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ESOPHAGUS
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CHAPTER OUTLINE
The Unremarkable Esophagus
1% Alcian Blue, pH 2.5 Recipe
PAS/AB pH 2.5 Recipe
Acute Esophagitis Pattern
• Gastroesophageal Reflux Disease
• Infections
• Medications
• Other
Eosinophilic Pattern
• Gastroesophageal Reflux Disease
• Eosinophilic Esophagitis
• Drug Reaction
• Allergy
• Photodynamic Therapy
• Systemic Collagen Vascular Disorders
Parakeratotic Pattern
• Gastroesophageal Reflux Disease
• Candida
• Leukoplakia/Epidermoid Metaplasia
• Esophagitis Dissecans Superficialis Pattern/Sloughing Esophagitis
Esophageal Lymphocytosis Pattern
• Gastroesophageal Reflux Disease
• Crohn Disease
• Contact Mucositis
• Lichen Planus/“Lichenoid” Pattern
• Common Variable Immunodeficiency
• Graft Versus Host Disease
• Infection
• Other
Pigments
• Iron Pill
• Resins
Near Misses
• Gastric Inlet Patch/Heterotopic Gastric Mucosa
• Pancreatic Heterotopia/Metaplasia
• Glycogenic Acanthosis
• Squamous Papilloma
• Multilayered Epithelium
• Amyloid
• Granular Cell Tumor
• Granulomata
• Apoptotic Body Prominence
• Ring Mitoses
• Malignancy
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THE UnremArkable Esophagus
Endoscopically, the unremarkable esophagus has smooth, homogenous pink-tinged
mucosa (Fig. 1.1). Clinicians often label the biopsy location in centimeters, which refers
to the distance from the patient’s incisors to the biopsy site (Fig. 1.2). Consequently, the
gastroesophageal junction varies with the patient’s height and anatomy, although it is most
typically at 40 cm in men. Histologically, the esophagus can be compartmentalized into
four layers (mucosa, submucosa, muscularis propria, and adventitia) (Fig. 1.3). The mucosa
consists of epithelium, lamina propria, and muscularis mucosae. Lamina propria is a loose
fibroconnective tissue rich in inflammatory cells, lymphovascular channels, and esophageal
glands and ducts. It spans the space between the epithelium and the muscularis mucosae.
Proceeding deeper into the esophageal wall, the submucosa is the next encountered layer.
It sits between the muscularis mucosae and the muscularis propria and it consists of loose
fibroconnective tissue and lymphovascular channels. The muscularis propria constitutes
the largest portion of muscle in the esophageal wall. It consists of inner circular and outer
longitudinally oriented muscle fibers. In the proximal esophagus, the muscularis propria
is composed of skeletal muscle and in the distal esophagus, it is composed of smooth
muscle. The outermost layer is the adventitia, which lacks serosa, facilitating potentially
rapid spread of infectious agents and malignancy.
Normal esophageal epithelium is stratified squamous epithelium (Fig. 1.4). The basal
layer is 1 to 2 cells thick and the vascular papillae are within the lower one-third of
the epithelium. Esophageal biopsies can also contain cardiac mucosa, which is almost
always chronically inflamed (Fig. 1.5). As a result, it is not necessary to routinely diagnose “chronic inflammation” in the cardia. Since many specimens are submitted with a
request to “rule-out Barrett esophagus,” diagnoses specifically including phrases such as
“no goblet cells are seen” can be helpful to clinicians in unremarkable esophageal biopsies
from adult patients.
10
Cricopharyngeus
20
Aortic arch
Bronchi
Diaphragm
Gastroesophageal
junction
Figure 1.1 Unremarkable endoscopic appearance of the esophagus. The pink-tinged mucosal surface appears relatively smooth
and homogenous throughout the esophagus. There are no visible
plaques, nodules, masses, ulcers, erythema, blood, varices, stenoses,
or diverticula. Variations of luminal caliber in the image may stem
from esophageal peristalsis, anatomic bends, and constriction points.
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30
cm from
40 incisors
(average)
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.
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Figure 1.3 This resection specimen illustrates the four main lay-
Figure 1.4 Unremarkable esophageal squamous mucosa. Note the
ers 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.
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.
Pearls & Pitfalls
Beware of pseudogoblet cells, which are important mimics of true goblet cells.
Pseudogoblet cells are foveolar epithelial cells with prominent cytoplasmic
distention and key distinctions from true goblet cells include the following: (1) Pseudogoblets tend to aggregate in clusters, whereas true goblet cells are
more sparsely distributed among absorptive cells (complete metaplasia) or foveolar cells (incomplete metaplasia). (2) Pseudogoblet cells have predominantly neutral mucin (magenta, PAS/AB) in contrast to the acid mucin of a true goblet cell
(deeply basophilic, PAS/AB) (Figs. 1.6–1.10).
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Figure 1.7 Pseudogoblet cells (PAS/AB). On PAS/AB stain, the
Figure 1.8 Pseudogoblet cells (arrowhead).
neutral mucin in the pseudogoblet cells is magenta. True goblet
cells contain acidic mucin, and are deeply basophilic on PAS/AB.
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.
FAQ: What is the utility of and recipe for Periodic acid Schiff/alcian blue, pH 2.5
special stain (PAS/AB)?
Answer: The combination PAS/AB allows for simultaneous evaluation of a number of important diagnostic features, such as fungal forms (magenta), goblet cells
(deeply basophilic), an intact small bowel brush border (crisp and uniform stain
condensation). The stain also highlights the mucin of sneaky adenocarcinomas.
1% Alcian blue, pH 2.5 recipe*
Alcian blue 8GX……..5 g
Acetic acid, 3% solution….500 mL
Adjust the pH to 2.5. Filter and add a few crystals of thymol.
*This solution is commercially available.
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PAS/AB pH 2.5 RECIPE
1. Deparaffinize and hydrate to distilled water.
2. One minute in 3% acetic acid. Do not rinse.
3. Stain in Alcian Blue pH 2.5 for 30 minutes.
4. Rinse in tap, then distilled water.
5. Oxidize in 0.5% periodic acid solution for 10 minutes.
6. Rinse in distilled water.
7. Place slides in Schiff reagent for 20 minutes.
8. Wash in running tap water for 5 minutes, or until water is clear and sections are pink.
9. Stain in Harris hematoxylin for 3 minutes.
10. Wash in tap water.
11. Clarifier for 1 minute.
12. Wash in tap water for 1 minute.
13. Bluing reagent for 1 minute.
14. Wash in running water for 1 minute.
15. Dehydrate through 95% alcohol, absolute and clear in xylene.
16. Mount.
Recipe courtesy of Deborah Duckworth, Johns Hopkins Hospital, Histology Laboratory.
FAQ: Are there histologic clues that confirm the biopsy site as esophagus (and
not cardia, for example)?
Answer: Yes. Establishing the tissue origin as esophagus is critical for the diag-
nosis of Barrett mucosa, a diagnosis that necessitates periodic surveillance
based on an increased risk of neoplasia. Usually correlation with the endoscopic
report provides the most effective means to determining the tissue site of origin. Unfortunately, detailed reports are not always provided, and clinicians may
not be confident that they are in the tubular esophagus, especially if a patient
has a sliding hiatal hernia. Since esophageal ducts transmit secretions from the
esophageal submucosal glands to the luminal surface, their histologic identification can establish the tissue site as esophagus, providing helpful diagnostic
clues (Figs. 1.11–1.20).
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.
6 A tlas o f G astroi n testi n al P atholog y
Figure 1.13 Esophageal ducts. This esophageal duct is present in
Figure 1.14 Esophageal ducts (arrows).
the lamina propria, amidst a background of lymphovascular spaces.
The overlying squamous epithelium can be seen (top).
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 predomi-
Figure 1.18 Esophageal duct. Higher power of previous figure.
nantly 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 cardiactype mucosa, others transition directly from esophagus to oxyntic
mucosa, like this patient.
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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.
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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).
Acute Esophagitis Pattern
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.
Acute esophagitis describes an injury pattern that includes intraepithelial neutrophils, erosions, and/or ulcerations (Fig. 1.21). This pattern of injury is entirely nonspecific, but is
most commonly caused by gastroesophageal reflux disease (GERD), infections, and medications. Malignancy, amyloidosis, radiation injury, and vasculitis are also potential causes
of acute esophagitis, particularly if erosions and ulcerations are present. While findings in
ulcer debris are easy to overlook since ulcers have a “busy” visual appearance, the cause of
the ulcer can occasionally be identified by careful inspection.
Checklist: Etiologic Considerations for the Acute Esophagitis Pattern
HH
HH
HH
HH
Gastroesophageal Reflux Disease
Infections
Medications
Other
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Figure 1.22 Erosion. The surface epithelium is eroded and accom-
Figure 1.23 Erosion versus ulceration. This resection specimen
panied 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.
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.
Pearls & Pitfalls
The distinction between erosion and ulceration occasionally presents a point of
confusion. Erosions are denudations limited to the mucosa (epithelium, lamina
propria, and muscularis mucosae). Characteristically erosions are accompanied by
a rind of fibrin and inflammatory debris, allowing distinction of a true erosion from
an artifactual epithelial denudation that occurs with aggressive tissue handling.
In contrast, ulcerations extend through and beyond the muscularis mucosae and
involve at least the submucosa (Figs. 1.22 and 1.23).
Gastroesophageal Reflux Disease (GERD)
GERD is a common cause of inflammation of the distal esophagus epithelium, caused by
reflux of the acidic gastric contents into the tubular esophagus, discussed in detail in GERD
subsection, Lymphocytic Pattern, this chapter. Histologically, it is comprised by a constellation of features, including dilatation of intercellular spaces, basal hyperplasia, elongation
of the vascular papillae, intraepithelial eosinophils, vascular lakes, increased intraepithelial
T lymphocytes, and balloon cells (epithelial cells with abundant pale cytoplasm). Of these
features, dilation of intercellular spaces was most consistently reported, seen in 41% to
100% of patients with GERD and 0% to 30% of control patients.1 Papillary elongation
is also a prominent finding, seen in up to 85% of those with GERD and 20% of control
patients. GERD can further be stratified into three categories to more accurately describe
the degree of pathology: Mild (subtle findings, including rare intraepithelial eosinophils),
moderate (conspicuous findings), or marked GERD (striking findings) (Figs. 1.24–1.32).
GERD is important to recognize owing to its association with strictures, Barrett mucosa,
and malignancy. At this time there are no official consensus recommendations on biopsy
protocol for GERD uncomplicated by Barrett esophagus or eosinophilic esophagitis (EoE).
Treatment typically includes lifestyle modification and proton-pump inhibitors, with surgical procedures reserved for severe, refractory cases.
Key Features of GERD (some, not all, of the following features are required):
• Dilatation of intercellular spaces
•
•
•
•
•
•
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Basal hyperplasia, >15% of epithelial thickness
Elongation of the vascular papillae, top half of epithelium thickness
Intraepithelial eosinophils
Vascular lakes
Increased intraepithelial T lymphocytes (squiggle cells)
Balloon cells (epithelial cells with abundant pale cytoplasm)
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Chapter 1
Figure 1.24 Balloon cells (arrowheads). Balloon cells are seen
throughout this biopsy as large squamous cells with abundant pale
eosinophilic/smudgy cytoplasm.
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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
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
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GERD cases with rare intraepithelial eosinophils (arrowhead). Also
depicted are basal hyperplasia and vascular papillae elongation.
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—the basal 12 layers are expanded from the 1 to 2 cell thickness expected in a normal esophagus.
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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.
FAQ: Could the findings in Figure 1.32 represent eosinophilic esophagitis (EoE)
instead of marked GERD?
Answer: Absolutely. It is clinically important to distinguish EoE from GERD
because of differing etiologic specific therapies. In general, features favoring EoE
include superficial eosinophilic microabscesses, eosinophil counts greater than
50/HPF, and basal hyperplasia greater than 50%. Since an unmapped biopsy of
EoE can be histologically indistinguishable from GERD, clinicopathologic correlation and mapping of tandem proximal and distal esophageal biopsies are
necessary to more definitively distinguish EoE from GERD. See also Eosinophilic
pattern, this chapter.
Infections
Candida Esophagitis
Candida esophagitis appears endoscopically as scattered yellow plaques, patches, exudates, and ulcerations (Figs. 1.33–1.34). These endoscopic appearances can overlap with
those of glycogenic acanthosis, esophageal leukoplakia/epidermoid metaplasia, lichen
planus/“lichenoid” pattern, making correlation with biopsy findings essential to arrive at
the correct diagnosis. Brushing samples sent to the microbiology or cytology laboratories
may be more sensitive than biopsies alone.2,3 A history of HIV/AIDS is an important red
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Figure 1.33 Candida esophagitis often appears as scattered
yellow plaques on endoscopy.
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.
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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 1.36 Candida esophagitis. Indeed, the diagnostic fungal
forms were identified with a PAS/AB (magenta, circle). They would
appear black on GMS.
flag to this diagnosis. In one study of 110 patients with HIV, 51.8% of patients were found
to have candidiasis.3 The plaques histologically correlate with desquamated debris, which
can coalesce to form extensive exudates and/or ulcerations in severe cases (Fig. 1.34).4 Histologically, acute inflammation in the squamous epithelium and hyperkeratosis are red flags
and prompt a thorough high-power examination for the pseudohyphae forms characteristic
of candidiasis (Figs. 1.35 and 1.36). Importantly, a complete absence of inflammation can
be seen in immunosuppressed patients. A low threshold for ordering special stains such
as PAS/D or Grocott methenamine-silver stain (GMS) is advised (Fig. 1.37). See also Parakeratotic pattern, this chapter.
FAQ: Do budding yeast signify Candida esophagitis?
Answer: No. Budding yeast often represent oral contamination. Pseudohyphal
forms, in contrast, signify tissue invasion and are required for the diagnosis of
Candida esophagitis.
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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).
FAQ: How are PAS, PAS/AB, or GMS special stains utilized in the evaluation of
pseudohyphae?
Answer: PAS, PAS/AB, and GMS special stains highlight fungal forms and are
advised in the following cases, assuming the fungal forms are not present on H&E:
• Clinical impression of candidiasis
• Striking acute inflammation
• Prominent parakeratosis
• Refractory GERD or EoE
Cytomegalovirus (CMV)
Key Features of CMV Esophagitis:
• Endoscopic findings are typically linear, serpiginous ulcerations with a propensity for
the distal esophagus (Fig. 1.38)
• CMV viral cytopathic effect can be seen in endothelial cells, columnar epithelium, and
stromal cells; biopsy of the ulcer base is critical for complete evaluation
• CMV viral cytopathic effect includes nuclear and cellular enlargement, smudged chromatin, and nuclear (“owl’s eye”) and/or cytoplasmic inclusions
• The inflammatory backdrop shows a prominence of mononuclear inflammation
(Figs. 1.39–1.44)
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.
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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.
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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
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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.
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Herpes simplex virus (HSV)
Key Features of HSV Esophagitis:
• Endoscopic findings include well-circumscribed ulcerations with raised yellow edges
(“volcano ulcers”) which can be seen in any region of the esophagus (Fig. 1.45)
• HSV infects squamous epithelium; biopsy of the edge of the ulcer is recommended to
ensure squamous epithelium is present5
• The classic nuclear features include molding of nuclear contours, margination of chromatin, and multinucleation (referred to as the “three M’s”) (Figs. 1.46–1.55)
• Cowdry A: Intranuclear inclusions with a clear halo
• Cowdry B: Intranuclear inclusions lacking a clear halo
Pearls & Pitfalls
In Figure 1.49, the subtle HSV diagnosis could be easily overlooked if the “rule-out
EoE” request narrowed the evaluation to counting eosinophils only, rather than
taking a more open, systematic approach to the tissue. This case highlights the
importance of always looking for the second and less obvious diagnosis. While
examining the requisition is always worthwhile, it is more important to avoid being
blinded by the history and endoscopic findings.
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.
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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.
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Chapter 1
Figure 1.48 HSV esophagitis (HSV immunostain). The corresponding HSV immunostain highlights more virally infected squamous epithelium than apparent on H&E.
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.
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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 1.51 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
Figure 1.53 HSV esophagitis (HSV immunostain). The correspond-
equivocal HSV viral cytopathic effect (arrowhead) and background
ulceration (not shown).
ing 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.
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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.
FAQ: Does HSV2 infection in a child imply sexual activity/abuse?
Answer: No. Historically, the HSV1 serotype has been associated with oral ulcerations and HSV2 with genital ulcerations. Studies that are more recent suggest
these historic associations may no longer be relevant.6,7 As a result, it is not necessary to routinely determine serotypes nor to suggest sexual abuse for HSV2 reactive cases, although the testing is technically feasible with HSV1- or HSV2-specific
immunohistochemical stains or molecular-based assays.
FAQ: Does a positive HSV immunohistochemical stain exclude varicella-zoster
virus (VZV)?
Answer: No. VZV is the causative agent of varicella (chickenpox) and herpes zoster
(shingles). Both HSV and VZV belong to the Herpesviridae family, show identical
viral cytopathic effect, and react identically with an HSV immunohistochemical
stain. HSV can be distinguished from VZV by a specific VZV immunohistochemical
stain, culture methods, or molecular assays.
FAQ: How are CMV, HSV immunostains utilized?
Answer: If the diagnosis can be made on H&E due to classic viral cytopathic effect,
additional immunostains are not necessary. However, a low threshold for requesting CMV and HSV immunostains (and fungal special stains) is recommended in the
setting of esophageal ulcerations because the diagnostic features can be easily
obscured by the intense background inflammation.
Helicobacter
Whereas acute inflammation in the esophagus is most associated with GERD, inflamed
cardia biopsies (which can be present in biopsies containing esophagus) are associated
with Helicobacter infections in the majority of cases (78% to 97.7%).8,9 The concept of the
cardia as a normal anatomic landmark is debated but, in general, the cardia is defined as the
small segment of stomach between the distal esophagus and proximal stomach with oxyntic
mucosa. Red flags to the diagnosis of Helicobacter infection include recognition of acute
and chronic inflammation, superficial lymphoplasmacytosis, and lymphoid aggregates
(Figs. 1.56–1.61), as discussed in detail in Acute Gastritis, Stomach chapter.
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Chapter 1
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 wellformed germinal center, and superficial lymphoplasmacytic inflammation strongly suggest Helicobacter infection.
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 1.60 Helicobacter heilmannii organisms are more slender
and tightly spiraled than Helicobacter pylori organisms.
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17
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 1.59 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 1.61 Helicobacter heilmannii (Diff-Quik). A Diff-Quik special stain highlights the tightly spiraled Helicobacter heilmannii
organisms embedded within the surface mucus.
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Medications
Medication-related injury is seen with some regularity in centers enriched for elderly
patients, and in the setting of polypharmacy. The resulting injury pattern can include a wide
range of histologic findings including nonspecific reactive changes, prominent apoptotic
bodies, intraepithelial lymphocytosis, mild acute esophagitis, eosinophilia, and/or marked
ulceration. Medication injury can be seen throughout the GI tract, but in the esophagus
so-called “pill esophagitis” is most common at the anatomic constriction points (Fig. 1.62).
Select Medications Considerations
• Iron
• Resins (Kayexalate, sevelamer, bile acid sequestrants)
• Bisphosphonates
Iron
Ferrous sulfate-mediated corrosive injury is seen in approximately 1% of individuals
undergoing upper endoscopy and is associated with erosions and ulceration.10 The pigment can have a coarse, crystalline, or subtle brown hue on H&E, and it is blue on a Prussian blue iron special stain (Figs. 1.62–1.66). Recognition is important to help prevent
Figure 1.62 Iron pill esophagitis. This dramatic example features
the pigmented crystalline form of iron pill deposition in a background of ulceration.
Figure 1.63 Iron encrustation, ulcerative esophagitis. Some cases
Figure 1.64 Iron encrustation, ulcerative esophagitis (Prussian blue
special stain). The iron pigment appears as a faint blue hue on a
Prussian blue special stain.
Figure 1.65 Iron pill esophagitis. Iron pill esophagitis with a rind
of coarse brown pigmentation admixed in ulcer debris. A Prussian
blue iron special stain was reactive, confirming the above diagnosis.
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of iron encrustation are quite subtle. In this case, a superficial rind of
light brown suggests iron, but a confirmatory iron stain was required
to arrive at the correct diagnosis.
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Figure 1.66 Iron pill esophagitis. Iron pill esophagitis with coarse
crystalline pigment deposition and ulcer debris. The patient
endorsed a history of taking her iron pill with a few sips of water
right before time. She was encouraged to take her pill with generous
amounts of yogurt a few hours before bedtime, and her symptoms
quickly resolved.
further injury and potential stricture formation. These patients benefit from behavioral
modifications such as maintaining upright posture for 30 minutes after taking the pill
and/or taking the pill with ample liquids or food. See also Pigments and Extras, Stomach
Chapter.
Pearls & PitfallS
Iron pill esophagitis occasionally raises concern for invasive carcinoma based on
the sometimes ominous endoscopic appearance and prominent reactive changes
seen in the corresponding biopsies. Recognition of the iron pigment is critical and,
when in doubt, an iron special stain can be helpful. Alternatively, mass lesions
constrict the esophageal lumen and can result in entrapped iron encrustation
overlying the mass lesion. If the clinical suspicious for malignancy is high, deeper
sections and repeat biopsy are often worthwhile.
Resins
Resins are nonabsorbable medications that exchange ions as they course through the GIT;
they are often referred to as “medication crystals.” The three most common include Kayexalate, sevelamer, and the bile acid sequestrants. The resins can usually be confidently identified on H&E and confirmed with a quick review of the medication list. Awareness of these
resins and comfort in discriminating between them is essential because the first two are
associated with mucosal injury. This section will focus on red flags in the chart and distinctive features of the crystal morphology to quickly navigate to the correct diagnosis.
Kayexalate
Also known as sodium polystyrene sulfonate, Kayexalate was introduced in 1958 as a cation
exchange resin used to treat hyperkalemia in renal failure patients.11–13 When administered
via the upper tract, the resin releases sodium ions and becomes protonated in the acidic
milieu of the stomach. As the resin traverses the bowel, the hydrogen is subsequently
exchanged for potassium. The potassium bound resin is then released in the feces, thereby
lowering serum potassium levels. Kayexalate was initially administered in an aqueous solution but initial reports found an association with constipation and, sometimes lethal, bezoar
formation.13–15 As a result, Kayexalate was combined with a sorbitol diluent that effectively
reduced these side effects but, unfortunately has been linked to ischemic and ulcerative GIT
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20 A tlas o f G astroi n testi n al P atholog y
injury. Historically, these changes have been attributed to the hyperosmotic sorbitol diluent,
although some suggest the resin itself may be a contributing factor.11,13,14 Today, the sorbitol
diluent is strongly discouraged in favor of emulsifying the medication directly into food
or drink.16 The resin can lodge anywhere along the GI tract since it can be administered
via a nasogastric tube, orally, or a rectal enema. Kayexalate displays a so-called “fish-scale”
or “mosaic” appearance due to regular, narrow cracking lines. It is purple on H&E, blackgreen on AFB, and hot pink on PAS/AB (Figs. 1.67–1.77).
Key Features of Kayexalate:
• Also known as sodium polystyrene sulfonate
• Administered via nasogastric tube, orally, or rectal enema (can be seen anywhere in the GIT)
• Used to treat hyperkalemia in renal failure patients
• The hyperosmotic sorbitol diluent is blamed for ischemic and ulcerative GIT injury
• Resin has narrow, regular “fish-scale” pattern
• Resin is purple on H&E, black-green on AFB, and hot pink on PAS/D (Figs. 1.67–1.77)
Figure 1.67 Kayexalate (sodium polystyrene sulfonate). Alternate
case showing Kayexalate’s characteristic purple color on H&E and
narrow, regularly positioned “fish-scales.”
Figure 1.68 Kayexalate (sodium polystyrene sulfonate). Note
the necrotic background. This resin was identified in a perforated
colon with transmural necrosis and inflammation. Kayexalate was
concentrated in the necrotic bowel, and was the likely cause of the
perforation.
Figure 1.69 Kayexalate (sodium polystyrene sulfonate). Alternate
Figure 1.70 Kayexalate (sodium polystyrene sulfonate). Alternate
field. Identification of these crystals in the perforated bowel resulted
in immediate contact with the clinician. As a result, Kayexalate was
discontinued and the patient had an uneventful recovery.
case. The purple color and narrow, regular “fish-scales” are consistent with Kayexalate.
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Figure 1.71 Kayexalate (sodium polystyrene sulfonate). Alternate
Figure 1.72 Kayexalate (sodium polystyrene sulfonate) (AFB).
field. Note the fibrinoinflammatory background.
Kayexalate is dark black with a hint of green on AFB, similar to the
skin of the wicked witch of the west in “The Wizard of Oz.”
Figure 1.73 Kayexalate (sodium polystyrene sulfonate) (PAS/D).
Kayexalate is bright pink on PAS/D. These additional stains are not
necessary on classic cases, but can be helpful if the specimen is
suboptimal.
Figure 1.74 Iron pill esophagitis with Kayexalate. This case shows
a rare Kayexalate resin (arrowhead) in a background of abundant
iron pill and ulceration.
Figure 1.75 Iron pill esophagitis with Kayexalate. Higher-power
Figure 1.76 Iron pill esophagitis with Kayexalate. The corresponding Prussian blue stain highlights the background iron pigment.
view of previous figure. Note the characteristic purple hue and “fishscale” appearance of the Kayexalate resin (arrowhead).
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22 A tlas o f G astroi n testi n al P atholog y
Figure 1.77 Kayexalate (sodium polystyrene sulfonate). Kayexalate
resins appear purple with a mosaic “fish-scale” appearance on H&E.
These resins are often seen in association with ulcer debris, which
has been historically attributed to the hyperosmotic sorbitol diluent.
Pearls & Pitfalls
Identification of Kayexalate is a medical emergency, particularly if an ulcerated
or ischemic background is seen. Kayexalate has been linked to fatality cases and
the clinicians should be alerted to its presence and educated about its notorious
association with GIT injury. If mucosa injury is seen, the patient should be closely
monitored and or the medication list safely adjusted. Accurate diagnosis of this
crystal and communication with the clinician is one way pathologists can potentially save a life without directly interacting with the patient.
Sample Note: Kayexalate
Esophageal, Biopsy:
• Squamous mucosa with Kayexalate resins concentrated within ulceration and necroinflammatory debris.
Note: The history of renal failure and esophageal ulcerations is noted. The biopsy shows
Kayexalate resins concentrated within the necroinflammatory and ulcer debris and are
likely a contributing factor to this injury pattern. This information was verbally shared
with Dr. Anderson by Dr. Arnold on 08/12/2013, 1613. CMV and HSV immunostains are
negative. A PAS/D for fungal organisms is negative.
References
Lillemoe KD, Romolo JL, Hamilton SR, et al. Intestinal necrosis due to sodium polystyrene
(Kayexalate) in sorbitol enemas: Clinical and experimental support for the hypothesis. Surgery.
1987;101:267–272.
Rashid A, Hamilton SR. Necrosis of the gastrointestinal tract in uremic patients as a result of sodium
polystyrene sulfonate (Kayexalate) in sorbitol: An underrecognized condition. Am J Surg Pathol.
1997;21:60–69.
Abraham SC, Bhagavan BS, Lee LA, et al. Upper gastrointestinal tract injury in patients receiving
Kayexalate (sodium polystyrene sulfonate) in sorbitol: Clinical, endoscopic, and histopathologic
findings. Am J Surg Pathol. 2001;25:637–644.
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Sevelamer
Sevelamer is a recently introduced, orally administered, ion-exchange resin. It lowers
phosphate levels in patients with chronic kidney disease; therefore, its clinical presentation overlaps with Kayexalate. It was introduced in the tablet form as Renagel (sevelamer
hydrochloride) in 2000 and in tablet and powder form as Renvela (sevelamer carbonate)
in 2007.17,18 Both formulations show similar efficacy, but sevelamer carbonate (Renvela) is
marketed as the preferred form based on a decreased incidence of metabolic acidosis.19–22
We recently reported the first morphologic description of sevelamer and found a provocative
association with mucosal injury, which we relay to the clinicians in pertinent cases, similar
to our approach to Kayexalate.23 We also disclose that the initial report is small and further
studies are needed to fully clarify the possibility of sevelamer-mediated injury. The core histologic features of the sevelamer resins include broad, curved, and irregularly spaced “fishscales” with a variable color.23 Whereas, most resins displayed a two-toned color imparted
by bright pink linear accentuations and a rusty yellow background, those crystals embedded
in extensive ulcer, ischemia, or necrotic debris acquired a deep eosinophilia or rusty brown
color. Sevelamer crystals are magenta on AFB and lavender on PAS/D (Figs. 1.78–1.86).
Key Features of Sevelamer:
• Also known as Renagel (sevelamer hydrochloride) and Renvela (sevelamer carbonate)
• Administered orally (can be seen anywhere along the GIT)
• Lowers phosphate levels in patients with chronic kidney disease
• May be associated with mucosal injury
• Resins show broad, curved, and irregularly spaced “fish-scales”
• Resins are two-toned color (bright pink linear accentuations and a rusty yellow background) on H&E, magenta on AFB, and lavender on PAS/D
• Resins embedded in extensive ulcer, ischemia, or necrotic debris acquired a deep eosinophilia or rusty brown color
Figure 1.78 Sevelamer resins characteristically display broad,
curved, and irregularly spaced “fish-scales” with a variable color.
Like this example, most have a two-toned color imparted by bright
pink linear accentuations and a rusty yellow background.
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Figure 1.79 Sevelamer. This resin features all the usual features of
Sevelamer: Two-toned color with bright pink lines amidst a rusty yellow
background. Compared to Kayexalate, note these “fish-scales” are
more broad and irregular.
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24 A tlas o f G astroi n testi n al P atholog y
Figure 1.80 Sevelamer. Sevelamer and Kayexalate are both seen
in the setting of renal failure and both have been associated with
mucosal injury. Awareness of their distinctive morphology is key to
the right diagnosis.
Figure 1.82 Sevelamer. In cases of severe mucosal injury, the
characteristic two-toned color of sevelamer transitions to deep
eosinophilia or rusty brown color. Note the “fish-scale” pattern is
consistent, providing helpful diagnostic clues to the diagnosis of
sevelamer.
Figure 1.84 Sevelamer. This resin was identified in an ischemic and
perforated small bowel. While the characteristic “fish-scale” pattern
is seen, the resin is deeply eosinophilic, typical of resins entrapped
in severe background mucosal injury.
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Figure 1.81 Sevelamer. Note the prominent background fibrinoinflammatory debris. Close examination of ulcer debris is always
worthwhile because it may contain “hidden” clues to the underlying
etiology, such as sevelamer resins in this case.
Figure 1.83 Sevelamer. This is a biopsy of a large esophageal
ulcer. Note the sevelamer resin displays its usual “fish-scale” pattern
but the color is rusty brown instead of the more typical two-toned
color. This color shift has been described in the setting of severe
background mucosal injury and may relate to varying binding capacity and pH properties of the entrapped resin.
Figure 1.85 Sevelamer is magenta on AFB. Note the typical broad,
irregular “fish-scale” pattern characteristic of sevelamer. Sevelamer
is also known by its trademark names Renvela (sevelamer carbonate)
and Renagel (sevelamer hydrochloride).
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Figure 1.86 Sevelamer is lavender on PAS/D, helpful distinguishing features from Kayexalate and the bile acid sequestrants.
Pearls & Pitfalls
Sevelamer is most commonly misdiagnosed as Kayexalate. Unfortunately, the
medication list is almost guaranteed to be missing from the disclosed requisition. “Renal failure”, however, is a common accompanying comment and
should invoke the possibility of both Kayexalate and sevelamer. Accurate discernment of sevelamer from Kayexalate relies on recognition of their distinct
morphologic features (sevelamer: broad, curved, and irregularly spaced “fishscales,” two-toned on H&E, magenta on AFB, and lavender on PAS/D; Kayexalate: narrow, regular “fish-scales,” purple on H&E, black-green on AFB, and hot
pink on PAS/D).
Sample Note: Sevelamer
Esophageal, Biopsy:
• Squamous mucosa with sevelamer resins concentrated within ulceration and necroinflammatory debris.
Note: The history of renal failure and esophageal ulcerations is noted. The biopsy shows
sevelamer resins concentrated within the necroinflammatory and ulcer debris. In the one
small study available, sevelamer was associated with mucosal injury in a dose-dependent
manner, suggesting sevelamer may be a contributing factor to the above pathology. Of
note, the referenced study is small and no definitive conclusions can be drawn at until
larger studies are available. This information was verbally shared with Dr. Anderson by
Dr. Arnold on 08/12/2013, 1613. CMV and HSV immunostains are negative. A PAS/D for
fungal organisms is negative.
Reference
Swanson BJ, Limketkai BN, Liu TC, et al. Sevelamer crystals in the gastrointestinal tract (GIT): A new
entity associated with mucosal injury. Am J Surg Pathol. 2013;37(11):1686–1693.
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Bile Acid Sequestrants
Cholestyramine (LoCholest, Prevalite, Questran) was introduced in 1973 and is the most
commonly encountered bile acid sequestrant. Others in this family include colestipol
(Colestid) and colesevelam (WelChol). Familiarity with these names, while cumbersome,
makes confirmatory chart review a cinch. These medications are available in powder form
for oral administration. The nonabsorbable resins bind negatively charged anions, such as
bile acids, which are then eliminated in the feces.24–26 It is primarily used to lower serum
cholesterol levels but can additionally be used to treat pruritus in patients with biliary tract
disease or to treat bile acid–mediated diarrhea in patients with decreased bile acid absorption due to ileal resection (e.g., in Crohn disease). Historically, bile acid sequestrants are
thought to be biologically inert and not associated with causing mucosal injury, unlike
Kayexalate and sevelamer. Cholestyramine can be readily identified based on its unique
morphology. The resin is smooth and glassy in texture because it lacks an internal “fishscale” pattern, unlike Kayexalate and sevelamer. Bile acid sequestrants are bright orange on
H&E, neon green on AFB, and variable gray or hot pink color on PAS/D (Figs. 1.87–1.94).
Figure 1.87 Cholestyramine resins are smooth and glassy in tex-
Figure 1.88 Cholestyramine. This resin is surrounded by ulcer
ture; they lack a “fish-scale” pattern. They are bright orange on
H&E.
debris. Cholestyramine crystals are biologically inert and do not cause
mucosal injury; therefore, a search for the underlying etiologic agent
of the ulcer debris is necessary. In this case, the background mucosa
showed prominent CMV viral cytopathic effect. Therefore, the resin
was an “innocent bystander” trapped within the CMV ulcer debris.
Figure 1.89 Cholestyramine. Alternate field. The clinician later
Figure 1.90 Cholestyramine. Note the characteristic smooth and
glassy texture, and bright orange color on H&E. Bile acid sequestrants are known by many names: Cholestyramine (LoCholest,
Prevalite, Questran); colestipol (Colestid); colesevelam (WelChol).
called to ask if the cholestyramine should be discontinued based on
the severe mucosal injury. We explained that cholestyramine does
not cause mucosal injury; there was no need to adjust the medication injury. The patient had an uneventful recovery following antiviral
therapy.
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Figure 1.91 Cholestyramine. Bile acid sequestrants reduce bile
acid levels and are most commonly used to treat hypercholesterolemia, pruritus, and bile acid–mediated diarrhea.
Figure 1.92 Cholestyramine.
Figure 1.93 Cholestyramine is neon green on AFB.
Figure 1.94 Cholestyramine resins display both gray or hot pink
color on PAS/D.
Key Features of Bile Acid Sequestrants:
• Cholestyramine (LoCholest, Prevalite, Questran); colestipol (Colestid); colesevelam
(WelChol)
• Lowers bile acids, most commonly used to treat hypercholesterolemia, pruritus, and
bile acid–mediated diarrhea
• Not associated with mucosal injury
• Resins are smooth and glassy in texture (lacks a “fish-scale” pattern)
• Resins are bright orange on H&E, neon green on AFB, and variable gray or hot pink
color on PAS/D
Pearls & Pitfalls
While the bile acid sequestrants are generally smooth in texture, larger resins can
have occasional, irregular “fracture” lines, which are a knife artifact from histologic
processing of larger, thicker resins. Such cases are occasionally misdiagnosed as
Kayexalate or sevelamer if the irregular fracture lines are mistaken for a “fish-scale”
pattern. A true “fish-scale” pattern, however, shows geometric, predictable, internal structures. Examples of true “fish-scales” are illustrated in Figures 1.67–1.86.
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28 A tlas o f G astroi n testi n al P atholog y
FAQ: What should I report if I see a luminal resin but have no access to the medical chart to confirm the resin identity?
Answer: If the resin morphology is classic, chart review is not essential for diagnosis. In suboptimal cases, AFB and PAS/D special stains can help clarify the identity
of the resin. If neither the medication list nor special stains are available, a careful
descriptive note is most prudent.
Sample Note: Luminal Crystal, Nos
Esophagus, Biopsy:
• Ulcer debris with entrapped luminal crystals.
• Negative for fungal elements and viral cytopathic effect (H&E).
Note: The history of esophageal ulceration is noted. Entrapped luminal crystals are identified which are not further classifiable based on pronounced histologic artifact. The differential diagnoses include Kayexalate (sodium polystyrene sulfonate), sevelamer (Renagel,
Renvela) and the bile acid sequestrants (cholestyramine [LoCholest, Prevalite, Questran]);
colestipol (Colestid); colesevelam (WelChol). The former two are associated with mucosal
injury. Correlation with the medication list is required for further identification.
References
Rashid A, Hamilton SR. Necrosis of the gastrointestinal tract in uremic patients as a result of sodium
polystyrene sulfonate (Kayexalate) in sorbitol: An underrecognized condition. Am J Surg Pathol.
1997;21:60–69.
Abraham SC, Bhagavan BS, Lee LA, et al. Upper gastrointestinal tract injury in patients receiving
Kayexalate (sodium polystyrene sulfonate) in sorbitol: Clinical, endoscopic, and histopathologic
findings. Am J Surg Pathol. 2001;25:637–644.
Swanson BJ, Limketkai BN, Liu TC, et al. Sevelamer crystals in the gastrointestinal tract (GIT): A new
entity associated with mucosal injury. Am J Surg Pathol. 2013;37(11):1686–1693.
Bisphosphonates
Bisphosphonates are medications that prevent bone reabsorption and are commonly used
in the treatment of osteoporosis. Examples of bisphosphonates include Alendronate (Fosamax), Ibandronate (Boniva), and Risedronate (Actonel), among others. These medications
are linked to acute esophagitis and ulcerations through direct mucosal irritation from the
impacted pill and toxicity through the pill itself.27 While these polarizable pill fragments
are capable of causing ulceration, they are not histologically specific and cannot be reliably
distinguished from “bystander” pill fragments incidentally trapped within the ulcer debris
(Fig. 1.95). Chart review and/or communication with the clinician can be helpful.
Figure 1.95 Ulcerative esophagitis seen in the setting of bisphosphonate usage. In this example of ulcerative esophagitis, no specific
etiologic clues are apparent such as polarizable pill fragments. However, a careful chart review revealed usage of a bisphosphonate, a
class of medications notorious for causing esophageal injury.
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Other (Malignancy, Amyloidosis, Radiation
Injury, and Vasculitis)
Esophageal ulcerations can also be caused by any infiltrative process or any process that
comprises the regional blood supply, such as malignancy, amyloidosis, radiation injury, or
vasculitis (Figs. 1.96–1.102). Careful inspection of the ulcer, ulcer debris, and adjacent
tissue is imperative for complete evaluation. Note, vasculitis is best evaluated in resection
specimens.
Figure 1.96 Poorly differentiated squamous cell carcinoma. This
patient had a history of esophageal squamous cell carcinoma status
post resection and radiation. The endoscopic examination identified
an ulcer, and histologic sections show markedly atypical cells with
prominent nuclear pleomorphism and hyperchromasia.
Figure 1.97 Poorly differentiated squamous cell carcinoma and
Figure 1.98 Diffuse large B cell lymphoma (DLBCL) arising in a
background of Barrett mucosa. This biopsy was adjacent to an ulcer
and shows large, monomorphic lymphocytes arranged in sheets.
Immunohistochemical studies confirmed the indicated malignant
cells as B-lineage cells (CD20 reactive) with a Ki-67 proliferation
index of 80%. Additional immunohistochemical stains were performed for prognostic information. The lesional cells were confirmed
to be germinal center derived (CD10, Bcl-6 reactive, MUM1 nonreactive) which carries a better prognosis than nongerminal centerderived DLBCL. Bcl-2 is an independent prognostic marker that can
confer a relatively worse prognosis, and was nonreactive in this case.
The finding of both Barrett mucosa and DLBCL is thought to be
coincidental.
Figure 1.99 Amyloidosis. Amyloidosis can have a varied endo-
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ulcer debris (p63). A p63 immunostain confirms the squamous origin
of the malignant cells, supporting the above diagnosis.
scopic appearance. In this case, an esophageal nodule was seen
(arrowhead).
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Figure 1.100 Amyloidosis. Considerable bleeding was noted after
nodule removal, and this post-biopsy image shows hemorrhagic
mucosa. Patients with amyloidosis often bleed easily due to the
fragile nature of the amyloid-laden vessels.
Figure 1.101 Amyloidosis. At low power the squamous mucosa
has prominent hemorrhage and abundant amorphous eosinophilic
material in the lamina propria. The deposition was bright orange on
Congo red with direct light, and apple-green under polarized light,
confirming the diagnosis of amyloidosis.
Figure 1.102 Amyloidosis. Higher power of the previous figure.
The lamina propria shows abundant eosinophilic material with cracking and tissue tears. This characteristic artifact is produced when
tissue sections containing amyloid are sectioned on a microtome
in the histology laboratory. This is a helpful clue in identifying this
subtle and easily missed entity.
EOSINOPHILIC PATTERN
Figure 1.103 Esophageal eosinophilia. Numerous eosinophils are
present in the squamous epithelium. This change is frequently, but not
always, accompanied by basal compartment hyperplasia, elongation
of the vascular papillae, and widened intercellular spaces (sometimes
referred to as intercellular edema or spongiosis). In the absence of
clinical history, the findings are nonspecific.
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