Gastrooesophageal reflux disease...GERD: a spectrum of clinical conditions and histologic...
Transcript of Gastrooesophageal reflux disease...GERD: a spectrum of clinical conditions and histologic...
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.