Reflux esophagitis (RE)
RE is defined as the inflammation of the lower esophagus du-e to damage caused by acid reflux resulting from lower esop-hageal sphincter dysfunction (1). RE occurs at all ages and in
both sexes, though there is a slight male predominance. Cli-nically, RE may present as nonerosive reflux disease (NERD)
including patients with normal endoscopy with or without
positive pH monitoring, as erosive reflux disease (ERD) inc-luding patients with positive endoscopy, or as complicated
RE comprising ulcers, strictures, hemorrhage, Barrett’s esop-hagus, and adenocarcinoma (4,5). Typical symptoms are he-artburn and regurgitation occurring more frequently after a
fatty meal (6). Epigastric pain, chronic hoarseness and prot-racted hiccups are less frequently observed, while there is a
large group of asymptomatic patients (6,10). RE is a multifac-torial disorder, with different abnormalities predominating in
different patients. Predisposing factors include i) decreased
esophageal sphincter pressure, ii) diminished esophageal cle-arance resulting from defective peristalsis, iii) delayed gastric
emptying or abnormal gastric contractility, iv) decreased sali-vary flow, and v) increased gastric acid production (1,2).
Esophageal dysmotility contributes to decreased clearance of
the refluxed material, thereby leading to an increased muco-sal contact time. The composition and length of time of mu-cosal contact of the reflux material determine the severity of
the disease (1,6). RE involves the most distal part of the esop-hagus, and the gastroesophageal junction in particular. Even
though most patients with RE have classic endoscopic fin-dings of erythema, mucosal edema, erosions, or ulcers, many
patients with typical reflux symptoms have normal or nearly
normal endoscopy (i.e. NERD) (6). In contrast to RE, eosi-nophilic esophagitis (EoE) involves not only the distal esop-hagus; the mid and upper esophagus are also frequently in-volved (7). RE is associated with a variety of histologic featu-res, representing changes from secondary to acid injury and
mucosal healing (2,5). Histopathologic features of acid reflux
are nonspecific and include epithelial hyperplasia, balloon
cells, basal cell hyperplasia, papillary elongation, vascular
congestion, inflammatory cell infiltration comprising
lymphocytes, neutrophils and eosinophils, and dilated inter-cellular spaces (DIS) representing epithelial edema (3,8). Se-veral investigators have developed grading schemes for each
of these histologic criteria in an attempt to correlate with di-sease severity and also to aid in the differential diagnosis
Eosinophilic esophagitis (EoE)
EoE is a chronic inflammatory disorder characterized by eo-sinophilic infiltration of the esophageal mucosa associated
with a history of atopy or allergy (9). EoE was first described
in a case report in 1978 by Landres et al. (11). Attwood and
colleagues (12) subsequently presented the first detailed
study of EoE in 1993, describing intense eosinophilic infiltra-tion in the esophageal mucosa of 12 patients presenting with
severe dysphagia and absence of acid reflux. Eosinophil infil-tration of the esophageal mucosa is the cardinal pathologic fe-ature, although it may occur secondary to several unrelated
diseases such as eosinophilic gastroenteritis, hypereosinophi-lic syndrome, drug exposure, parasitic and fungal infections,
RE, esophageal leiomyomatosis, and scleroderma (7,13,14).
EoE shows an age predilection of children and young adults,
with a male predominance (9,13). Progressive dysphagia
typically described as intermittent and mostly induced with
solid foods (15) and food impaction are the most common
presenting symptoms in adult patients with EoE (13,16), while children typically present with feeding refusal, food in-tolerance, vomiting, abdominal pain, and failure to thrive
(15,17). EoE involves not only the distal esophagus; the mid
and upper esophagus are also frequently involved. Despite
the lack of a pathognomonic endoscopic sign for EoE, red
furrows, white exudates, “crepe paper” mucosa (i.e. fragile
mucosa), corrugated rings, and severe stenosis are the most
characteristic endoscopic findings (15,18). They seem to be
related to the architectural changes resulting from chronic
inflammation leading to fibrosis (15). In contrast to reflux di-sease, patients with EoE have normal pH monitoring and
usually do not respond to acid suppression (12,16). Accor-ding to the criteria of FIGERS (First International Gastrointes-tinal Eosinophil Research Symposium), the diagnosis of EoE
relies upon clinical and histological exclusion of RE and other
causes of mucosal eosinophilia (19). Therefore, ambulatory
pH monitoring, endoscopy and biopsy appear to be the most
valuable procedures for the diagnosis of EoE (15,18).
A different pathogenetic mechanism is involved in EoE,
which seems to be linked to allergic responses to food or air-borne allergens, but cases have also been reported in which
patients have EoE without detectable food allergies by patch
or prick skin testing (14,20). This indicates that EoE could al-so be associated with immune dysregulation, and these tests
might not reflect hypersensitivity driven by discrete antigens
(20). The mechanism is believed to be mediated through ac-tivation of Th2 lymphocytes leading to an increased produc-tion of proallergenic interleukins (IL), especially IL-4, IL-5
and IL-13. While IL-5 promotes maturation of eosinophils
and migration from the bone marrow into the circulating blo-od stream, IL-4 and IL-13 upregulate the production of eota-xin 3 by the epithelium, a chemokine responsible for attrac-ting the eosinophils into the esophagus (13). As a result, ma-ture eosinophils accumulate in the esophagus, are activated
and degranulate, releasing multiple cytotoxic agents. Though
the mechanism of fibrogenesis is still unclear, IL-5, by indu-cing fibroblast-myofibroblast transdifferentiation, may be the
critical molecule for tissue fibrosis as well as smooth muscle
hyperplasia that leads to esophageal stricture formation in Eo-E (14).
In EoE, biopsies show marked eosinophilic infiltrate at diffe-rent levels of the esophagus. However, the presence of an in-creased number of eosinophils in the esophageal squamous
epithelium is a nonspecific finding that may be seen in seve-ral disorders, including RE, infections, drugs, and Crohn’s di-sease (9,14). In order to distinguish EoE from other causes of
mucosal eosinophilia, major and minor histologic criteria for
the diagnosis of EoE have been described (18). Major features
include epithelial eosinophilia >15 eosinophils/high-power fi-eld (hpf) and “microabscesses”, described as clustering of 4 or
more eosinophils and superficial layering of eosinophils. Mi-nor criteria include basal cell hyperplasia, papillary elongati-on, spongiosis (intercellular edema), which is currently
known as DIS, and inflammatory cell infiltration (14,18,26). Infectious esophagitis
Infection is an important cause of esophagitis, especially in
immunocompromised hosts. It can occur under various clini-cal settings including gastroesophageal reflux disease
(GERD), advanced age, immunodeficiency states, chronic al-coholism, diabetes, and motility disorders (2). C. albicans,
cytomegalovirus (CMV), and herpes simplex virus (HSV) are
the most frequently observed causative agents of infectious
The presence of bacteria within esophageal specimens does
not always imply the presence of an infection. Organisms can
be swallowed or carried into the esophagus by the endosco-pe. Bacteria lying freely on the surface or in the lumen are un-likely to be pathogens. Mostly, bacteria are found in biopsies
from patients with CMV, HSV, or Candida esophagitis (1).
Bacterial esophagitis, on the other hand, is defined as the pre-sence of bacterial invasion of the esophageal epithelium or
deeper layers with no concomitant fungal or viral infection
(1,2). It usually involves the previously damaged mucosa, by
GERD, radiation, chemotherapy, or nasogastric intubation
(1,21). The commonest causes of bacterial esophagitis inclu-de Staphylococcus aureus, epidermidis, and Streptococcus
strains (21). Bacterial esophagitis presents with odynophagia,
dysphagia, chest pain, or upper gastrointestinal bleeding. The
most significant complications are perforation, fistulas and
sepsis; the risk correlates with the severity of esophagitis. Bac-teria can be found on Gram-stained sections in the vicinity of
ulcers and erosions (22).
Viral esophagitis is very common, particularly in immuno-compromised hosts. This includes HSV, CMV, Epstein-Barr
virus (EBV), and human papilloma virus (HPV) (1).
Herpes esophagitis is primarily a disease of immunocompro-mised patients with solid organ or bone marrow transplants
(23). Herpes esophagitis can be caused by either HSV type 1
or type 2. Primary infection is common in neonates with dis-seminated HSV, while in adults most cases represent reactiva-tion of latent HSV type (24). Patients typically present with
acute- onset nausea and vomiting, fever, odynophagia,
dysphagia, and chest pain (15,24). Oral herpetic blisters may
suggest the diagnosis, though they are found in only one-fo-urth of the patients (23). Endoscopically, multiple vesicles,
erosions and ulcers with an exudate can be seen (23). Histo-logically, characteristic lesions include the presence of multi-nucleated giant cells and intranuclear inclusions within the
squamous epithelium (24). There are two types of herpetic
intranuclear inclusions: large basophilic inclusions that fill
the entire nucleus – Cowdry type B, and small eosinophilic
inclusions with a clear halo around them – Cowdry type A.
Inclusions are usually found at later stages of the disease and
are located at the edge of an ulcer (24). When viral inclusions
are absent due to sampling error, presence of mononuclear
cell infiltrate including macrophages with convoluted nucle-i adjacent to the infected epithelium is a helpful diagnostic fe-ature. Immunohistochemistry (IHC) may be useful but is ra-rely necessary (24).
Cytomegalovirus (CMV) esophagitis
Immunocompromised hosts, particularly acquired immuno-deficiency syndrome (AIDS) patients and transplant recipi-ents, are at high risk for CMV esophagitis, which is usually ac-companied by systemic CMV infection (23). Patients with
disseminated CMV infection have circulating cytomegalic inc-lusion-containing endothelial cells in their peripheral blood.
Though clinical findings are similar to herpes esophagitis, en-doscopically, a single ulcer located in the distal esophagus is
the most common finding in CMV esophagitis (25). The his-tologic diagnosis is made on biopsies from the ulcer base.
Characteristic cytopathic effects include prominent eosinop-hilic intranuclear Cowdry type A inclusions and cellular en-largement, and occasional granular basophilic cytoplasmic
inclusions are found in endothelial and stromal cells deep in
the ulcer base (24). The classic inclusion has amphophilic
staining with a clear halo around it giving the impression of
an “owl’s eye” (25). These differ from HSV infection, since
CMV inclusions are mostly found in the glandular epitheli-um, endothelial cells, and fibroblasts rather than the squamo-us epithelium. IHC may highlight infected cells without typi-cal CMV morphology. Clusters of macrophages in a perivas-cular distribution at the ulcer base, though smaller, are also
found in CMV infection, similar to HSV esophagitis (25).
The affected patients are almost always immunocompromi-sed. Fungal esophagitis most commonly results from Candi-da species, although Histoplasma, Aspergillus, Paracoccidioi-des, and Cryptococcus can rarely cause esophagitis (1).
C. albicansis the predominant cause of fungal esophagitis (1).
Patients present with acute odynophagia and/or dysphagia in
immunocompromised patients (15,23). Most patients also
have concomitant oropharyngeal candidiasis (1). Endoscopi-cally, whitish, raised, longitudinal, focal, or confluent plaqu-es or membranes cover a friable mucosa in the mid or distal
part of the esophagus. Histologically, erosions and ulcers co-vered with necrotic squamous debris that contains budding
spores and pseudohyphae without true branching and lying
perpendicular to the surface epithelium, are seen (23). Inva-sion of the mucosal or submucosal blood vessels is a common feature. In the absence of pseudohyphae, oral contamination
should be considered before making a diagnosis of candidal
esophagitis (22,23). A periodic acid-Schiff (PAS) or methena-mine silver stain can be useful when no spores are seen on he-matoxylin and eosin (H&E)-stained sections. Parakeratosis
and acute inflammation characterized by the presence of ne-utrophils in the superficial mucosa may call attention to the
presence of Candida (22).
Esophagitis in AIDS patients
Though Candida, HSV and CMV esophagitis are common in
AIDS patients, a proportion present with large discrete ulcers
defined as “giant esophageal ulcers” or “chronic idiopathic
esophageal ulcers” in the mid or distal part of the esophagus.
Evidence of human immunodeficiency virus (HIV) has been
confirmed in these ulcers with a combination of molecular
techniques and IHC (23).
Esophagitis and inflammatory bowel disease (IBD)
Esophageal involvement is an uncommon presentation of
Crohn’s disease. When present, it is usually associated with
extra-esophageal disease. The most common clinical presen-tation is with dysphagia (15,22). Endoscopic findings vary
from erosions and aphthous ulcers to punched-out ulcers and
strictures (21). Histology is rather nonspecific, with erosions,
ulcers and mixed cellular inflammation within the mucosa
and submucosa. Granulomas are found in one-third of the ca-ses. Ulcerative colitis may also involve the esophageal muco-sa especially in pediatric cases (21,22).
The drugs that cause esophagitis comprise antibiotics, non-steroidal antiinflammatory drugs, iron supplements, potassi-um chloride, ascorbic acid, azathioprine, and bisphosphona-tes (1). There is no characteristic finding for drug-induced
esophagitis, since the injury results from either a complicati-on of the therapeutic action of the drug or from direct muco-sal injury caused by the drug, so-called “pill esophagitis” (22).
Pill esophagitis was first described in a patient taking potassi-um chloride tablets (27). Pills lodge in the mid-esophagus at
the level of the aortic arch or in the distal esophagus, where
they have prolonged contact with the mucosa. This occurs
when the drugs are taken with little or no water (22). The ma-in symptoms are sudden retrosternal pain and painful swallo-wing. Endoscopically, discrete punched-out ulcer is the cha-racteristic finding of pill esophagitis (27). Most are superfici-al ulcers that heal readily, except those formed by potassium
chloride, which are deep and may even perforate (27). Besi-des ulcers and erosions, numerous eosinophils may be seen in
the squamous epithelium resembling EoE (7). Remnants of
the pill may be present at the base of the ulcer in some cases
Caustic esophagitis results from ingestion of strong alkalis or
acids either as a suicide attempt in adults or accidentally in
children. Common agents include sodium carbonate, ammo-nium hydroxide and bleaches. Drain cleaners and detergents
are also highly caustic. The extent of injury depends on the
amount and type of the ingested agent and the duration of ex-posure (22). Dysphagia and odynophagia are the main symp-toms. Severe corrosive injury leads to hemorrhage, perforati-on and strictures. The entire mucosa can be separated and ex-truded in the form of a cast. Damage with alkalis is more se-vere than with acids since they penetrate the tissue (1). The
degree of caustic burns can be graded according to the level
of injury within the mucosa, in a similar manner as with skin
Patients receiving radiotherapy and/or chemotherapy for va-rious malignant tumors may develop esophagitis (1). The ex-tent of injury is determined by the type of treatment, durati-on, dose, and tissue sensitivity. The spectrum of injury ranges
from acute self-limited esophagitis to perforation (22). Pati-ents present with dysphagia and chest pain similar to other
causes of esophagitis. In acute cases, mucositis and ulcers can
be found, while strictures and webs develop in chronic cases.
Histologically, significant atypia with bizarre nucle-i and multinucleation is present (2).
Lymphocytic esophagitis is a recently described variant of
chronic esophagitis. It is characterized by extensive
lymphocytosis mainly concentrated in the peripapillary zone
of the squamous epithelium (1). Patients may have as many
as 20-50 lymphocytes/hpf. It has been described in patients
with GERD, celiac disease, Helicobacter pylorigastritis and
Crohn’s disease. It may, however, represent a tissue reaction
rather than a specific entity (22).
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