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Fibrovascular polyps of the esophagus
Clinical features
These lesions may not be truly neoplastic but are included here as tumefactions that are occasionally encountered in clinical practice. Fibrovascular polyps are extremely rare submucosal tumors of the esophagus that have been variably classified as “lipomas,” “fibromas,” and “fibrolipomatous” polyps. There is only one such case in the “in-house” surgical pathology files at The Johns Hopkins Hospital between the years 1984 and 2009. Indeed, although the dramatic presentation of these polyps has resulted in about 50 (including hypopharyngeal cases) individual patients reported in the English-language literature between 1969 and the present, only a single case-series of 16 fibrovascular polyps has been compiled: from cases seen at the Armed Forces Institute of Pathology (AFIP).
Most patients with esophageal fibrovascular polyps are middle-aged or older men, although children, infants, and women are rarely affected. In all age-groups, common presenting complaints include dysphagia, substernal discomfort, and sensation of a mass. In the series of Levine and colleagues, all 16 patients with giant fibrovascular polyps were symptomatic; dysphagia was the most common complaint (present in 87%), followed by respiratory symptoms (25%) and regurgitation of the polyp into the pharynx or mouth (12%). Although that series did not show examples of asphyxiation, this is a feared complication that can result in sudden death from impingement of the mass on the larynx. The patient who was seen at our hospital had intermittent airway obstruction that occurred during episodes of vomiting and caused syncope.
The duration of symptoms from giant esophageal polyps has varied greatly among the reported cases. In the AFIP series of Levine and colleagues, the mean duration of symptoms was 17 months, and only 44% of the patients reported symptoms for 6 months or less. However, as noted, some patients present emergently and others have had symptoms for 2 months or less.
Most clinically recognized fibrovascular polyps of the esophagus merit the term “giant” when discussed in clinical reports. Lesions reaching 17 and 25 cm in length have been reported. They usually arise in the cervical esophagus, near the region of the cricopharyngeal muscle, which accounts for their tendency to prolapse into the mouth and their ability to impinge on the larynx. The characteristically elongated architecture of these polyps is believed to result from traction created during peristalsis and swallowing.
Definition
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Submucosal-based tumors of the esophagus composed of an admixture of adipose tissue, vessels, and fibrous connective tissue
Incidence and location
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Very rare; arise anywhere in the esophagus
Morbidity and mortality
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May cause morbidity and rare mortality based on obstruction of the esophagus or aspiration, but they are not malignant.
Gender, race, and age distribution
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Male predominance
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No known racial predilection
Clinical features
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Present with dysphagia, mass sensation, and retrosternal discomfort
Radiologic features
Chest radiographs reveal a right-sided superior mediastinal mass and anterior tracheal bowing, or both. Barium studies show smooth but variably lobulated intraluminal masses that originate in the lower cervical esophagus, with variable sizes and distal extents, and an average length of about 15 cm. Depending on the amount of fat and fibrovascular tissue in the lesion, computed tomography reveals a heterogeneous appearance in most cases, with some lesions consisting of predominantly fat density and other of predominantly soft tissue density.
Pathologic features
Gross findings
On gross examination, these are sausage-like pedunculated polyps arising from the wall of the esophagus. Their surface is covered by squamous mucosa, and their cores consist of an admixture of grossly identifiable adipose tissue and firm whitish connective tissue.
Microscopic findings
Fibrovascular polyps are histologically uniform lesions composed of variable admixtures of mature adipose tissue lobules, collagenous and sometimes myxoid tissue, and prominent vasculature, all surrounded by mature squamous epithelium ( Figs. 2-1 and 2-2 ).
Differential diagnosis
The appearance of these lesions is relatively unique. Some examples display degenerative atypia in zones of adipose tissue, which may raise the possibility of a well-differentiated liposarcoma, but the latter tumor type is even more rare in the esophagus. However, there are occasional cases that can be diagnosed as such ( Figs. 2-3 through 2-5 ).
Prognosis and therapy
Despite their often dramatic clinical presentation and their potential for morbidity and even sudden death, giant fibrovascular polyps of the esophagus should be recognized as uniformly benign lesions; local excision is curative. Depending on their size and the estimated risk of airway impingement, a variety of methods can be employed for resection. If the stalk can be visualized endoscopically, endoscopic ligation can be performed. Endoscopic polypectomy is the ideal management. However, in many other cases, surgical excision is required because of poor visualization, the site of attachment of the stalk, or impending respiratory compromise.
Although there are rare instances of recurrence, metastasis has never been reported from these lesions. Secondary tumors such as squamous cell carcinoma arising within a fibrovascular polyp are exceptional.
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Squamous papillomas
Clinical features
These are uncommon lesions that are usually incidental findings at endoscopy. They usually occur in adults (rare examples are reported in children) and most (85%) are solitary, although some patients have multiple papillomas. They are usually found in the distal esophagus. In Western populations, their presence is associated with reflux disease but this may be coincidental. In the United States, most lesions arise in the distal esophagus, whereas in Japan, they are more likely to arise in the midesophagus.
Definition
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Small, usually incidental nodules of the esophagus composed of proliferated squamous epithelium
Incidence and location
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Uncommon (estimated, 0.01% to 0.4%) and usually found in the distal esophagus
Morbidity and mortality
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Essentially none except in rare examples that are associated with laryngeal papillomatosis, which may result in obstruction based on being numerous and uncontrollable
Gender, race, and age distribution
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Sporadic small papillomas are more common in women, usually whites, with a wide age range, but most often in women in their early 40s
Clinical features
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Incidental finding at endoscopy
Pathologic features
Gross findings
Squamous papillomas are grossly seen as tiny polyps at endoscopy. Mucosal biopsy samples appear as small whitish nodules.
Microscopic findings
These lesions are simply composed of bland polypoid squamous mucosa with fibrovascular cores ( Fig. 2-6 ). Exceptional cases display viral cytopathic effects ( Figs. 2-7 and 2-8 ).
Gross findings
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Small nodule seen at endoscopy
Microscopic findings
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Small nodular squamous proliferation aligned in papillary configuration with fibrovascular cores and squamous coating
Immunohistochemistry
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Immunohistochemical, polymerase chain reaction, and in situ hybridization studies for HPV are negative in most series but occasional positive cases are reported
Differential diagnosis
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Readily separated from squamous cell carcinoma in most cases on the basis of extremely bland cytology
Ancillary studies
Immunohistochemistry
Because the appearance of these polyps has led to the concern that they are related to human papillomavirus (HPV), several studies have evaluated the presence of HPV in these lesions by both immunohistochemistry and in situ hybridization. The results have been negative in most cases, although a subset (<10%) appears to be associated with HPV. However, a subset of patients with HPV-associated laryngeal papillomatosis has HPV-related squamous papillomas of the esophagus, and occasional esophageal examples have been reported unassociated with laryngeal lesions.
Differential diagnosis
The diagnosis is seldom a problem. Theoretically the differential diagnosis includes squamous epithelial dysplasia/intraepithelial neoplasia, but in practice the features of these lesions are so bland that there is no difficulty in distinguishing between diagnoses.
Prognosis and therapy
Squamous papillomas of the esophagus do not appear to “degenerate” into esophageal malignancies (or if they do it is a very rare event), and no dysplasia is seen histologically. Evidence of recurrence is unusual, but synchronous or metachronous carcinomas of the ororespiratory tract have been described. Many reports suggest a role for mucosal injury and regeneration in the pathogenesis of these lesions. The association with other malignancies may be significant.
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Barrett’s esophagus, “goblet cells at the gastroesophageal junction,” dysplasia in barrett’s esophagus
Clinical features
The prototype patient with Barrett’s esophagus is a 55-year-old white man who is overweight and has long-term symptomatic gastroesophageal (GE) reflux disease. He is less likely than controls to have Helicobacter pylori gastritis. Barrett’s esophagus is distinctly uncommon in African Americans.
The presence of Barrett’s mucosa in the esophagus does not in and of itself cause symptoms beyond the symptoms caused by the associated gastroesophageal reflux. The major importance of Barrett’s esophagus lies in its status as a preneoplastic condition that predisposes to the development of esophageal adenocarcinoma. There is a well-defined metaplasia-dysplasia-adenocarcinoma sequence in Barrett’s esophagus. From a histologic standpoint, dysplasia is recognized when there is abnormal hyperchromatism, enlargement, crowding, and stratification of nuclei of the columnar-lining cells; dysplasia is categorized as low-grade and high-grade. Dysplastic Barrett’s mucosa does not appear any different from nondysplastic Barrett mucosa on routine endoscopy, and the condition is defined histologically.
The pathogenesis of Barrett’s esophagus is not clear. It is associated with chronic, severe reflux in most cases. It is unlikely that squamous epithelium directly undergoes metaplasia into columnar epithelium. Rather, it is considered more likely that destruction of the squamous epithelium first occurs from injury by acid or alkaline gastroesophageal reflux, followed by re-epithelialization by columnar epithelium, perhaps first with a hybrid-type epithelium that some have termed multilayered epithelium ( Fig. 2-9 ). It is possible that the acid component sets up initial erosions and that the alkaline component may inform the reparative process (epidemiologically, bile is a carcinogen).
Definition
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A change of any length that is found in the esophagus and is shown to have intestinal metaplasia on biopsy (US definition). In Japan and the United Kingdom, intestinal metaplasia is not required.
Incidence and location
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Common; found in 5% to 8% of individuals with gastroesophageal reflux disease.
Morbidity and mortality
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Barrett’s esophagus in and of itself does not result in mortality but is a strong risk factor for esophageal adenocarcinoma, with an estimated annual rate of transformation of approximately 0.5%.
Gender, race, and age distribution
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Strong white male predominance with median age in the early 50s.
Clinical features
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Symptomatic reflux usually leads to biopsy, but the Barrett’s esophagus itself is asymptomatic; in fact, once metaplasia occurs, reflux symptoms are said to decrease.
Radiologic features
There are no specific features of Barrett’s esophagus, but the presence of a hiatal hernia on imaging studies is a clue, because this condition is a risk factor.
Pathologic features
Gross findings
During the endoscopic procedure, Barrett’s mucosa appears as tongues and patches of reddish salmon-colored mucosa (in contrast to the normal pearly gray-pink color of the squamous epithelium) that extend from the GE junction for varying distances up into the tubular esophagus. Short-segment Barrett’s esophagus is defined as less than 3 cm of metaplastic columnar epithelium ( Fig. 2-10 ), and long-segment Barrett’s esophagus is defined as greater than 3 cm of metaplastic columnar epithelium ( Fig. 2-11 ). This distinction is important because, although short-segment Barrett’s esophagus is more common, it is less likely than long-segment Barrett’s esophagus to give rise to esophageal adenocarcinoma.
Microscopic findings
Barrett’s esophagus is defined as the replacement of the normal squamous epithelial lining of the tubular esophagus by columnar epithelium. In the past, this metaplastic columnar mucosa was classified as one of three types: (1) cardiac-type mucosa, (2) oxyntic-type mucosa, and (3) distinctive-type mucosa (also called specialized Barrett’s mucosa ). Distinctive-type mucosa is columnar mucosa that contains goblet cells (normally present only in the small bowel and colon); typically these goblet cells are admixed with gastric-type lining cells, and this type of metaplasia is termed incomplete ( Figs. 2-12 and 2-13 ). Distinctive-type Barrett mucosa is the most important of these three types; in fact, in current practice, Barrett’s esophagus is equated with the presence of distinctive-type mucosa in conjunction with endoscopic findings of Barrett’s in the United States and Germany. However, in Japan and much of Europe and the United Kingdom, goblet cells are not required to diagnose Barrett’s esophagus and it is thus an endoscopic rather than histologic diagnosis. The U.S. and German requirement for goblet cells is based on the assumption that patients with distinctive-type Barrett’s esophagus are most susceptible to development of dysplasia and adenocarcinoma. However, there is evidence that any columnar mucosa can be associated with neoplasia and the criteria may change.
Alcian blue (pH 2.5) may be used to highlight goblet cells, but other cell types can display a blue staining that is not indicative of intestinal metaplasia. Esophageal submucosal glands are nearly always Alcian blue–positive, as are some gastric foveolar cells.
Gross findings
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Salmon-colored velvety mucosa in the esophagus
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Originates distally and progresses proximally
Microscopic findings
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Usually incomplete intestinal metaplasia (goblet cells interspersed with cells resembling gastric foveolar cells)
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Examples: epithelial changes graded as indefinite for dysplasia, low-grade dysplasia, or high-grade dysplasia
Immunohistochemistry
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CK7+, Das1+, racemase+, CDX2+, MUC2+, variable MUC 5AC, and MUC6
Differential diagnosis
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With intestinal metaplasia of the gastric cardia; requires clinicopathologic correlation
Summary of definition of barrett’s esophagus
According to the 2008 definition of the American College of Gastroenterology, Barrett’s mucosa is a change in the esophageal epithelium of any length that (1) can be recognized at endoscopy and (2) is confirmed to have intestinal metaplasia by biopsy. As a result, pathologists cannot make the diagnosis of Barrett’s mucosa in the absence of endoscopic findings, and regardless of the endoscopic findings, in the United States, Barrett’s mucosa is diagnosed only when there are goblet cells—a definition that may be modified over time.
Dysplasia in barrett’s esophagus
Grading dysplasia in barrett’s esophagus—algorithm
The algorithm outlined is based on four major mucosal features in Barrett’s esophagus, but with additional histologic features aimed at helping observers better distinguish among indefinite for dysplasia (IND), low-grade dysplasia (LGD), and high-grade dysplasia (HGD). The algorithm presupposes that the biopsy in question is taken from the esophagus containing compatible endoscopic features of Barrett’s esophagus and that intestinal metaplasia is found. However, the same criteria can be used without intestinal metaplasia.
There are four features:
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Surface maturation in comparison with the underlying glands
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Architecture of the glands on the biopsy
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Cytologic features of the proliferating cells
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Inflammation and erosions/ulcers
Each feature may vary, and they are combined to arrive at a diagnosis.
Surface maturation
Surface maturation is assessed at low magnification and confirmed at high magnification. In nondysplastic Barrett’s esophagus, the proliferating nuclei in the most basal layers of the glands are larger, more hyperchromatic, and more stratified than those at the surface, which are generally arranged in a monolayer with polarized basal nuclei. The glands in Barrett’s esophagus are characteristically mildly atypical, especially when viewed in comparison with adjacent nonmetaplastic gastric fundic or cardiac-type glands. Thus, an eye-catching feature when scanning a biopsy at low magnification is the tinctorial comparison between the deep portions of the biopsy and the surface. This may be one of the following: the glands have proportionally larger nuclei, the glands and surface are similar as to nuclear size, or the surface has proportionally larger nuclei.
Architecture
Architecture is also best assessed at low magnification. The glandular architecture of a biopsy is the relation between the glands and the lamina propria and also encompasses the outline of the glands. Architectural abnormalities encompass both increased numbers of glands and changes in their shape. In the nondysplastic setting, the glands tend to be round with little budding and are surrounded by abundant laminae propria. Crowding of normal-appearing glands is considered a mild architectural abnormality. Crowding of abnormal glands is a feature of dysplasia. Cribriform glands, cystic dilation, and necrotic luminal debris are considered severe architectural abnormalities.
Cytologic features
Cytologic features are mostly assessed at high magnification in zones selected as abnormal during the assessment of surface maturation and architecture. Some degree of nuclear enlargement and atypia are inherent in Barrett’s metaplasia in the absence of dysplasia, especially in the basal zone. In summary, cytologic atypia in Barrett’s esophagus can be caused by dysplasia, in which case it should be cytologically and architecturally unequivocal; reactive changes, particularly associated with inflammation; or inherent changes in the deeper glands of Barrett’s esophagus, in which case the changes are mild and mature toward the surface. Dysplastic cells are generally hyperchromatic, and once the cells have been interpreted as dysplastic, assigning a low- and high-grade category reflects a matter of degree along a morphologic continuum, a point emphasized in the 2001 criteria. Also included in the assessment of cytologic features is the assessment of the relationship of nuclei, one to another, referred to as nuclear 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 orientation and a random “jumbled” appearance of the nuclei in relation to the basement membrane and one another.
Inflammation and erosions/ulcers
Inflammation and erosions add difficulty and are assessed at both scanning and high magnification. They can obscure a truly malignant lesion or impart worrisome cytologic alterations that are attributable to a reparative process.
With application of the algorithm, the classification of dysplasia follows.
Barrett’s esophagus, negative for dysplasia
In Barrett’s esophagus without dysplasia ( Figs. 2-12 and 2-14 ), the surface appears more mature than the underlying glands in that the nuclear-to-cytoplasmic ratio of surface cells is lower than that of the deeper glands. The architecture is normal, with abundant laminae propria between glands. The cytologic features are normal; mitoses may be present in deeper glands, and there may be nuclear stratification. The individual nuclei should have smooth nuclear membranes, and nucleoli, if present, should be small with smooth outlines. Nuclear polarity should be maintained in deep and superficial aspects of the biopsy. If inflammation is a component, reparative features may be present. In this setting, nuclear membranes should remain smooth, although the cells may display nuclear-to-cytoplasmic enlargement and nucleoli may become more prominent but retain smooth contours. The surface should show maturation compared with the deeper glands but there may be some loss of surface mucin.
Barrett’s esophagus, indefinite for dysplasia
By using the algorithm, we include cases that have deeper cytologic changes suggestive of dysplasia but that show surface maturation in IND category ( Fig. 2-15 ). Cases in the IND category could have normal architecture or some degree of glandular crowding. On cytologic evaluation, lesions could have hyperchromasia, nuclear membrane irregularities, and increased mitoses in the deeper aspects and all of these matured to the surface. Loss of nuclear polarity is not a feature of IND. In the presence of inflammation, more striking architectural abnormalities can be included in the IND category. A helpful feature in separating IND from low-grade dysplasia is the presence of an abrupt “clonal” demarcation of the epithelial changes as seen in Figure 2-16 . The presence of surface maturation is a helpful feature in separating potentially reactive lesions from truly neoplastic (dysplastic) ones, but some dysplastic lesions do display surface maturation, either as a result of tangential embedding or because they are early. The term basal crypt dysplasia has been applied to this appearance ( Fig. 2-17 ).
