Jera Jeruc

Institute of pathology, Faculty of Medicine,

Ljubljana, Slovenia

Gastrooesophageal reflux disease

GERD: a spectrum of clinical conditions and histologic alterations resulting from GE reflux

RE: a subset of GERD patients with histopathologic evidence of esophageal ingury

> 50% of patients without distal mocosal breaks

histology considered as a tool of limited value in the diagnosis of GERD

Reflux

esophagitis (RE)

Gastrooesophageal reflux disease

pathogenesis

clinical features

pathology / histology

differential diagnosis

natural history and

complications

treatment of GERD

histological features of NERD

histological features of erosive RD

histological features of cardiac mucosa

in GERD

the value of histological examination in

the diagnosis of GERD

Histological features of RE squamous hyperplasia

increased intraepithelial inflammation (including

eosinophils, neutrophils, lymphocytes)

epithelial cell necrosis

lack of surface maturation (nucleated cells at surface

of epithelium)

distended pale squamous “balloon” cells

intercellular edema (acantholysis)

surface erosions or ulcerations (ERD)

Nonspecific!

Histological features of RE

squamous hyperplasia

increased intraepithelial inflammation (including

eosinophils, neutrophils, lymphocytes)

epithelial cell necrosis

lack of surface maturation (nucleated cells at

surface of epithelium)

distended pale squamous “balloon” cells

intercellular edema (acantholysis)

surface erosions or ulcerations

Squamous hyperplasia Defined by:

lengthening of the subepithelial lamina propria to >2/3 of the

thickness of the squamous epithelium

expansion of the basal zone of the squamous epithelium to

more than 15% of the thickness

increased mitoses, ↑basal and suprabasal nuclei, prominent

nucleoli and hyperchromatism

early manifestation of reflux-induced injury (normal or only

minimally abnormal endoscopic appearance)

correlation between the severity of reflux (24-hour pH score) and

the length of the lamina propria papillae

well-oriented tissue sections with at least three consecutive

papillae - rare in small biopsy samples

caution not to overinterpret “mild” changes as esophagitis

Papillary elongation

normal mild (50-75% of total

epithelial thickness)

Papillary elongation

severe (>75% of total epithelial

thickness)

Papillary length = distance between

upper limit of papillary vessel wall and

base of papilla

Base of papilla = lowest adjacent

basal membrane or, in broad-based

papillae, an ideal line connecting two

adjacent basal membranes

Basal cell layer

hyperplasia

mild (15-30% of total epithelial

thickness)

The uppermost limit of the basal zone

is the point at which >50% of epithelial

cell nuclei are separated by a distance

of < 1 nuclear diameter.

severe (>30%)

Histological features of RE squamous hyperplasia

increased intraepithelial inflammation (including eosinophils, neutrophils, lymphocytes)

epithelial cell necrosis

lack of surface maturation (nucleated cells at surface of epithelium)

distended pale squamous “balloon” cells

intercellular edema (acantholysis) - a useful marker of early injury in the absence of endoscopic evidence

surface erosions or ulcerations

Inflammation - neutrophils

not a sensitive indicator of

RE (<30% of GERD pts with

documented reflux)

not specific for GERD

associated with severe

GERD (erosion, ulceration)

a significant number of

neutrophils → exclude viral

or fungal (Candida) infection

degranulated eosinophils

may mimic neutrophils!

Inflammation - Eosinophils

isolated Eo in normal adults, in the distal 1-2 cm

in adults not diagnostic of E if not associated

with other features

present in 20-40% of RE pts

! not normally present in children

→ even rare Eo, particulary in the lamina

propria - a valuable aid in evaluating RE

large numbers of Eo: adult with reflux primary EoE drug reaction (Stevens-Johnson sy) pill-induced esophagitis collagen vascular disease parasitic infection

Inflammation - lymphocytes a normal intraepithelial

component of the esophageal mucosa, CD8+ T lymphocytes,

10-12 lymphocytes /HPF

a round or an irregular nuclear contour (dd: granulocytes)

more prominent in the peripapillary epithelium

no independent diagnostic significance

present also in other disorders: achalasia, Crohn’s disease

Inflammation A diagnosis of RE can be established in the absence

of inflammation if the basal cell and lamina propria

papillae changes are present, particularly in a patient

who has begun treatment with antireflux agents.

Reflux of gastric juice stimulates squamous epithelial

cells to secrete chemokines that attract inflammatory

cells, and it is the inflammatory cells, not the direct

effect of acid, that is the initial factor responsible for

damaging esophageal mucosa. (Souza RF. Gastroenterology

2009)

Histological features squamous hyperplasia

epithelial cell necrosis

increased intraepithelial inflammation

lack of surface maturation (nucleated cells at surface

of epithelium)

distended pale squamous “balloon” cells

intercellular edema (acantholysis)

surface erosions or ulcerations

Dilated intercellular spaces frequent but nonspecific feature

in the basal layer

a marker for early injury in GERD

loss of tight junctions between cells → increased paracellular permeability → leaking of the acid and direct contact with terminal dendritic processes of sensory neurons in the epithelium

triggering GERD symptoms in the absence of an endoscopic lesion

the prevalence of DIS in GERD varies from 67% to 94%

present also in pts with normal acid exposure

must be differentiated from

intracellular vacuoles

small <1 ly diameter

large ≥ 1 ly diameter

Dilated intercellular spaces

“balloon” cells & capillary ectasia

distended, pale, PAS

negative

in the midzone

chemical injury

Histological features squamous hyperplasia

epithelial cell necrosis

increased intraepithelial inflammation

lack of surface maturation (nucleated cells at surface

of epithelium)

distended pale squamous “balloon” cells

intercellular edema (acantholysis) - a useful marker

of early injury in the absence of endoscopic evidence

surface erosions or ulcerations

Erosions or

ulcerations

active erosions:

necrosis, granulation

tissue or fibrin and

neutrophils

healed erosions:

granulation tissue

covered by thinned,

regenerative

epithelium withot

necrosis, fibrin, and

neutrophils

Erosive ERD

diagnosed on endoscopy

biopsy to rule out infection,

dysplasia, Barrett

esophagus

Reactive hyperplasia Dysplasia

cytoarchitectural uniformity

papillae extend to equal depths

and are of similar width

nuclei uniformly enlarged;

smooth nuclear membranes,

open chromatin, often

prominent nucleoli, no atypical

mitoses

cytoarchitectural

pleomorphism

absent, sharply angulated, or

markedly irregular papillae

nuclei pleomorphic, more

hyperchromatic, irregular

nuclear contours, nuclear

overlapping and loss of

polarity

Cardiac mucosa at the GE

junction: indicator of GERD?

Histologically, columnar lined epithelium

at the GEJ can be classified into:

oxyntic mucosa

oxyntocardiac mucosa

cardiac mucosa (glands composed of

mucous cells without parietal cells)

the significance, location and extent

of CM are controversial (normal

structure present from birth, specific

and sensitive marker of GERD)

cardiac mucosa is a common finding in biopsy specimens taken from the gastro-oesophageal junction

association with reflux symptoms, histological changes indicating GERD and the endoscopic diagnosis of esophagitis

CM is an acquired lesion - a metaplastic response to persistent reflux

represents a sensitive histological criterion for the diagnosis of GERD, the length of the involved segment providing information on the severity of disease (Chandrasoma PT. AmJSurg Pathol 2000)

Biopsy in NERD – yes or no? no gold standard diagnostic test for GERD

50-60% of symptomatic patients have normal mucosa at

endoscopy

hyperemia does not indicate the presence of esophagitis

microscopically

sensitivity and specificity of esophageal biopsy considered

unsatisfactory

general belief that histological examination cannot be

recommended in the diagnosis of non-erosive GERD

(although considered more useful for dg. GERD in infants)

2/3 of symptomatic pts with normal endoscopy have

microscopic esophageal lesions

international group of GIT pathologists

to develope and standardize criteria for recognising microscopic esophageal lesions in GERD

high interobserver agreement

Criteria for microscopic esophageal lesions

in GERD

A combined severity score was developed:

summing up lesion scores and dividing by the number of lesion types assessed

the calculation restricted to basal cell layer hyperplasia, papillary elongation, dilation of intercellular spaces, and the presence of intraepithelial eosinophils (the most informative)

scores 0 to 0.25 were regarded as normal

scores 0.5 to 0.75 qualified for diagnosis of “mild” esophagitis,

scores ≥ 1 qualified for diagnosis of “severe” esophagitis

Central European multicenter histoGERD trial recruited 1071 subjects:

proliferative changes are more common than inflammatory cell infiltration

the microscopic E associated with symptoms, history of PPI intake and the endoscopic diagnosis of E

microscopic E present in 59% of pts with normal endoscopy → histologic diagnosis is more sensitive

Conclusion

Although not rutinely recommended in current

practice guidelines histology can serve as a

useful diagnostic tool.

Biopsies should routinely be obtained when

patients undergo upper GI endoscopy for

evaluation of GERD and may particularly be

beneficial in patients with NERD.

Conclusion

An accurate diagnosis of reflux esophagitis

requires correlation with the patient’s clinical,

endoscopic, manometric, and histologic data.

In the absence of clinical information, a diagnosis of

reflux esophagitis cannot be established on the

basis of biopsy findings alone - in this case a

diagnosis of “esophagitis consistent with reflux”

shoud be made.