COLUMNAR-LINED ESOPHAGUS IN CHILDREN

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THE COLUMNAR-LINED ESOPHAGUS

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COLUMNAR-LINED ESOPHAGUS IN CHILDREN Eric Hassall, MBChB, FRCP(C)

Children with columnar-lined esophagus (CLE) become adults with CLE. Therefore, an understanding of the disorder as it occurs in children may be important for physicians caring for adults with CLE as well as for pediatric gastroenterologists and surgeons. Although there are many features of CLE common to children and adults, this article focuses on those special features of CLE in children and the issues that pertain particularly to children. DEFINITIONS

For the purposes of this article, childhkd is defined as the first 18 years of life. The terms columnar-lined esophagus and Barrett's esophagus (BE) cannot be defined as succinctly. Although issues of terminology are dealt with in detail in the article by Spe~hler,7~ some clarification is required for the terminology used in referring to childhood CLE. In the past, a commonly used definition of CLE or BE in adults was the presence of columnar epithelium extending more than 3 cm above the top of the lower esophageal sphincter (LES).7,76 There are problems with this definition because there is an imprecise relationship between the LES and the squamocolumnar junction (i.e,, there may be a 2- to 3-cm dissociation between the Z line and the LES in normal adults).= Furthermore, limiting the definition to only length of columnar mucosa above the LES makes for problems in defining shortsegment BE.75,84 In addition, basing the definition on a manometric landmark may confuse the investigating gastroenterologist who usually (and appropriately) relies on endoscopy with biopsies to diagnose BE. A special problem for children also arises; if a more than 3-cm extension of the Z line is abnormal in adults, because esophageal length is proportional to stature, what would be a From the Division of Pediatric Gastroenterology, Department of Pediatrics, University of British Columbia, British Columbia Children's Hospital, Vancouver, British Columbia, Canada

GASTROENTEROLOGY CLINICS OF NORTH AMERICA VOLUME 26 * NUMBER 3 * SEPTEMBER 1997

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correspondingly abnormal extension of the Z line in a 12-year-old, or in a 7year-old? The arbitrary nature and pitfalls of a purely endoscopic definition become apparent. Another major potential pitfall in defining CLE only by its apparent endoscopic length is the presence of a hiatal hernia.",84 In children, this is by far the most common potentially confusing fact0r.2~The endoscopist may fail to recognize that the pink mucosa below an lzpparently proximally relocated Z line is actually that of a hernial sac. Because hiatal hernia is highly prevalent in both adults and children with severe gastroesophageal reflux, CLE is often diagnosed 29, 55, 84

Therefore a different definition has been proposed, based on the nature of the epithelium rather than its length.29, 57, 75, 84 Barrett's specialized epithelium is a metaplastic epithelium, the pathognomonic feature being goblet cells containing acid mucin, which stains positively with Alcian blue at pH 2.5. The presence in the tubular esophagus of this mucosa, long or short segment, 54, 64; it is only this mucosa that is premaconstitutes a premalignant condition26, lignant, not purely fundic or cardiac mucosa.26,57 This CLE or BE is a premalignant condition, the diagnosis carrying implications for long-term surveillance; treatment; and possibly for life insurance, medical insurance, and longevity. Therefore it seems reasonable to restrict the diagnosis of BE to those patients who have epithelium that may be premalignant. The sole purpose of using the label BE is to identify those individuals who require surveillance endoscopy and biopsies because of their risk of developing adenocarcinoma. If not for this risk, this specialized epithelium might be just a "technicolor curiosity" in patients with severe gastroesophageal reflux. Some problems do arise from use of this definition.57,73 In Barrett's specialized epithelium, Alcian blue-positive goblet cells are pathognomonic but constitute the minority of the epithelial cells. Other cell types that predominate include gastric columnar cells with Alcian blue-positive apical mucus and similar columnar cells that are clear Because the epithelial types are present in a mosaic, goblet cells may be absent on a biopsy specimen despite being present in the patient's esophagus. This problem is usually easily obviated by taking multiple biopsy specimens. A second problem arises because a significant number of adults7' as well as some children19appear to have goblet cells or Alcian blue gastric surface cells present focally at a normally located Z line. Are these individuals at risk for adenocarcinoma, and do they require surveillance? The answer to this is unknown as yet; the prudent approach is probably yes, at least while further studies elucidate the issues. Use of the term CLE implies that any type of columnar mucosa apparently lining the tubular esophagus might put the patient at risk. This would vastly overestimate the number of cases requiring surveillance. Ideally, clinicians should describe each case as they find it, for example, "goblet cell-containing mucosa for a length of 5 cm" or "goblet cell-containing mucosa in two biopsy samples at a normally located Z line." For the purposes of identifying those atrisk patients who require surveillance endoscopy, in this article B E is used to denote children with specialized mucosa with goblet cells present for any length in the tubular esophagus. A broader approach is presented under Diagnosis. ETIOLOGY

BE is much more prevalent in adults than in children, but largely because of its occurrence in children, a congenital cause for BE has been proposed by

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COLUMNAR-LINEDESOPHAGUS IN CHILDREN

Table 1. REPORTS OF CHILDHOOD BARRETT'S ESOPHAGUS 1984-1 996' ~~

Author, Year

No. of Patients

Duration of Patient Accrual

Dahms, 198417

13

1978-1 982

Hassall, 198P

11

1977-1 983

3

1978-1 983

Cooper, 1 98712

11

1981-1985

Dahms, 1987'6 Conti Nibali,

3 1

1981-1 986 1987

10 10 28 16 2

Lindahl, 1993"

5

Bar-Maor, 199F

1 5

Rothstein. 1 98Y0

Biopsies in Columnar Mucosa Per Patient (mean)

Length of Barrett's Mucosa (mean)

No. of Patients with Goblet Cell Metaplasia

1 -3 (1-3) 2-7 (4.6) 1 -2 (15) 1-3 (1.4) NS 1

3-8 cm (4cm) 4-13 cm (74 NS

2

NS

1

NS NS

0 0

1975-1988 1982-1 986 1984-1 988 1974-1 991 1990-1991

NS NS NS NS

0 7 14 7 2

1981-1985 1994 1985-1 996

NS Surgical

NS NS NS NS 8-9 cm (8.5cm) NS NS 1-11 cm (6cm)

5 0

1988l' Lindahl, 1 99043 Snyder, 1 99069 Qualman, 199P3 Cheu, 19921° Hassall, 1 99332

Hassall, 1996 (unpublished) Totals

20

20

119

0 0 5

43

'Excluding reported cases of esophageal adenocarcinoma. NS = Not stated.

some. There is extensive, compelling evidence, however, to indicate that Barrett's 28 respecialized metaplasia is an acquired disorder in children and adult~,2~, sulting from both a severe mucosal injury and an abnormal intraesophageal milieu during mucosal repair.6, 74 Acid reflux has been emphasized as being the usual inciting and ongoing injurious factor, but more recently the additional 56 Despite importance of refluxed duodenal contents has been recogni~ed.~~, advances in understanding, it remains unclear why pathologic gastroesophageal reflux results in squamous esophagitis in some persons and Barrett's specialized metaplasia in others. Although the evidence cited for a purely congenital cause of BE can be readily refuted, a congenital component in combination with severe mucosal injury cannot be ruled out.z8 PREVALENCEOFBARREWSESOPHAGUS

Table 1 shows data from 14 reports, 1984 through 1996, in which 119 children were reported to have BE; of these, only 43 had specialized intestinal metaplasia.* Of note is that in many of these studies patients were accrued *References3, 10-12, 16, 17, 32, 35, 42, 43, 53, 60, 69.

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HASSALL

retrospectively from as early as 1974. Therefore the figures do not represent incidence data. The true prevalence of BE in children is unknown; however, some sense of its prevalence may be gained from experiences at two children’s hospitals. In unpublished data from British Columbia Children’s Hospital in Vancouver, BC, over a 12-year period (1985-1996), only seven children were newly diagnosed as having BE (i.e., with specialized metaplasia), for a prevalence of 0.02% of all pediatric upper gastrointestinal endoscopies during that period. Their ages were 8 to 17 years (mean 14 years). In this unit, it is routine practice at endoscopy to document esophagogastric landmarks and take biopsy specimens from the Z line and tubular esophagus; use of this protocol makes it unlikely that BE would be missed. From Children’s Hospital in only seven children with BE (specialized metaplasia) were reported over a 5-year period from 1982 through 1986, for a prevalence of 0.6% of all pediatric upper gastrointestinalendoscopies. In this report, the patients’ ages were 13 to 27 years (mean 20 years), and all seven patients had severe neurologic diseases. Although data regarding prevalence in adults vary, certain features of BE in adults are agreed on: BE is recognized to be primarily a disorder of adults, average age at diagnosis 55 years” to 63 years: with a prevalence increasing with age.8 It is clearly a disorder much less prevalent in children than adults, the true prevalence in childhood depending in part on the definition of child and the group under study. REPORTS OF B A R R E T S ESOPHAGUS IN CHILDREN

Some features of the largest childhood studies are given in Table 1. When data in many childhood reports are examined closely, questions arise regarding the validity of the diagnosis of BE. For example, in many children reported to have BE, the diagnosis has been made on the basis of only a single biopsy specimen 3 or 4 cm above the LES showing fundic mucosa only: many were blind suction biopsies, and details of careful landmark documentation were seldom given. In many pediatric series, the absence of reporting of hiatal hernias, specific endoscopic landmarks, raises the strong possibility that biopsy specimens were taken from hernias, not tubular esophagus. In most reported pediatric series, specialized mucosa has been found in only a minority of patients. In one only 5 of 11 children had specialized mucosa with goblet cells. Those five had been studied recently, prospectively, and with multiple large jumbo biopsy specimens. The current proposal to limit the diagnosis of BE to only those with goblet cell metaplasia would exclude six patients who had biopsy specimens containing cardiac mucosa as proximal as 4 to 15 cm above the LES. Compared to the five patients with specialized mucosa, slides and endoscopy reports were obtained retrospectively, there were fewer and smaller biopsy specimens, and the landmarks had not been documented with the same thoroughness. Although one could exclude those whose most proximal biopsy specimens were 4, 5, and 6 cm above the LES by suggesting that the landmarks had not been well documented, it is less likely that biopsy specimens 8, 10, and 15 cm above the LES containing cardiac mucosa were actually in proximal hiatal hernia. There are two possible explanations for the absence of goblet cell metaplasia in these circumstances: 1. That biopsy specimens were insufficient in number and size and that areas of goblet cell metaplasia were missed. This seems likely.

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2. That even a 10- or 15-cm CLE in a child does not contain some goblet cell metaplasia. This seems much less likely.

Qualman and colleagues53have shown that even when goblet cell metaplasia is present in children or young adults, it is quantitatively much less than in older patients. A 5-year-old patient in that study is the youngest patient in the literature to have well-documented goblet cell metaplasia, suggesting that this type of metaplasia likely takes years to develop. There are some unknowns in the process of evolution of BE; in some children, clinicians are possibly seeing an earlier stage of that evolution. Perhaps BE evolves in some children by the development of goblet cell metaplasia in cardiac mucosa. In other words, perhaps cardiac mucosa in the tubular esophagus is a precursor of BE in children. This issue is explored further under Diagnosis. COMORBlDlTlES IN BARRETT’S ESOPHAGUS In children with BE, the coexisting underlying systemic disorders, or cornorbidities, may be regarded as falling into four categories-neurologic impairment, chronic lung disease (primarily cystic fibrosis), repaired esophageal atresia, and malignancies treated with chemotherapy. In addition, there is a group of children with BE who are otherwise healthy (i.e., without a significant underlying systemic disorder). In Table 2, the numbers and types of comorbidities are juxtaposed with the

Table 2. COMORBlDlTlES IN CHILDHOOD BARRETT’S ESOPHAGUS*

Author, Year

Dahrns, 1984” Hassall, 1985% Rothstein 1 9 8 P Cooper, 198712 Dahms, 198716 Conti Nibali, 1988’’ Lindahl, 199043

No. of Patients

13 11 3 11 3 1

10

No. of Patients with Goblet Cell Metaplasia

2 5 0 1

0 0 0

Snyder, 199069 Qualman, 199053

28

7 14

Cheu, 1992’O

16

7

2 5 1 5

2

Hassall, 199332 Lindahl, 199342 Bar-Maor, 19953 Hassall, 1996 (unpublished)

10

0 0 5

Comorbidities

1 MRlCP 2 MRICP 3 esophageal atresia 2 MR/CP, 1 esophageal atresia 3 leukemia NS

10 gastric tube reconstruction for esophageal atresia 7 MWCP

13 MR/CP (including 3 Cornelia de Lange, 2 Down’s, postencephalitis, leukodystrophy,microcephaly, neurofibrornatosis) 6 MWCP, 1 neuroblastoma, 1 leukemia, 2 autopsy diagnoses 2 cystic fibrosis 5 esophageal atresia NS

3 MWCP, 2 esophageal atresia

*Excluding reported cases of esophageal adenocarcinoma. MR = Mental retardation; CP = cerebral palsy; NS = not stated.

538

HASSALL

childhood reported cases of BE. Because in these studies the diagnosis of BE in many cases was made in the absence of specialized intestinal epithelium, it is not always clear which patients had the comorbidity-those claimed to have BE on the basis of endoscopic appearance either without biopsy specimens or with only fundic or cardiac epithelium present or those with true specialized intestinal metaplasia. For this reason, it is not possible to determine an exact prevalence of underlying systemic disease in children with BE, but, as can be seen from Table 2, probably at least 60% to 70% of children with BE do have a significant comorbidity. A minority of children with BE have no significant comorbidity. These are otherwise healthy children usually with hiatal hernias or perhaps abnormal transient LES relaxations. In the author's experience, hiatal hernia is present in almost all children with BE whether or not a comorbidity is present. In adults with BE, the main comorbidities reported are neurologic impairment,59scleroderma,66and Heller's myotomy for all conditions recognized to predispose to gastroesophageal reflux and poor acid clearance. Other than neurologic irn~airment?~ these conditions were reported in small numbers and appear to constitute a tiny fraction of cases of BE in adults. Neurologic Impairment

The association between major underlying or systemic disorders in BE was first reported in adults rather than children by Roberts and c~lleagues"~ in 1986. They performed upper gastrointestinal endoscopy with biopsies in 27 patients from an institution for the developmentally disabled. Seven (26%) of the 27 patients had BE with specialized epithelium. The patient's ages were 19 to 63 years. Snyder and Goldman- subsequently drew attention to the presence of comorbidities in children (and young adults) with BE. They reported seven children or young adults with specialized intestinal metaplasia, all of whom had underlying mental retardation or cerebral palsy (or both). The mean age of these seven patients was 20 years (range 13 to 27 years). The comorbidities reported in childhood BE are summarized in Table 2; by far the most prevalent are those in which significant neurologic impairment is present. The term neurologic impairment is used to include mental retardation or cerebral palsy of any cause, including that present in various syndromes. Neurologically impaired children often have many factors predisposing to severe gastroesophageal reflux,', 9, 24, 25, 37, 39, 69, 70 such as esophageal dysmotility, poor esophageal acid clearance, gastroduodenal dysmotility, LES dysfunction, and hiatal hernia. They also may have kyphoscoliosis, muscle spasticity, and seizures and may be nursed and fed in the recumbent position for prolonged periods. In addition, mental retardation and cerebral palsy make verbal or motor responses to esophageal symptoms difficult, subtle, nonspecific, or absent. These factors contribute to the relative silence of gastroesophageal reflux in this group, allowing progression to complications before presentation. These same factors also compound the often silent and late presentation of BE itself; late presentation of BE is a problem at all ages, perhaps because the metaplastic epithelium exhibits decreased esophageal pain sensitivity?', 38, 86 Chronic Lung Disease

Another major comorbidity reported with BE is chronic lung disease, specifically cystic fibrosis. Because of several pathogenetic mechanisms, including

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539

chronic cough, negative intrathoracic pressure, raised intra-abdominal pressure, LES dysfunction, and hiatal hernias, children with cystic fibrosis or other chronic lung diseases have a marked predilection to develop pathologic gastroesophageal reflux,* which is silent in the majority of cystic fibrosis patients. Reflux may be silent because gastrointestinal symptoms are truly absent, or these symptoms may be relatively ignored by cystic fibrosis patients because of their plethora of other problems. Some children with cystic fibrosis may consider upper gastrointestinal symptoms such as heartburn, chest pain, and occasional vomiting to be “part of cystic fibrosis” and therefore may not report them.32This delays diagnosis, resulting in presentation with complications of gastroesophageal reflux. BE was first described in two children with cystic fibrosis in 1993; an additional three were reported anecdotally in that With the high prevalence of pathologic reflux in cystic fibrosis patients, it is perhaps surprising that BE had not been previously described in cystic fibrosis. Perhaps BE is truly rare in cystic fibrosis because specialized intestinal metaplasia takes some years to develop in response to chronic severe gastroesophageal reflux and the life span of cystic fibrosis patients is relatively short. BE does occur in children with chronic severe reflux, and the median life span in cystic fibrosis patients doubled from 14 to 28 years between 1969 and 1990.22A more likely conclusion is that cases of BE are being missed in children and young adults with cystic fibrosis, as the literature reflects an apparent reluctance to perform detailed endoscopy with documentation of landmarks and multiple esophageal biopsy specimens in patients with cystic fibrosis. In most reports of esophageal disease in cystic fibrosis, the diagnosis of esophagitis has been made by inference without endoscopy4,13,44,78,80,82 or by endoscopic appearance alone (i.e., without multiple biopsy 20, When severe or erosive esophagitis is present, as in the cystic spec~mens).~, fibrosis patients reported, the squamocolumnar junction and endoscopic features of BE may be obscured by purulent pseudomembranes, ulcers, and bleeding, and unless multiple biopsy specimens are taken, the endoscopist diagnoses only esophagitis and misses the The presence of gastroesophageal reflux is important in cystic fibrosis because it is a major cause of added morbidity for these children. For example, children with cystic fibrosis and gastroesophageal reflux present earlier and spend 10 times more time in the hospital than do cystic fibrosis patients without reflux?* Effective antireflux treatment may lead to a dramatic improvement in pulmonary as well as gastrointestinal symptoms and improved quality of BE carries its own morbidity and implications,but in cystic fibrosis it is additionally important because it is a marker for particularly severe reflux that may exacerbate the nutritional and pulmonary problems of cystic fibrosis patients.

Esophageal Atresia Patients with repaired esophageal atresia have many factors predisposing to severe gastroesophageal reflux: They have a congenitally abnormal (dysmotile) esophagus, and although surgical anastomosis establishes continuity of the esophagus, of necessity the esophagus is foreshortened and a hiatal hernia is often “brought up”.14,25, 85 BE is alleged to occur in children with repaired esophageal atresia,”43,60but these reports are worth examining more closely. In one report,M three children were said to have BE, based on the presence of *References 4, 13, 15, 20, 32, 44,47, 65, 79, 80, 82.

540

HASSALL

fundic or fundic and cardiac mucosa at 3.5 and 10 cm above the LES in one or two biopsy specimens. It is likely that columnar mucosa was present proximally in these patients because the surgeon ”put it there” at the time of anastomosis, by approximating proximal stomach into the mid or proximal chest. Patients with esophageal atresia are recognized to be at high risk for complications of severe gastroesophageal reflux and are therefore candidates for the development of BE. Because of their surgically altered anatomy, however, the diagnosis of BE in these patients should be made only if landmarks are carefully documented and specialized mucosa is present. Surprisingly, thus far none of the patients with esophageal atresia described in the literature have had specialized intestinal epithelium, probably because biopsy specimens have been too few in number and not stained for sialomucins. Of the many patients the author follows with repaired esophageal atresia, one child has developed two foci of specialized intestinal epithelium present in two of multiple biopsy specimens; she is 14 years old, and despite having undergone six endoscopies each with multiple biopsy specimens over a period of 8 years, specialized intestinal mucosa was present at the Z line only at her most recent endoscopy. She had three failed fundoplications and had been receiving omeprazole for 7 years before biopsy specimens showing specialized metaplasia. One other patient of ours with esophageal atresia has a 5 cm BE. Chemotherapy for Malignancies

BE has been reported in patients who received chemotherapy for leukemia, but only in a few adult cases was specialized mucosa with goblet cells The putative mechanism is chemotherapy-induced severe mucositis, which, in a milieu of ongoing reflux owing to chemotherapy-induced chronic emesis, heals in the distal tubular esophagus by columnar metapla~ia.~~, 73 Peters and coworker~:~however, found no increased prevalence of BE in patients treated with chemotherapy for testicular cancer or breast cancer. In addition, three children reported to have columnar metaplasia after chemotherapy did not appear to have goblet cell metaplasia.I6The hypothesis that chemotherapy poses a substantially increased risk for the development of BE requires prospective study of a large cohort of patients. CLINICAL FEATURES

The presence of Barrett’s epithelium per se does not cause symptoms; in fact, it may protect from some symptoms because it is more resistant to peptic digestion than squamous epithelium. Rather the presentation is that of gastro76 Children appear to present more esophageal reflux or its ~omplications.2~~ frequently with vomiting, hematemesis, esophageal food impaction, and respiratory symptoms than do adults; less often with heartburn; and as often with dysphagia.29Perhaps this presentation is due to delayed diagnosis in children. This could be due to nonrecognition of the condition earlier in its course because of reluctance to perform endoscopy or multiple biopsies or due to a comorbidity such as neurologic impairment or cystic fibrosis, in which symptoms and signs are relatively silent. Although the more severe symptoms of vomiting, hematemesis, or esophageal obstruction bring the child to medical attention, a careful history reveals that in the first year of life, severe recurrent vomiting”, 35 or nocturnal cough and documented pneumonias were usually present.35Of these early severe symptoms, reassurance had usually been given that the child would outgrow the symptoms. These severe symptoms do usually abate, often because

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of the development of a protective stricture or because of recurrently injured mucosa replaced by columnar epithelium that is less sensitive to acid reflux. As the reflux becomes silent, the child grows up with symptoms of ”difficulty with eating” or gagging as the norm, until a more severe symptom brings the child to medical attention. The fact that metaplastic epithelium exhibits decreased esophageal pain sensitivity likely accounts for the high frequency of late presentation (i.e., with complications). For example, one third of adults68and most children3I with adenocarcinoma arising in BE presented with a mass and no history of heartburn. Thus, many childhood cases likely go unrecognized until complications occur later in life. Rapid development or progression of dysphagia with or without weight loss suggests that adenocarcinoma of the esophagus may have developed, an uncommon but well-described occurrence in childhood3I (see under Adenocarcinoma of the Esophagus).

DIAGNOSIS

Although the history (and occasionally barium esophagram) may lead to suspicion that BE is present, only a careful and detailed endoscopic examination with targeted biopsy specimens leads to an accurate, definitive diagnosis of BE, its extent, and presence or absence of complications. Initial suspicion of BE should be raised by any of the following: a history of severe gastroesophageal reflux symptoms in the first year of life, esophageal stricture in the absence of caustic ingestion or repaired esophageal atresia, dysphagia or pyrosis, or food impaction in the absence of a primary esophageal motility disorder. Upper gastrointestinal symptoms or signs in children with neurologic impairment, chronic lung disease, or repaired esophageal atresia should increase the index of suspicion. Radiologic findings are not diagnostic of BE; that is, a contrast esophagram cannot distinguish peptic esophagitis from BE. Some radiographic signs of esophagitis, such as mucosal irregularity, nodularity, and thickening, presumably as a result of edema and inflammation, may even be difficult to distinguish from varices or carcinoma.81BE should be suspected, however, if an esophageal stricture is present, especially when accompanied by hiatal hernia.58,81 Strictures have been reported in 30% to 80% of adults with BE2,41, 58, 81 and greater than 70% of children.35In one study of childhood seven of eight strictures were in the midesophagus and one in the proximal esophagus. Endoscopy usually shows a Z line that is proximally relocated into the tubular esophagus. The sharp demarcation between white squamous mucosa and pink columnar mucosa may not be obvious in the presence of ulcerative esophagitis with spontaneous bleeding or friability, exudate, or pseudomem84 Severe inflammation may camouflage the landmarks and nature of brane~.~, the mucosa. The diagnosis could therefore be missed if multiple biopsy specimens are not taken from these areas. If only poor biopsy specimens (i.e., pus or debris with little mucosa) are obtained because of severe esophagitis, treatment with a proton-pump inhibitor (PPI) for 8 to 12 weeks is likely to remove the “inflammatory camouflage” and allow accurate recognition of landmarks at a subsequent endoscopy. Details of landmark documentation at endoscopy and taking targeted biopsy specimens in children and adults are given elsewhere.29* The endoscopist should suspect that BE is present if pink mucosa is seen greater than 2 cm above the LES in a child, but the diagnosis is made definitively only if biopsy specimens of this mucosa show specialized intestinal metaplasia

542

HASSALL

(i.e., with goblet cells). Short-segment BE is present if specialized metaplasia is present within the distal 2 cm of the tubular esophagus in a child. There are some unknowns in the process of evolution of BE; in some children, an earlier stage of that evolution is possibly being seen. Perhaps BE evolves over time in some children by the development of goblet cell metaplasia in cardiac mucosa. In other words, perhaps cardiac mucosa in the tubular esophagus is a precursor of BE in children. So as not to exclude this possibility, the following is proposed for the diagnosis of BE in children. 1. When specialized mucosa with goblet cell metaplasia is unequivocally demonstrated on multiple biopsy specimens in the tubular esophagus for any length above the LES, BE is present. 2. When only fundic mucosa is present, the condition should not be considered BE. 3. When only cardiac mucosa (without specialized mucosa or goblet cell metaplasia) is present greater than 2 cm above the LES in a child, the child should be diagnosed as "possible BE, requires endoscopic and biopsy follow-up." The diagnosis should be verified within a year with endoscopy and biopsies. Because these patients probably are not at increased risk for malignancy, regular surveillance endoscopy is not indicated. Repeat evaluation with endoscopy and biopsy is advisable 3 to 5 years later to determine whether goblet cell metaplasia has developed. ADENOCARCINOMA OF THE ESOPHAGUS

Gastrointestinal cancer is rare in children, accounting for fewer than 2% of all neoplasms in children under age 14 years and fewer than 10% in individuals between the ages of 15 and 29 years.50Adenocarcinoma does occur in children, however, and BE in children may be complicated by the development of adenocarcinoma in adulthood. Therefore, the approach to treatment and surveillance of BE in children has important implications for both children and adults. Most children and one third of adults with adenocarcinoma developing in BE present with a mass and no history of heartburn. To date, 10 patients 11 to 25 years of age have had documented adenocarcinoma of the es~phagus.~' The nine who died all presented late (i.e., with an esophageal mass). SURVEILLANCE

To attempt a scientific approach to this issue, the author used an existing model designed to examine surveillance in adults5I and extrapolated it to children.33This model showed that for a 5-year-old patient with BE and no dysplasia or cancer, even the most aggressive strategy (ie., annual surveillance with esophagectomy for high-grade dysplasia) would result in a remaining qualityadjusted life expectancy of only 52 years. Similarly the most aggressive strategy in a 15-year-old would result in a remaining life expectancy of only 48 years. The possible reasons for this relatively small gain in remaining life expectancy may be that (1)the incidence of cancer in childhood BE is unknown and may be lower earlier on, perhaps rising into the 1% to 2% range only in midlife, and (2) the younger the patient, the greater the cumulative (i.e., lifetime) incidence of cancer. To modify the model for children with BE, it might be more appropriate to use a changing incidence of cancer (i.e., low early, rising with age, as in ulcera-

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tive The model should also include modifiers for comorbidities affecting longevity (i.e., neurologic impairment and cystic fibrosis). In addition, more data are needed regarding the biologic behavior of BE (i.e., duration in years from no dysplasia through to high grade of cancer). A modified model using parameters more appropriate for children has not yet been constructed. At present, a practical approach to surveillance in children must rely on anecdotal data. There are only 10 reported cases of adenocarcinoma of the esophagus in children or young adults (up to 25 years of age).31From the paucity of reports in the literature and the absence of encounters with adenocarcinoma in the experience of most pediatric gastroenterologists and surgeons, one may reasonably conclude that esophageal adenocarcinoma rarely develops in children. Given the reports showing that most patients who are dysplasia negative do not progress to dysplasia over a mean of 34 months,= in those adults followed-up on prospectively who developed cancer, there was an interval of approximately 5 years between diagnosis of BE and development of and the youngest child with specialized intestinal epithelium was 5 years the youngest child with adenocarcinoma developing in BE was 11 years the following recommendations for screening children with BE are offered. 1. Endoscopic surveillance is considered only in those children in whom specialized intestinal metaplasia is present. 2. After the initial diagnostic endoscopy and biopsy specimens have revealed the presence of specialized intestinal epithelium, it is treated with potent acid suppression for 3 months; this removes any exudate camouflaging landmarks and decreases the likelihood of inflammation leading to an erroneous diagnosis of some degree of dysplasia. Then baseline screening is performed as follows: a. Three to four biopsy specimens per centimeter are taken starting at the top of gastric b. Multiple biopsy specimens are taken from any suspicious lesions, specifically ulcers still unhealed after 3 months of acid-suppression treatment or raised lesions. c. Biopsy specimens are reviewed by at least two pathologists experienced in this area. If there is no evidence of dysplasia: (1) Below 10 years of age, endoscopic surveillance is performed with biopsies every 3 to 4 years. (2) 10 to 20 years of age, endoscopic surveillance is performed every 2 to 3 years with the above-mentioned biopsy protocol. 3. Surveillancefrequency is modified on a case-by-casebasis if a major comorbidity is present, specifically life-limiting neurologic impairment or cystic fibrosis.

REGRESSION

The term regression in BE refers to the (possible)event in which the columnar mucosa of the esophagus reverts to squamous mucosa once the chronic insult of reflux is removed.%The potential importance of regression is that if metaplasia can be reversed, can the progression to dysplasia and cancer be prevented? To date, there has not been a well-documented case of complete regression of BE after medical or surgical therapy. When regression has been claimed to occur, it has either been questionable or partial at best. Possible explanations for this disparity are that perhaps complete regression never occurs, histologic mapping has been insufficiently detailed and duration of follow-up too short, or intervention has been too late. Use of PPI therapy for 1 to 3 years in

544

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adults results in an increased number of squamous islands replacing or burying intestinal-type mucosa and a decrease in the overall area of columnar mucosa (i.e., partial regression).61One case of partial regression in a teenager has been reported,34in which multiple areas of white squamous mucosa replaced or buried specialized intestinal mucosa after fundoplication; however, most of the specialized mucosa remained (Fig. 1). Despite partial regression, adenocarciA

B

cm from incisors

cm from incisors

C

I21

22 23 24 ~Whlte Islands

25 sg

29

30 31 32

1333 ItIC

Upper end of fundoplicatlon

34

*

35

Upper end of fundopliutlon

Figure 1. Histologic maps. Representationof the endoscopic and biopsy findings on three occasions. A, At diagnosis, prefundoplication.6, Twenty-one months postfundoplication.C, Five years postfundoplication.The maps show an increasing number of biopsies with purely squamous mucosa or both squamous and columnar mucosa in the same biopsy. Symbols represent surface type epithelium only, even when surface type is buried. Pit and gland epithelium is not shown. S = specialized columnar; sq = squamous; and G = gastric columnar. Each symbol or pair of symbols in apposition represents mucosa found in a given biopsy. For pairs, the predominant epithelial type in the biopsy is shown first. Encircled symbols represent an island seen at endoscopy with the specific histology from that island. (From Hassall E, Weinstein WM: Am J Gastroenterol 87:506-512, 1992; with permission.)

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noma has occurred in residual metaplastic mucosa, suggesting that partial regression is not an adequate goal in itself.6zPerhaps quantitative endoscopy will provide new insights in this area.4O

TREATMENT

The first major goal of treatment in childhood BE is to control the symptoms and signs of gastroesophageal reflux. The second major goal should be to eradicate the specialized intestinal mucosa itself, thereby removing the risk of adenocarcinoma and obviating the need for lifetime endoscopic surveillance. Antireflux surgery or high-dose PPIs have been effective in controlling the symptoms of gastroesophageal reflux disease with which BE often presents and healing the severe erosive esophagitis that often accompanies the ~ondition?~, 71, 74 Children thus treated have also derived significant positive systemic effects, such as increased appetite, weight gain, resolution of blood loss anemia, and an overall sense of improved well-being.25,30, 32, 34 Antireflux surgery and long-term medical therapy with PPIs each has pros and cons, and the issues as they pertain to children are dealt with elsewhere.30Briefly stated, the surgical morbidity and operative failure rates of antireflux surgery are particularly high in children with neurologic impairment, repaired esophageal atresia, and chronic lung disease. The alternative, long-term treatment with PPIs, appears to be efficacious and safe, at least up to 6 or 7 years so far, with few treatment failures. Issues of cost and compliance are also important because one therapy or another is required indefinitely. At present, for children who are at high risk for operative morbidity or failure of antireflux surgery, long-term medical therapy may be the best initial option. Low-risk children should have antireflux surgery as the initial approach. The second goal of treatment, eradication of Barrett’s mucosa, has not been achieved as yet. Despite effective exclusion of gastric contents from the esophagus after antireflux surgery or effective control of acid reflux by high-dose PPIs, only partial regression of Barrett’s mucosa has resulted. At best, white squamous islands may replace or bury relatively small areas of Barrett’s m ~ c o s a .61~ ~ , Various therapies aimed at ablation of Barrett’s mucosa are currently in trials in adults. These include thermal ablation5and ablation by laser alone or as part of photodynamic therapy.48A combination of antireflux and ablative therapies is likely to be the future treatment for children with BE.

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Address reprint requests to Eric Hassall, MBChB, FRCP(C) Division of Gastroenterology B.C. Children’s Hospital 4480 Oak Street Vancouver, British Columbia V6H 3V4 CANADA