years), with a slight (2 : 1) male predilection.^199,200 Grossly, the tumors usually form large exophytic or polypoid masses and arise in the middle or distal third of the esophagus. Similar to the large cell type, they have a high nuclear grade, with a high proliferative rate (>20% Ki67 labeling index) and/or a high mitotic rate (>20 per 10 high-power fields).³⁹ In small cell carcinomas, the tumor cells are small to intermediate in size, with scant cytoplasm, irregular hyperchromatic nuclei with molding, absent nucleoli, and frequent single-cell necrosis (see Fig. 24.27, D). Reactivity for neuroendocrine markers, such as chromogranin or synaptophysin, is usually present. Approximately 10% to 20% of reported cases of small cell carcinoma reveal admixed areas of squamous cell carcinoma or, less commonly, adenocarcinoma (see later discussion). The differential diagnosis includes metastasis or spread of tumor from other anatomic sites (e.g., lung). Immunostains are of limited utility in this distinction, because TTF-1 (a marker of pulmonary epithelial differentiation) is positive in as much as 71% of esophageal small cell carcinomas.²⁰⁰

Mixed Adenocarcinoma/Neuroendocrine Carcinoma (Grade 3)

As discussed earlier, some esophageal malignancies reveal multiple cell lineages. A mixture of adenocarcinoma and NEC is an example of this phenomenon, which is defined as a tumor that contains at least 30% of each cellular component.³⁹ For instance, in one study of 40 esophageal NECs, 15 tumors (12 large cell, 3 small cell) also contained distinct areas of glandular differentiation.⁷³ Because of the occurrence of mixed tumors, a finding of NEC in an esophageal biopsy does not necessarily exclude the possibility of another malignant cell lineage, which may be diagnosed only on further sampling or after analysis of a resection.

Esophageal neuroendocrine neoplasms likely arise from a multipotential cell in the squamous epithelium. However, another theory is that these tumors arise from neuroendocrine (or Merkel) cells in the squamous epithelium, which are present in a high proportion of the general population.²⁰¹

Overall, esophageal NECs are highly aggressive neoplasms. Median survival time is typically 12 to 24 months and is slightly less for patients with pure NECs compared with those with an admixed non-neuroendocrine compoent.^73,199,200