Tumors of the Esophagus

Clinical Features

These are uncommon, incidental findings at endoscopy that usually occur in women in the fifth decade of life. The vast majority are solitary; some may present as a papillomatosis. They are thought to be a reactive proliferation secondary to gastroesophageal reflux disease (GERD). In the Western population, most lesions arise in the distal esophagus, whereas mid-esophagus is the most common site of involvement reported in Japan.

Pathologic Features

Microscopic Findings

These lesions are composed of bland polypoid squamous mucosa with fibrovascular cores ( Fig. 2.1 ). Exceptional cases may display viral cytopathic effect, and these appear to be more prevalent in the upper esophagus.

Ancillary Studies

Immunohistochemistry

The majority of squamous papilloma are negative for human papillomavirus (HPV) by both immunohistochemistry and in situ hybridization. A subset of patients with HPV-associated laryngeal papillomatosis are reported to also have concurrent HPV-related squamous papillomatosis of the esophagus ( Fig. 2.2 ).

Differential Diagnosis

The differential diagnosis includes squamous dysplasia, but squamous papillomas show no epithelial atypia, and the diagnosis is usually straightforward.

Prognosis and Therapy

Squamous papillomas have no risk of recurrence or malignant transformation.

Clinical Features

Fibrovascular polyps are extremely rare submucosal tumors of the esophagus that have been variably classified as lipomas, fibromas , and fibrolipomatous polyps . Most patients described in literature are middle-aged or older men, although children, infants, and women may also be affected. Presenting complaints include dysphagia, substernal discomfort, and sensation of a mass. Recent data suggest these lesions are almost universally positive for MDM2 and CDK4 and show MDM2 amplification on fluorescence in situ hybridization, suggesting that the so-called “giant fibrovascular polyp” is actually a unique macroscopic appearance of atypical lipomatous tumor involving the esophagus.

Pathologic Features

Microscopic Findings

The lesions are composed of variable amount of mature adipose tissue, often separated by thick fibrous bands or sometimes a myxoid stroma and prominent vasculature, all surrounded by mature squamous epithelium ( Fig. 2.3A ). Scattered, large, atypical cells with hyperchromatic nuclei and classic atypical multivacuolated lipoblasts may also be seen ( Fig. 2.3B ). Rarely, dedifferentiated foci may also occur, similar to atypical lipomatous tumors of soft tissue.

Immunohistochemistry

MDM2 and CDK4 show positive staining in the adipocytic component and the atypical stromal cells in almost all cases.

Molecular Findings

Fluorescence in situ hybridization shows MDM2 amplification and ring chromosome involving chromosome 12q have been described in these lesions, similar to atypical lipomatous tumors of somatic soft tissue.

Differential Diagnosis

The main differential diagnosis is secondary esophageal involvement of the esophagus by contiguous extension of a primary mediastinal liposarcoma. The latter typically presents as a large mural mass while primary esophageal atypical lipomatous tumors presents as a slender elongated polyp with a narrow base. Inflammatory polyps of the esophagus usually occur in the distal third and show a fibromuscular stroma without an adipocytic component. The diagnosis of a “giant fibrovascular polyp” should not be made unless careful microscopic evaluation and ancillary work-up have completely excluded the possibility of an atypical lipomatous tumor.

Prognosis and Therapy

Complete excision is curative in most cases, although local recurrences have also been described. Excision can be accomplished by endoscopic ligation or surgical excision when the base of the lesion is poorly visualized by endoscopy. Metastasis has not yet been reported from these lesions.

Clinical Features

Barrett’s esophagus (BE) arises as a complication of chronic GERD. Its incidence is rising in the Western Hemisphere and parallels the increase in esophageal adenocarcinoma. Other risk factors for BE include male sex, white race, advanced age, and truncal obesity; cigarette smoking is a minor contributor. The presence of Barrett’s mucosa in the esophagus does not cause symptoms, which makes it hard to screen the population for this precursor lesion of significant clinical consequence. The major importance of BE is the marked predisposition it confers on patients for subsequent development of esophageal adenocarcinoma through inflammation to metaplasia to dysplasia to adenocarcinoma sequence. However, most patients with esophageal adenocarcinoma present with cancer and do not carry a prior diagnosis of BE. Periodic surveillance and biopsy for early detection of neoplasia is the current standard of care for BE patients, but only a small minority of those under surveillance develop adenocarcinoma.

The 2011 American Gastroenterology Association (AGA) guidelines defined BE as intestinal-type metaplastic epithelium that replaces stratified squamous mucosa in the esophagus and predisposes to cancer development, requiring both endoscopic evidence of columnar metaplasia and histologic demonstration of goblet cells. However, in Japan and much of Europe and the United Kingdom, goblet cells are not required to diagnose BE. The term columnar lined esophagus is used instead of BE, emphasizing the endoscopic rather than histologic definition of the entity. The requirement for goblet cells is still used in the United States because population-based studies have shown a much higher risk of esophageal adenocarcinoma in patients with intestinal metaplasia than in those without intestinal metaplasia. Including patients without goblet cells into the periodic surveillance pool has major implications for cost of care and cannot be justified unless the risk in nongoblet metaplastic columnar epithelium is shown to be significant and comparable to those with goblet cells in longitudinal outcome studies. Detection of goblet cells is susceptible to sampling error. At least eight random biopsies or four biopsies per centimeter of columnar epithelium are recommended to obtain the maximum yield of intestinal metaplasia on histologic examination. According to the recently published 2016 American College of Gastroenterology guidelines, BE should only be diagnosed if there is extension of metaplastic columnar epithelium 1 cm or greater proximal to the GEJ. This change was recommended because patients with less than 1 cm of metaplastic columnar epithelium have a very low risk of esophageal adenocarcinoma in long-term follow-up studies, which does not justify routine surveillance. However, the AGA criteria do not have a length requirement and only require definite columnar mucosa lining the distal esophagus with intestinal metaplasia detected on biopsies from this segment.

Pathologic Features

Gross Findings

Barrett’s esophagus appears as tongues and patches of red salmon-colored mucosa that extend up from the gastroesophageal junction (GEJ) for variable distance into the tubular esophagus and contrasts with the pearly gray-pink color of the normal squamous epithelium ( Figs. 2.4 and 2.5 ). Traditionally, short-segment BE is defined as less than 3 cm of metaplastic columnar epithelium, and long-segment BE is defined as greater than 3 cm of metaplastic columnar epithelium. This distinction is important because although short-segment BE is more common, it is less likely than long-segment BE to give rise to esophageal adenocarcinoma.

Microscopic Findings

A majority of patients with BE have a concurrent hiatal hernia, and biopsies from the columnar segment in the distal esophagus may show a cardia- or oxyntocardiac-type glandular epithelium or an intestinalized epithelium with goblet cells. Goblet cells are readily identifiable on hematoxylin and eosin–stained slides, and ancillary stains are unnecessary ( Fig. 2.6 ). Typically, these goblet cells are admixed with gastric-type lining cells, and this type of metaplasia is termed incomplete . Multilayered epithelium is a hybrid epithelium consisting of mucin-containing glandular cells and basally located squamous cells, frequently seen in patients with GERD and may be a precursor of BE ( Fig. 2.7 ). Its presence is not routinely reported in GEJ or esophageal biopsies, and it should not be considered to represent BE. The metaplastic intestinalized mucosa often lays down a new muscularis mucosae, resulting in two distinct layers: a delicate, frayed, superficial layer and a deep, thick, compact, native muscularis mucosae. The latter can be mistaken for muscularis propria because of its thickness.

Differential Diagnosis

The differential diagnosis of BE includes gastric carditis with intestinal metaplasia (CIM), seen in approximately 30% of patients with an abnormal squamocolumnar junction. CIM is most often associated with Helicobacter pylori infection and has a lower incidence of dysplasia compared with BE. Autoimmune gastritis may also cause CIM and should be considered in the differential diagnosis when only GEJ biopsies are available. Certain histologic features have been described to help distinguish BE from CIM. These include metaplastic crypts buried underneath squamous mucosa, hybrid glands consisting of cardia-type and intestinalized glands, and esophageal glands and ducts. The presence of esophageal glands or ducts adjacent to foci of intestinal metaplasia is diagnostic of BE ( Fig. 2.8 ); other features are suggestive but not definitive.

Grading Dysplasia in Barrett’s Esophagus

Surveillance biopsies from patients with BE are classified as negative for dysplasia, indefinite for dysplasia (IND), low-grade dysplasia (LGD), and high-grade dysplasia (HGD) ( Table 2.1 ). Histologic features that are helpful in evaluation of BE biopsies include the presence of architectural complexity, cytologic atypia involving the surface epithelium, and the presence of lamina propria inflammation, erosions, or ulcers. Surface maturation is key to diagnosis of nondysplastic BE. The proliferating nuclei in the basal part of the intestinalized crypts are larger, more hyperchromatic, and more stratified than those at the surface, which are generally arranged in a monolayer with polarized basal nuclei. Architectural abnormalities include gland crowding, crypt branching and budding, and villiform change. Cytologic features of dysplasia include nuclear enlargement and hyperchromasia, irregular nuclear contours, coarse chromatin with prominent nucleoli, and loss of polarity. In “normal polarity,” the long axis of the nucleus remains perpendicular to the basement membrane and the nuclei are aligned parallel one to another, whereas “loss of nuclear polarity” refers to loss of this perpendicular and parallel orientation. Inflammation with consequent reparative changes can impart worrisome cytologic alterations that can be mistaken for dysplasia. An abrupt morphologic change from adjacent mucosa favors a diagnosis of dysplasia.

Barrett’s Esophagus, Negative for Dysplasia

In BE without dysplasia, the glands tend to be straight with smooth contours, crypt budding or branching is minimal, and abundant lamina propria is present between glands. The cytologic atypia, if any, is confined to the basal aspect of the crypts, while the surface epithelium shows maturation with small basally located nuclei and abundant cytoplasm ( Fig. 2.9 ). Mitoses may be present but are localized to the basal crypt epithelium. Nuclei have smooth nuclear membranes with fine chromatin and inconspicuous nucleoli. In the setting of reactive changes, epithelial cells in the zone of inflammation may display nuclear enlargement, and nucleoli may become more prominent, but nuclear contours are generally smooth with a vesicular chromatin, small nucleoli and the overall nuclear-to-cytoplasmic ratio is preserved. There may be loss of cytoplasmic mucin, but surface maturation is preserved.