Figure 1.2 Anatomic esophageal constriction points include the esophageal inlet, crossing of the aortic arch, left main bronchus, and diaphragmatic hiatus. These sites are prone to narrowing and can lead to pill impaction and associated local tissue damage.

Figure 1.3 This resection specimen illustrates the four main layers of the esophagus: Mucosa, submucosa, muscularis propria, and adventitia. The mucosa consists of epithelium (E), lamina propria (L), and muscularis mucosae (MM). The submucosa sits between the muscularis mucosae and the muscularis propria (MP) and it consists of loose fibroconnective tissue and lymphovascular channels. The MP consists of inner circular and outer longitudinally oriented muscle fibers. Finally, the outermost layer is the adventitia. The esophagus lacks a serosa.

Figure 1.4 Unremarkable esophageal squamous mucosa. Note the basal layer is only a few cell layers thick (bracket) and the vascular papillae are confined to the lower one-third of the epithelial thickness (arrowheads).

Figure 1.5 Unremarkable cardiac mucosa at the gastroesophageal junction. The columnar cells are of foveolar type, with apical intracytoplasmic neutral mucin that would be magenta on a PAS/AB.

Figure 1.6 Pseudogoblet cells. Pseudogoblet cells are important mimics of true goblet cells of Barrett esophagus and are typically found in clusters. They can be mistaken for true goblet cells due to their abundant cytoplasmic mucin.

Figure 1.7 Pseudogoblet cells (PAS/AB). On PAS/AB stain, the neutral mucin in the pseudogoblet cells is magenta. True goblet cells contain acidic mucin, and are deeply basophilic on PAS/AB.

Figure 1.8 Pseudogoblet cells (arrowhead).

Figure 1.9 True goblet cells. In contrast to pseudogoblet cells, true goblet cells are sparsely distributed (arrowheads).

Figure 1.10 True goblet cells (PAS/AB). In contrast to pseudogoblet cells, true goblet cells (arrowheads) have a deeply basophilic appearance on a PAS/AB.

Figure 1.11 Esophageal ducts. Esophageal ducts confirm the site of origin as esophageal (arrow). If goblet cells were present on this tissue fragment, they would signify Barrett esophagus, assuming an abnormal endoscopic examination.

Figure 1.12 Esophageal duct. Higher power of previous figure. Periductal chronic inflammation is a typical finding. Squamoid metaplasia of the ducts is not uncommon.

Figure 1.13 Esophageal ducts. This esophageal duct is present in the lamina propria, amidst a background of lymphovascular spaces. The overlying squamous epithelium can be seen (top).

Figure 1.14 Esophageal ducts (arrows).

Figure 1.15 Esophageal duct. Higher power of previous figure.

Figure 1.16 Esophageal ducts. These ducts are traversing the muscularis mucosae en route from submucosal glands. Their presence indicates that the tissue origin is esophageal.

Figure 1.17 Esophageal duct (arrowhead). This biopsy predominantly consists of oxyntic-type glandular mucosa. An esophageal duct (arrowhead) signifies that this biopsy was taken from the tubular esophagus. The proximity to gastric oxyntic glands emphasizes the variability of gastric cardia length among patients; while some patients may demonstrate several centimeters of gastric cardiac-type mucosa, others transition directly from esophagus to oxyntic mucosa, like this patient.

Figure 1.18 Esophageal duct. Higher power of previous figure.

Figure 1.19 Esophageal glands. Esophageal glands produce mucoprotective products that help lubricate the passage of food and, at the same time, protect the integrity of the esophageal mucosa.

Figure 1.20 Esophageal glands (PAS/AB). The esophageal glands stain deeply basophilic on PAS/AB. In contrast, cardiac-type mucosal glands would appear magenta on PAS/AB (Fig. 1.7).

Figure 1.21 CMV esophagitis. This example of acute esophagitis shows prominent ulceration, mixed inflammation, and reactive endothelial and stromal cells. A CMV immunostain confirmed a diagnosis of CMV esophagitis.

Figure 1.22 Erosion. The surface epithelium is eroded and accompanied by fibroinflammatory debris (bracket). By definition, an erosion is confined to the mucosa (arrowheads highlight the muscularis mucosae). Ulcerations, in contrast to erosions, extend through the mucosa and involve at least the submucosa.

Figure 1.23 Erosion versus ulceration. This resection specimen illustrates the compartments of the esophageal wall. Note that erosions are limited to the mucosa (epithelium, lamina propria, and muscularis mucosae), while ulcerations extend through the mucosa into at least the submucosa.

Figure 1.24 Balloon cells (arrowheads). Balloon cells are seen throughout this biopsy as large squamous cells with abundant pale eosinophilic/smudgy cytoplasm.

Figure 1.25 Balloon cells. This example shows the balloon cells’ smudgy cytoplasm is similar to frosted glass.

Figure 1.26 Balloon cells. Higher power of previous figure.

Figure 1.27 Mild GERD. The descriptor “mild” can be used in GERD cases with rare intraepithelial eosinophils (arrowhead). Also depicted are basal hyperplasia and vascular papillae elongation.

Figure 1.28 Mild GERD. In this example, a single degranulated intraepithelial eosinophil is identified (arrowhead) along with mild basal hyperplasia.

Figure 1.29 Moderate GERD refers to more conspicuous GERD histologic changes. This case shows more readily identifiable intraepithelial eosinophils (no arrowhead is needed to appreciate the scattered intraepithelial eosinophils). Also note the basal hyperplasia&emdash;the basal 12 layers are expanded from the 1 to 2 cell thickness expected in a normal esophagus.

Figure 1.30 Moderate GERD. The easily identified intraepithelial eosinophils, basal hyperplasia, and elongation of vascular papillae meet the criteria for GERD. However, the findings are nonspecific and in the absence of clinical information, eosinophilic diseases of the esophagus should be considered.

Figure 1.31 Marked GERD shows striking histologic changes, easily appreciated at low power, as in this case. This epithelium is “too blue” due to the prominent basal hyperplasia. In addition, the vascular papillae are approaching the midpoint of the thickness (papillae should normally be confined to the lower third of the epithelial thickness). Eosinophils are abundant. Amyloidosis is also seen (arrowhead).

Figure 1.32 Marked GERD.

Figure 1.33 Candida esophagitis often appears as scattered yellow plaques on endoscopy.

Figure 1.34 Candida esophagitis. In severe cases of candida esophagitis, the plaques coalesce to form confluent exudates and ulceration, as in this case.

Figure 1.35 Candida esophagitis. This biopsy is “too blue” because of marked inflammation and reactive squamous epithelium. Acute inflammation in the esophagus is often caused by GERD, but should also serve as a red flag to search carefully for Candida and viral cytopathic effect.

Figure 1.36 Candida esophagitis. Indeed, the diagnostic fungal forms were identified with a PAS/AB (magenta, circle). They would appear black on GMS.

Figure 1.37 Candida esophagitis (GMS). True hyphae are defined by the presence of septa, an uncommon finding in Candida. Pseudohyphae, in contrast, are composed of budding yeast-like forms (blastoconidia) joined end to end. The constrictions formed by the buds give the appearance of septations (pseudohyphae) (arrow).

Figure 1.38 CMV esophagitis. Discrete erosive changes and ulcerations are seen in the distal esophagus. These ulcers sometimes coalesce to broadly involve large regions of the esophagus, although small solitary ulcers are most commonly found.

Figure 1.39 CMV esophagitis. CMV viral cytopathic effect is identified with nuclear and cytoplasmic viral inclusions (arrowhead) and is sufficient for the diagnosis of CMV esophagitis: A CMV immunostain was not required for this diagnosis.

Figure 1.40 CMV esophagitis. Higher power of previous figure. Note the characteristic smudgy nuclear and coarse cytoplasmic inclusions with a deep magenta tinctorial quality.

Figure 1.41 CMV esophagitis (CMV immunostain). Although the H&E impression was diagnostic of CMV infection, less obvious cases often require a CMV immunostain. Note the nuclear reactivity in a large (“megalic”) cell.

Figure 1.42 CMV esophagitis (arrowhead). The affected cells are “megalic” or enlarged at low power and typically found in the endothelial or stromal cells at the ulcer base. The background shows prominent mixed inflammation with reactive endothelial cells, important red flags to the diagnosis.

Figure 1.43 CMV esophagitis. In this example, the indicated cell (arrowhead) is a markedly enlarged endothelial cell with prominent glassy and smudged cytoplasm. The features are highly suspicious for CMV infection but the nuclear detail is unclear and the characteristic deep magenta inclusion is not seen in this plane.

Figure 1.44 CMV esophagitis (CMV immunostain). Although CMV immunostains can be tricky to evaluate when there is high background or a suboptimal specimen, look for nuclear reactivity in “megalic” cells, as seen in this case.

Figure 1.45 HSV esophagitis. This endoscopic image shows ulcerations, patchy erosions, and white exudates. HSV cannot be reliably distinguished from CMV or Candida by endoscopic evaluation. A complete evaluation should therefore include biopsy of the ulcer base (for CMV) and ulcer edge (for HSV).

Figure 1.46 HSV esophagitis. An HSV immunostain is not necessary because the classic diagnostic features are present (the three “M’s”): (1) Molding of nuclear contours; (2) margination of chromatin to the periphery of the nucleus resulting in a pale nuclear center and darkened peripheral rim; (3) multinucleation.

Figure 1.47 HSV esophagitis. This case of acute esophagitis features a rare cell suspicious for HSV viral cytopathic effect with multinucleation and equivocal molding (arrowhead). Since similar findings are occasionally seen in degenerating, reactive squamous cells, an HSV immunostain was performed.

Figure 1.48 HSV esophagitis (HSV immunostain). The corresponding HSV immunostain highlights more virally infected squamous epithelium than apparent on H&E.

Figure 1.49 HSV esophagitis. This case was from a patient with a history of eosinophilic esophagitis (EoE), although characteristic features of EoE are not seen in this field. Note the subtle viral cytopathic effect in the basal aspect of the squamous epithelium (arrowheads highlight nuclear molding and chromatin margination).

Figure 1.50 HSV esophagitis. Subtle viral cytopathic effect is seen in the lateral aspects of this specimen and in the free-floating fragment at the top right.

Figure 1.51 HSV esophagitis. Careful examination of ulcer debris can provide valuable clues to the etiology of the ulcer. In this example, viral cytopathic effect diagnostic of HSV esophagitis is identified within the ulcer debris. Numerous multinucleated cells show molding of nuclear contours and margination of chromatin. An HSV immunohistochemical stain is not necessary for these unequivocal morphologic features.

Figure 1.52 HSV esophagitis. This example shows a rare cell with equivocal HSV viral cytopathic effect (arrowhead) and background ulceration (not shown).

Figure 1.53 HSV esophagitis (HSV immunostain). The corresponding HSV immunostain confirms HSV esophagitis, and emphasizes that a low threshold for CMV, HSV, and PAS stains is prudent in the case of esophageal ulcerations.

Figure 1.54 HSV esophagitis. Cells suspicious for HSV viral cytopathic effect are seen at the base.

Figure 1.55 HSV esophagitis (HSV immunostain). The corresponding HSV immunostain highlights the virally infected cells.

Figure 1.56 Helicobacter. Esophageal biopsies with columnar mucosa offer an opportunity to make additional diagnoses, such as Helicobacter carditis, as in this case. On low power, the active chronic inflammation, prominent lymphoid aggregate with a well-formed germinal center, and superficial lymphoplasmacytic inflammation strongly suggest Helicobacter infection.

Figure 1.57 Helicobacter pylori. The organisms were found in mucin-rich foci (arrowheads) and in gland lumina (not shown). Their wide one-and-a-half-turn spiral gives them a slightly bent appearance.

Figure 1.58 Helicobacter pylori (Diff-Quik). A Diff-Quik special stain highlights the Helicobacter pylori organisms (special stains are not necessary if the organisms are apparent on H&E).

Figure 1.59 Helicobacter pylori (Warthin–Starry). A Warthin–Starry special stain highlights the Helicobacter pylori organisms. This silver-based stain coats the organisms, making them slightly larger and easier to identify than the previous Diff-Quik stain.

Figure 1.60 Helicobacter heilmannii organisms are more slender and tightly spiraled than Helicobacter pylori organisms.