Esophageal Biopsy in Children Essential,.11

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Esophageal Biopsy in Children Essential, Valuable, or a Waste

of Time? It all Depends

Eric Hassall

BC Childrens Hospital/University of British Columbia Vancouver BC, Canada

Pediatric gastroenterologists spend a lot of time andenergy on esophageal biopsies - taking them, readingthem, discussing them, sometimes making therapeuticdecisions based on them. While there are a number ofesophageal conditions diagnosable by esophageal biopsy(Table 1) far and away the most common is refluxesophagitis.

The practice of esophageal biopsy is so ingrained inpediatric GI that its utility is seldom subjected to critical

evaluation. Not infrequently, we take esophageal biop-sies that dont contribute to management of the patient.Often, biopsies are insufficient for evaluation, or read asnormal or equivocalthe scourge of the term chronicnonspecific! In these circumstances, we use basic clin-ical common sense, and manage patients according totheir symptoms, usually with a trial of medication. Per-haps that is where we should have started in the firstplace, and omitted the upper endoscopy (EGD) and bi-opsies entirely.

That approach is discussed in this article, in which theutility of esophageal biopsy in patient management isexamined. Its less meaningful to consider biopsy outsideof the context of, so the real question is whether EGD

with biopsy changes management (where with biopsymeans with multiple biopsies). The issue is examinedmostly with reference to GE reflux disease [GERD], butalso other esophageal conditions that occur in children.Such an analysis is more meaningful in the real worldcontext of clinical and endoscopic findings.

ENDOSCOPIC FINDINGS

Some endoscopic findings in the esophagus are con-sidered to be nonspecific and within normal, or have suchmarked interobserver variability as to be unhelpful fordiagnosis. These include erythema, increase or loss of

vascularity, and pallor. While magnification endoscopyand other techniques hold promise for identification ofsubtle changes in the future (1,2), at present it seems thaterosions, ie, mucosal breaks, are the main endoscopicfindings that are considered definitely abnormal, withgood interobserver agreement in reporting (3). In

children and adults, GE reflux is far and away thecommonest cause of erosions, though they occur alsowith other conditions (Table 1). For example, fine linearerosions just above the GE junction can be due to forcefulvomiting from any cause, even of short durationanesophageal extension of Mallory-Weiss tears.

Of course, in many cases the clinical picture narrowsthe differential diagnosis. For example, in the context ofrecurrent substernal pain or heartburn, the presence of

erosions has a high specificity for reflux as the cause. Or,in the context of bloody diarrhea or weight loss orpubertal delay, Crohns disease would likely be the cause.On the other hand, in a patient with epigastric pain orchest pain, the diagnosis might be GERD, eosinophilicesophagitis, peptic ulcer disease, or one of the gastritidesor gastropathies (4).

Lower grades of esophagitis often manifest as discreteerosions on the tops of folds in the distal esophagus.More severe erosive disease can present diagnosticproblems - for example, in confluent erosive disease,hemorrhage, pus and debris may camouflage landmarks,and thereby hide Barretts mucosa (56). Esophagealinfections may also present in this way, especially in the

immune-compromised host (7).

HISTOLOGY

We often get poor quality tissue from the esophagus, inpart because the esophagus is somewhat difficult to bi-opsy, its axis being parallel to the endoscope, but alsobecause small biopsy forceps are often used in pedia-tricsand these skid off the mucosa more easily thanlarger forceps. These problems can be avoided with carefulbiopsy techniques involving turning into the mucosa andapplying suction (7,8), and by using large cup ( jumbo)forceps. These yield biopsies of greater surface area(though not necessarily greater depth) for morphometrythan smaller forceps. Their larger size allows for easiermounting of biopsies, orientation and cutting in the coreof the biopsy block, facilitating morphometric evaluationof changes such as elongation of papillae. Large biopsiesare less compromised by crush artefact. These biopsiesare standard of care in many adult GI units with minor,basic precautions, they can be also taken in children withEric Hassall, MBChB, FRCPC, FACG (e-mail: [email protected]).

Journal of Pediatric Gastroenterology and Nutrition41:S24S27 September 2005 Lippincott Williams & Wilkins, Philadelphia

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safety (8). The quality and quantity of tissue influencesdiagnostic utility (79).

FOR REFLUX ESOPHAGITIS

Reflux esophagitis is a patchy lesion (9,10). Therefore,its not surprising that even when erosive esophagitis ispresent, biopsies may be normal, or show mild throughsevere changes. While sampling errorcan be minimizedby obtaining more tissuemore biopsies, larger biop-siesfrom multiple sites, in reflux esophagitis thereremain some qualitative limitations. For example, onerecent study (11) in adults showed that some 20% ofbiopsies for GERD were insufficient for analysis; buteven with tissue that was adequate, there was an inter-observer variability of 34% and intraobserver variation of10% in diagnosing the presence and severity of refluxesophagitis on pre-op biopsies, and 21% and 6% inpost-op biopsies.

While several abnormalities have been described inreflux esophagitis, histological criteria for reflux esoph-agitis vary among even expert pathologists. For example,although much store is set by the presence and number ofintraepithelial eosinophils, they are not pathognomonicfor reflux esophagitis, being present also in infectiousesophagitis (candida, herpes), idiopathic eosinophilicesophagitis, drug-associated esophagitis, and Crohnsdisease (9). The density of eosinophils on biopsy does notcorrelate with the severity of reflux (12,13), and they maypersist in the epithelium after antireflux surgery (11). Forthese reasons, and because they lack sensitivity for reflux,some expert pathologists use scoring systems that dontinclude eosinophils as a diagnostic criterion for reflux(1,11,12) (Table 2). Intraepithelial lymphocytes, whilemore sensitive than eosinophils or neutrophils in erosiveesophagitis, similarly are relatively insensitive indicatorsfor esophagitis in nonerosive reflux disease (12).

An additional strike against histology for GERD is thatthere is poor correlation between esophageal histologyand symptoms, endoscopic findings, or pH monitoring,both qualitatively and quantitatively in children (1416).

Recent data show that ultrastructural abnormalities arediscernible even in nonerosive disease, and that these healwith PPI treatment (17), but this requires transmissionelectron microscopy. Other data suggest that elongationof the papillae, and basal cell hyperplasia are sensitiveindicators for reflux disease in biopsies taken from 2 cm

above the Z-line, and at the Z-line itself (12); however,there were no controls involved, and these may be normalfindings (7). Taking biopsies at the Z-line might be usefulwhen metaplasia or H. pyloriinfection is suspected (18),but it is the gastric columnar side of the biopsy that is ofinterest in these circumstances.

Utility in patient management: A recent study in adults(19) showed that an EGD altered antireflux therapy onlyin about one-third of cases, in which either stricturedilatation was performed, or Barretts esophagus waspresent, or severe esophagitis was found. The authors

TABLE 1. Esophageal mucosal conditions in children

Reflux esophagitis Caustic ingestion Barretts esophagus Trauma [suction, tubes] Inlet patch Post-sclerotherapy/-banding Eosinophilic esophagitis Radiation-/chemotherapy-induced Infections Collagen vascular disease [scleroderma, Behcets]

-candida albicans Graft-versus-host disease

-herpes simplex-cytomegalovirus

Bullous skin diseases [Stevens-Johnson, epidermolysisbullosa, bullous pemphigoid] Crohns disease Lymphoma Pill-induced esophagitis [eg, NSAIDs, doxycycline] Persistent vomiting, bulimia Mallory-Weiss tears

TABLE 2. Histologic features of reflux disease in a

specific study11

Grade Features

None/indefinite0 No features of oesophagitis1 Elevation of papillae

to .30% mucosal lengthand basal zone increaseto .15% of mucosal length

Mild2 Elevation of papillae to .50%

mucosal length and basalzone .15%of mucosal length

Moderate3 One of the above plus

neutrophil exudateSevere

4 Severe inflammatory exudate,granulation tissue, or markedreparative changes

5 Necrotic mucosa withdense inflammation

6 Fibrosis

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recommended that EGD not be used to tailor protonpump inhibitor (PPI) therapyif the response to PPI ispoor or absent, the dose should be increased and EGDperformed only in case of persistent non-response, oralarm symptoms, or risk for Barretts, or need for chronictherapy. Recent practice guidelines from the US andCanada (20,21) support the approach of empiric therapy

for GERD at the outset. This approach is well-illustratedby the entity of nonerosive reflux disease [NERD], inwhich patients may have symptoms, but no changes atendoscopy or on biopsy. Because not all esophagealsymptoms are due to acid reflux, histology might beuseful in cases that dont respond to PPI treatment thesepatients may have functional heartburn, ie, a motilitydisorder, non-acid reflux, which might require differenttreatment (22).

FOR BARRETTS ESOPHAGUS

Barretts esophagus [BE] is an uncommon disorder inchildren, but an important one not to miss or overcall.The diagnosis carries major implications for the patient risk of malignancy, need for endoscopic surveillance, andpossibly hefty premiums for health insurance and lifeinsurance. Even though the diagnosis of BE may be sus-pected by the presence of pink mucosa extending into thetubular esophagus at endoscopy, confluent erosive dis-ease or hiatal hernia can also mimic this appearance. Inany endoscopic scenario, tissue will make or rule out thediagnosis (5,6,23). The diagnosis is made definitively inadults and children only by the presence of goblet cellscontaining acid mucin that stains with Alcian blue atpH 2.5 (5,6,23) False-positive and -negative diagnosis ofBE may result from poor identification of landmarks andpoor targeting of biopsies, too few biopsies, failure to usespecialized stains, goblet cells missed or overcalled.Sometimes the diagnosis of BE is missed or cannot beruled out because the esophagus is severely inflamed, andbiopsies yield poor tissue or just debris. In this case,repeat EGD with biopsy after a trial of a proton pumpinhibitor [PPI] is important to be determine whether BEis present.

Utility in patient management: In established BE, en-doscopic surveillance is indicated; for dysplasia or cancer,further therapies are indicated. In the absence of BE,surveillance endoscopy is not indicated. Therefore, his-tology is essential for patient management when thisdisorder is suspected or present.

FOR EOSINOPHILIC ESOPHAGITIS [EE]

This is a specific disorder characterized by the pres-ence of high eosinophil counts [.1520/hpf] in theesophageal epithelium, typically through the length ofthe esophageal body (9,24). In contrast, when eosinophilsare present as a feature of reflux esophagitis, they arepresent in fewer numbers and only or prevalently in the

distal esophagus. In addition, in EE, typically, there is nobasal cell hyperplasia or elongation of papillae, featuresof reflux disease. However, in some cases, there are higheosinophil counts and features of basal cell activation. Inthese cases, the diagnosis may be reflux esophagitis, oreosinophilic esophagitis complicated by reflux anunsurprising circumstance, given the presence of esoph-

ageal dysmotility secondary to EE. In these circum-stances, intraesophageal pH study may help, but giventhat it is not always reliable/reproducible, a therapeutictrial, ie, a trial of proton pump inhibitors vs trial ofcorticosteroids may determine the diagnosis.

The clinical presentation is sometimes suggestive ofEE, but there is much overlap with GERD (24). Someendoscopic features are strongly suggestive of the pres-ence of EE, such as small-caliber esophagus, corrugatedor ringed esophagus, proximal stricture, or white specksor papules in patches or through the length of the esoph-agus (24,25) the latter resemble candida infection, andare eosinophilic abscesses. Vertical lines or furrowing isa sign of esophageal inflammation, less specific to EE.The esophagus may also be normal at endoscopy.

It appears that in pediatrics, we may have misinter-preted the significance of intraepithelial eosinophils.Given their poor sensitivity as indicators of reflux, it maybe that esophageal eosinophils more often represent foodallergy or a form of eosinophilic esophagitis than reflux;and the treatment is different. Utility in patient manage-ment: EE is a biopsy diagnosis, and this governs treat-ment. Corticosteroids, inhaled or systemic, are the maintreatment for EE, and generally should be given on thebasis of a tissue diagnosis.

CONCLUSIONS

It seems self-evident that for esophageal disorderswith specific histologic characteristics with specific man-agement, for which biopsy is sensitive and specific, EGDwith biopsy is essential. These include Barretts esoph-agus, eosinophilic esophagitis, or rarer conditions.

In contrast, for GERD, the sensitivity and specificity ofhistology are relatively poor, even in expert hands, andthe diagnosis often can be imputed from other approaches.Pope argued that for adults biopsy in the usual case oferosive esophagitis is a waste of time and money (10).His usual caseis an adult presenting with typical symp-toms of reflux, ie, heartburn, regurgitation, etc. In thiscase, one could justify not doing an endoscopy at all, justgiving the patient a trial of PPI, and performing EGD andbiopsy only in case of a chronic need for drug. This ap-proach is supported by recent guidelines for adults (2023). The reason to perform EGD in the chronic relapsingcase, is to verify the diagnosis as GERD (rather than pep-tic ulcer disease, for example), and to rule out Barretts(6,26). Then the patient can be committed to long-termPPI or antireflux surgery.

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Therefore, for reflux esophagitis without Barretts,theres little evidence that esophageal histology makesa difference to initial clinical care decisions, beyondruling out other conditions. Severity is determined bysymptoms and endoscopic changes (27). Most importantis the patients response to an adequate dose of antirefluxmedication. These practices make sense for pediatrics as

well, and reflect what many practitioners are doing. Thedifference in pediatrics is that heartburn is much lesscommon than in adults and reflux often presents with up-per abdominal pain, or atypical manifestations, ie, thereare fewer usual cases. Nevertheless, in cases of sus-pected GERD, EGD with biopsy can be used in the sameway, to make a diagnosis in case of poor response to PPI,and to have a diagnosis in those cases requiring chronictherapy. The most common scenario would be to deter-mine whether the diagnosis is GERD, or EE, or a com-bination. Prior to endoscopy, in some cases, it is morehelpful for patients to come off drug at least a week ortwo before endoscopy, so that there can be positivefindings (28).

There is no evidence that in the absence of erosions,abnormal squamous histology has any sequelae or bear-ing on patient outcome. In other words, in the asymp-tomatic patient on or off treatment, there is no indicationto perform follow-up endoscopy to look for residualinflammation. The same is the case for eosinophilicesophagitis.

Finally, a key factor is the diligence and skill theendoscopist brings to the procedure. This involves iden-tifying landmarks, obtaining adequate quantity and qual-ity of tissue, and communicating to the pathologist keyinformation such as what drugs the patient is taking, thelocation of biopsies in relation to landmarks, and thedifferential diagnosis based on clinical and endoscopicfindings. With this approach, the utility of esophagealhistology as a patient care tool is maximized.

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Esophageal Biopsy in Children Essential,.11

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