Gastrooesophageal reflux disease Jera Jeruc Institute of pathology, Faculty of Medicine, Ljubljana, Slovenia
Reflux esophagitis (RE) 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
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
Dilated intercellular spaces must be differentiated from intracellular vacuoles small <1 ly diameter large 1 ly diameter
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 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 Dysplasia 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.