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Selected Topics in the Evaluation of Pediatric Gastrointestinal Mucosal Biopsies

Scudiere, Jennifer R. MD*; Maitra, Anirban MBBS* †; Montgomery, Elizabeth A. MD*

Advances in Anatomic Pathology: May 2009 - Volume 16 - Issue 3 - pp 154-160
doi: 10.1097/PAP.0b013e3181a12dec
Review Articles

The practice of pediatric gastrointestinal pathology provides specific challenges to the pathologist. Often the clinical information accompanying a biopsy specimen will read simply, “failure to thrive.” Other situations, such as the evaluation of a neonate's rectal suction biopsy for Hirschsprung disease, are notorious for providing diagnostic challenges in high-pressure situations. In this review, we will discuss several commonly encountered situations in pediatric pathology: the evaluation of pediatric esophageal eosinophilia, a child who has swallowed a non food item, caustic substance, or hot liquid, the evaluation of a pediatric colorectal biopsy with focal active colitis, and the evaluation of rectal suction biopsies for Hirschsprung disease. With each topic, we will discuss a general approach to the case, diagnostic tips, and how to avoid commonly encountered pitfalls. Finally, we highlight key references pertinent to these issues that can he used to help convey pathologic findings to pediatric gastroenterologists.

*Department of Pathology, The Johns Hopkins Medical Institutions

The McKusick-Nathans Institute of Genetic Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD

No funding was received for this work.

No authors claim sources of support that require acknowledgement.

Correspondence: Elizabeth A. Montgomery, MD, Department of Pathology, The Johns Hopkins Medical Institutions, Weinberg Building, Room 2242, 401 North Broadway, Baltimore, MD 21231-2410 (e-mail:

All figures can be viewed online in color at

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The child with intraepithelial eosinophils in the esophagus can present in a myriad of ways: with signs of malnutrition, failure to thrive, chronic cough, persistent vomiting, hoarseness, choking spells, irritability, prolonged crying, and even aspiration and recurrent pneumonias.1 Diagnostic considerations for the pathologist include gastroesophageal reflux disease (GERD), allergic esophagitis, upper tract involvement of Crohn disease, infectious esophagitis, and idiopathic eosinophilic esophagitis. Distinguishing these entities requires careful examination of histologic clues along with correlation with the clinical history.

Frequently pediatric gastroenterologists ask the pathologist to differentiate between allergic esophagitis and GERD. Although there are several overlapping histologic features, finding a constellation of characteristic features and a characteristic distribution of disease can assist the pathologist in making this distinction. Regardless of the etiology, multiple biopsies are preferred, as some diseases can be focal.1 Epithelial hyperplasia, characterized by a basal zone thickened to greater than 25% of the total mucosal thickness, can support a diagnosis of GERD. Elongation of the vascular papillae (reaching more than 75% of the mucosal thickness) and an increase in total number of papillae are also useful findings in establishing a diagnosis of GERD. Reflux can also cause basal layer spongiosis (edema, manifest by readily visible intercellular bridges, which are usually inconspicuous in the esophagus) and, in severe cases, erosions and ulcerations. The intraepithelial inflammatory cell component in GERD contains both eosinophils and lymphocytes, with the finding of intraepithelial eosinophils being the most specific criterion for reflux. The presence of eosinophils is not particularly sensitive for reflux, however, as eosinophils are seen in only 40% to 50% of cases.1 In some cases, the eosinophilia is severe, but the presence or numbers of eosinophils does not seem to correlate with severity of patient symptoms (Fig. 1). “Soft signs” of reflux disease include vascular lakes or vascular dilatation and balloon cells, which are cells whose membrane permeability has been altered to allow plasma proteins to enter the cell and distend the cytoplasm.1 Severe or longstanding GERD may result in ulceration with or without stricture formation and Barrett esophagus, even in the pediatric population.1

Allergic disease as seen in the esophagus, unfortunately, has many of the same characteristic histologic findings as GERD, so often the distribution of disease plays an important role in distinguishing these entities. Proximal eosinophilia that diminishes in distal biopsies favors an allergic etiology, whereas a distal eosinophilia may indicate reflux. In general, severe eosinophilia is the hallmark of allergic esophagitis. Although specific eosinophil counts can be misleading, usually allergic disease will harbor more than 20 eosinophils/high power field. Eosinophilic microabscesses may also be present in allergic disease, and clusters of eosinophils tend to be oriented toward the luminal surface of the mucosa with sloughing of degranulated eosinophils.1 A subset of patients with eosinophilic esophagitis has mural predominant disease, which is not sampled on mucosal biopsies; some patients manifest their eosinophilia in the muscularis mucosae or submucosa. Eosinophilia in another gastrointestinal (GI) tract organ may also indicate allergic disease. The patient's history can assist the pathologist as well; failure of antireflux therapy in a child with esophageal eosinophils is an indication that allergic disease should be considered.

Sometimes clinicians request that the pathologist count the number of eosinophils to assess severity of disease or treatment response. Although the desire for some sort of concrete quantification is understandable, there are several reasons why eosinophil count alone should not be used as a diagnostic method or a measure of disease severity or treatment success. First, esophageal eosinophilia is patchy; therefore the numbers attained at each biopsy session are somewhat dependent on chance. If the endoscopist happens to catch a particularly eosinophil-rich or eosinophil-poor area, the eosinophil count will not be representative of the patient's actual disease state. Using “cut-off” values to distinguish types of eosinophilic disease is arbitrary and not evidence based. In a 2007 study, Dellon et al2 found wide variability in diagnostic criteria for eosinophilic esophagitis, including 10 different histologic definitions of eosinophilic esophagitis ranging from 5 to 30 eosinophils/high power field. When presented with these data, many clinicians will agree that direct comparison of biopsies from prior examination dates, when available, is the best way to evaluate interval disease status.

How should the report read? Reporting styles vary, but one way to stress the variable causes of esophageal eosinophilia while emphasizing the importance of careful clinical correlation is as follows: “esophagus (biopsy); squamous mucosa with markedly prominent intraepithelial eosinophils, consistent with eosinophilic esophagitis. Note: the differential diagnosis of eosinophilic esophagitis includes allergic esophagitis, GERD, and idiopathic eosinophilic esophagitis, among others.” Others choose to simply state, “eosinophilic esophagitis.” Regardless of the report wording, the key element is clear understanding between pathologist and clinician.

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Ingested nonfood items can cause significant GI pathology in the pediatric population. Although most small foreign objects ingested by children pass through the GI tract without intervention, some ingested items can cause GI pathology such as perforation, obstruction, and fistula formation.3–6 Other objects (eg, batteries) may also cause caustic injury or systemic effects (such as lead intoxication from lead objects).3,4 The ingestion of nonbeverage liquids can likewise cause significant GI pathology, and many acid and alkaline caustic agents can cause full thickness damage to the GI wall with subsequent perforation and stricture formation.7,8

Although extensive literature is available concerning the treatment of patients who have ingested nonfood items, this review will focus on the pathologist's perspective in the course of examining surgical/histologic specimens.

When an ingested battery passes without intervention through the esophagus into the stomach, it is likely to pass through the remaining GI tract without intervention. Batteries that lodge in the esophagus, however, can cause significant pathology in a surprisingly short duration of time. In a review of pediatric foreign body ingestions, Kay and Wyllie3 describe esophageal perforation occurring within 6 hours. Slamon et al4 described the case of a 17-month-old girl who suffered a tracheoesophageal fistula after swallowing a button battery. At the microscope, the pathologist is likely to see liquefactive necrosis in the esophageal area contacted by the battery.3 Edema can also be present.4

The ileum is the most common site for GI perforation caused by blunt ingested foreign bodies, most likely due in part to the change in bowel lumen size at the ileocecal junction.6 The ingestion of multiple magnets, or ingestion of a single magnet along with a metal object, has also been reported to lead to obstruction, perforation, peritonitis, volvulus, and necrosis.9 Dutta and Barzin5 report a case of a 4-year-old boy who developed fistulization between the cecum and terminal ileum after the ingestion of multiple magnets. Pathologic findings of the affected bowel are nonspecific, but include full-thickness necrosis with or without associated ulceration, suppuration, and associated serosal inflammatory changes.6 In some cases, fragments of the foreign material are found within the pathologic specimen. Cross and Holland6 report a case of small bowel perforation in a 16-month-old boy who ingested driveway gravel.

In most cases of foreign object ingestion, the patient's clinical history will be communicated to the pathologist at the time of specimen submission. When the patient has ingested a caustic liquid, however, the history is not always available to the clinician at the time of endoscopic biopsies (and hence will not be communicated to the pathologist). While describing esophageal changes in debilitated patients,10 the term “sloughing esophagitis” can also describe the sloughing of the superficial epithelial layer in a blister-like fashion after exposure to a caustic substance.11 The endoscopist may describe a blackened mucosal surface and occasionally will report a characteristic odor, such as the odor of household bleach. Pace and colleagues7 report the phenomenon of sloughing esophagitis as a result of the ingestion of toluene-containing household glue. Both acid and alkaline substances can cause severe mucosal damage, but a review by Poley and colleagues8 show that mucosal damage in the upper GI tract was more severe when caused by acid ingestion as compared with alkaline ingestion, with perforation occurring only in those ingesting acid compounds. A review by Arevalo-Silva and colleagues,12 however, describes perforation after both alkaline and acid substance ingestions. Biopsies of the affected esophageal mucosa show superficial epithelial coagulative necrosis. The mucosa gains a “2-tone” or striped appearance, with ghost-like nuclei and a condensed-appearing keratin in the superficial layer contrasting with the paler, nearly unaffected-appearing deep layer (Fig. 2). Areas of intraepithelial vesicle formation, sometimes with neutrophils mimicking bullae, are also seen at the junction of the 2 layers. Sequelae include the development of strictures and fistulas. It is important to note that patients with severe corrosive injury are at a lifelong increased risk for squamous cell carcinoma and must be followed accordingly.13

Thermal injury in the esophagus has been described in the adult population by Dutta and colleagues.14 Esophageal mucosal biopsies of patients who have ingested boiling-hot beverages and soups have shown mucosal changes similar to those encountered in caustic injuries, with “mummified” appearing superficial layers of squamous epithelium that is nonviable and directly opposed to the underlying viable cells.14 Accompanying inflammatory cells are generally not a feature of thermal injury. Endoscopists may report a striped appearance of the mucosa, with alternating areas of pink and white mucosa with adherent pseudomembranes resembling a candy cane.14 In contrast, Choi and colleagues15 report a case with largely whitish-endoscopic appearance and ulceration with granulation tissue and inflammation on histologic evaluation. It is likely that the thermal injury findings in pediatric patients are similar to those seen in adults.

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The pathologist who is accustomed of reviewing adult biopsies will be glad to find that many of the normal findings in the adult colon are mirrored in the pediatric colon, with a few additions. Histologic sections of the normal pediatric colon show parallel crypts, resembling test tubes in a rack. The crypts extend to the luminal aspect of the muscularis mucosae; however, they may fall just short of the muscularis mucosae in the normal rectum. Occasional bifid crypts (some showing an inverted “v” shape) are within the range of normal findings. Paneth cells are normally present proximally to the midtransverse colon, and may be normal even to the splenic flexure. In the descending colon, however, the presence of paneth cells indicates a metaplastic process resulting from some type of mucosal injury. Lymphoid nodules may be present in the lamina propria, submucosa, or in both areas. Lymphoglandular complexes may be present, some with associated crypts, causing focal crypt splaying, branching, and depletion of mucin. As in adults, it is normal to observe intraepithelial lymphocytes over lymphoid aggregates. Intraepithelial lymphocytes should be present but sparse in other areas.

Enema effects may include mild lamina propria edema, fresh lamina propria hemorrhage, and apoptosis at crypt apices. Focal active colitis may also be present, especially after the use of sodium phosphate bowel preps.16,17 This type of focal active colitis consists of only rare neutrophils (fewer than 1 to 3/mucosal biopsy specimen), typically restricted to the deep crypts. Pseudolipomatosis can occur with bowel insufflations (Fig. 3).

Changes associated with inflammatory bowel disease in the pediatric population mimic those seen in adults, with 2 important caveats. Just as from adults, biopsies from children with established inflammatory bowel disease can exhibit crypt distortion, crypt atrophy, basal plasmacytosis, basal lymphoid nodules, paneth cell metaplasia, pyloric metaplasia, and mucosal granulomata (the latter 2 being more characteristic of Crohn disease). However, the long-term significance of focal active colitis in children must receive special consideration, as it is different from that of the adults. Additionally, the pattern of rectal involvement should be considered carefully, as the pattern of rectal involvement (useful for inflammatory bowel disease subclassification) can differ significantly from that seen in adults. When focal active colitis (Fig. 4) is encountered, infection is always included on the differential diagnosis list. In the pediatric population, however, inflammatory bowel disease should also be considered, despite a paucity (or even absence) of additional findings.

The long-term clinical significance of focal active colitis in the adult population was evaluated by Greenson and colleagues in 1997.18 In their study population of 49 adults with focal active colitis, none were found to subsequently develop chronic colitis on follow-up, even when the focal active colitis was accompanied by mild changes of chronicity including basal plasmacytosis and mild crypt distortion. Volk and colleagues19 also evaluated a population of adult patients with focal active colitis, and found that focal active colitis was a harbinger for Crohn disease in 13% of their study population of 31 patients. The most common cause of focal active colitis in the adult population is infection.18

In some children, however, focal active colitis may be a more ominous sign. Children with inflammatory bowel disease may present with no other findings than that of focal active colitis.20 Xin and colleagues21 found that 8 out of 29 (27.6%) pediatric patients who presented with focal active colitis eventually developed Crohn disease and 1 out of 29 (3.4%) developed ulcerative colitis. The remaining patients had infectious colitis (n=9), idiopathic colitis (n=8), allergic colitis (n=2), and Hirschsprung disease (n=1). Unfortunately, no reliable histologic criteria have been found to differentiate self-limited focal active colitis from inflammatory bowel disease-associated focal active colitis. The difference in outcome between children and adults is most likely owing to the different reasons for the endoscopic procedures; many adults receive surveillance colonoscopy, whereas few children undergo this procedure without significant clinical symptoms.21 Although it is fortunate that only a minority of pediatric inflammatory bowel disease patients will present with isolated focal active colitis, it is important to identify and communicate its presence when it occurs in the pediatric population.20,21

Another important diagnostic difference between children and adults comes into play when evaluating inflammatory bowel disease changes in the colon. Although most histologic changes of inflammatory bowel disease in children are the same as those seen in the adult, the pattern of rectal involvement in children can have special significance for disease typing.22,23 The process of differentiation between ulcerative colitis and Crohn disease is riddled with challenges, recognition of which prompted the development of a working group which produced a set of guidelines to facilitate the process.20 The group emphasizes that the lack of standardization and frequent use of the term “indeterminate colitis” can lead to ineffective or inappropriate treatment for patients, inappropriate enrollment in clinical trials, and inappropriate prognostic stratification.20

In untreated adults, rectal sparing (defined as lack of inflammatory changes and lack of chronic changes) essentially excludes a diagnosis of ulcerative colitis. In children, however, new onset ulcerative colitis can present with rectal sparing.20,22,23 Rectal sparing in the pediatric population is sometimes described as “absolute” or “relative” sparing; absolute sparing refers to the absence of both inflammatory changes and changes of chronicity, whereas relative rectal sparing refers to the presence of inflammation in the absence of changes of chronicity.23 Fortunately, absolute rectal sparing is rare (3% of pediatric ulcerative colitis patients in a study by Glickman and colleagues23). Glickman and colleagues23 found that 23% of ulcerative colitis patients had relative rectal sparing. Most commonly, pediatric patients with ulcerative colitis will present with active colitis in the rectum without chronic changes.22 These differences may be restricted to children of 10 years and younger.24 Presumably the minimal findings in children compared with adults at first diagnosis reflect earlier biopsies prompted by concerned parents. It is important to keep in mind these idiosyncrasies of pediatric inflammatory bowel disease to appropriately classify patients for treatment and prognostic purposes.

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The evaluation of rectal suction biopsy specimens for Hirschsprung disease is notoriously stressful and challenging for the pathologist, especially when performed as frozen section evaluations during surgical procedures. Diagnosing Hirschsprung disease on frozen sections of suction biopsies is not recommended. In these tricky cases, non-neural tissues can be mistaken for nerves (such as endothelial cells and tangential sections of blood vessel walls). Very immature ganglion cells lack the eccentric cytoplasm of more mature cells and can be mistaken for lymphocytes. Tissue can also be twisted, turned, and distorted in a frozen section, making the pathologist's job even more difficult.25 On some occasions, however, frozen section evaluation is unavoidable. Of course, frozen sections are valuable for helping surgeons determine an appropriate anastomotic site at the time of resection.

Hirschsprung disease is the first diagnostic consideration in a newborn who has not passed meconium after 24 to 48 hours. This malformation of the enteric nervous system affects an estimated 1 in 5000 live births, and can manifest in neonates, toddlers, school age children, and even adults.26,27 The Hirschsprung disease phenotype is a result of abnormal migration of neural crest elements, and has been associated with multiple mutations in at least 10 different genes.27 Diagnosis of Hirschsprung conventionally requires 2 histologic features: the absence of submucosal ganglion cells and evidence of an increase in presynaptic parasympathetic nerve fibers with abnormal extension into the mucosa (the latter evaluated best with an acetylcholinesterase stain).26–31 Additional adjunct studies, however, can be helpful, and are used more and more frequently in general practice (discussed below).

The ideal biopsy specimen for the evaluation of Hirschsprung disease is a rectal suction biopsy. Several pieces are optimal, with each piece measuring at least 0.2 cm and containing a submucosal thickness that equals the mucosal thickness. Processing preferences vary, but at our institution we prefer to place 1 biopsy in formalin and submit 1 biopsy frozen for acetylcholinesterase staining. Although there is marked controversy over how many slides to evaluate, we prefer a minimum of 75 tissue cuts, keeping in mind that some observers prefer to exhaust the submitted material before rendering a diagnosis of aganglionosis.

Acetylcholinesterase stain examination is a useful adjunctive method, but should not be relied upon as the sole method of diagnosis (see Scenario 2 below for one of the pitfall associated with acetylcholinesterase). This stain is particularly useful (when positive) if the biopsy specimens do not contain an optimal amount of submucosal tissue, as it allows the diagnosis of aganglionosis to be suspected (but not definitively confirmed). In a patient with Hirschsprung disease, the acetylcholinesterase stain demonstrates thickened nerve fibers in the muscularis mucosae that extend into the lamina propria (Fig. 5). These fibers are often coarse-appearing and refractile.32 The age of the patient plays a key role in the evaluation. It is important to note that the proliferation of nerves in the muscularis mucosae can be seen as early as 30 weeks gestation, but abnormal acetylcholinesterase activity (especially in the lamina propria) is less likely to be seen in infants who present within 3 months of birth.32

Many adjunctive tests in addition to the acetylcholinesterase stain have been proposed to assist the pathologist in the evaluation of rectal suction biopsy specimens. A review by Kapur in 200626 discusses 5 categories of immunohistochemical stains proposed as diagnostic aids for Hirschsprung disease: stains for ganglion cell bodies, stains for intrinsic and extrinsic neuronal cell bodies and nerves, stains for intrinsic and extrinsic nerves, stains for extrinsic nerves only, and stains for intrinsic nerves only. Among these suggested stains, one of the most promising is calretinin.26,28 Immunostains for calretinin, an intracellular calcium binding protein, stain some nerve cell bodies in the submucosa and myenteric ganglia of normal (ganglionated) colon, whereas there is an absence of staining in areas that correspond to pathologically aganglionic areas.28 Kapur and colleagues29 compared calretinin immunohistochemistry to acetylcholinesterase histochemistry in a study of rectal suction biopsies from 14 Hirschsprung disease patients and 17 patients without Hirschsprung disease. They found no interobserver discrepancies and no misdiagnoses when calretinin was evaluated, but found significant interobserver disagreement and 2 misdiagnoses when acetylcholinesterase was evaluated.29 From these data, it would appear that calretinin is potentially more useful than acetylcholinesterase in the right hands, and certainly makes a reasonable addition to the panel of diagnostic tests performed on these biopsies, although it remains to be seen whether or not calretinin will gain the popularity that acetylcholinesterase has enjoyed.

Some pitfall diagnostic areas in evaluating aganglionosis are highlighted in Table 1 and shown in Figures 6 to 8.

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Pathologists are usually able to provide helpful information to complete the evaluation of pediatric GI diseases. At times, however, some colleagues may have unrealistic expectations for biopsy interpretation, and believe that biopsy interpretation is a precise science. For example, clinical colleagues often believe that eosinophil counts in the esophagus are akin to a cell count from a cell-sorter, a misimpression noted by Dellon et al.2 Table 2 shows references that we often share with clinical colleagues to underscore the imprecision of certain pathologic features and to address other common questions. We would note that in the GI tract in general, there is a limited set of responses to a variety of injuries and elucidating the particular injury often requires specific understanding of the clinical scenario. We have addressed 4 commonly encountered entities in pediatric GI biopsy interpretation, all of which can usually be resolved with the combination of good morphology skills and dialog with clinical colleagues caring for the patients.

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pediatric; gastroesophageal reflux disease; eosinophils; Hirschsprung disease; focally active colitis; foreign body ingestion; pathology

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