The gastrointestinal tract forms during the 4th week as the cephalocaudal and lateral folds of the trilaminar germ disk develop and incorporate the dorsal part of the endoderm-lined yolk sac into the body cavity to form a tubelike gut. During early embryonic life, the vitelline or omphalomes-enteric duct provides an open connection between the midgut and the yolk sac (Figure 14-1
). This connection becomes progressively longer and narrower as gestation proceeds and eventually forms part of the umbilical cord. By week 10, the communication between the lumen of the midgut and the umbilicus becomes obliterated and soon disappears.
The laryngotracheal diverticulum develops from the ventral foregut during week 4 of gestation (Chapter 12
). Gradual formation of an esophagotracheal septum along the length of the laryngotracheal diverticulum separates the ventral respiratory and the dorsal digestive tubes (Figure 14-2
). The common origin of the trachea and esophagus from the foregut results in various forms of fistulas if separation is incomplete.
During the 2nd month of embryonic life, rapid cellular proliferation within the digestive tube results in a transient partial obliteration of the duodenal lumen, the so-called solid stage of development. Recanalization occurs by week 8 of gestation. Rapid midgut growth within the relatively small body cavity results in a temporary herniation of the lengthening midgut into the umbilical stalk during weeks 6 to 11 (Figure 14-3
). During this physiologic herniation, the intestinal loops rotate counterclockwise, a process that continues as the intestinal loops return to the abdominal cavity during weeks 10 and 11, so that the cecum comes to lie in the right side of the abdomen. If this orderly process fails to occur or is anomalous, the locations of the small and large intestine, mesentery, and fixation points of the intestine to the body wall will be abnormal. The hindgut, or posterior portion of the primitive digestive tube, initially ends posteriorly in the cloaca, separated from superficial ectoderm by the cloacal membrane (Figure 14-4
). A transverse ridge, the urorectal septum, grows posteriorly from the umbilical stalk and gradually divides the cloaca into a ventral portion, the urogenital sinus, and a dorsal portion, the future rectum and anus. This division is normally complete at the end of week 6 of gestation. The membrane covering the anal canal disappears by week 9, so that communication between the digestive tract and the amniotic cavity is established caudally.
DISORDERS OF THE STOMACH
Hypertrophic Pyloric Stenosis
Although pyloric stenosis (PS) most likely presents between the 2nd and 4th week of life, there have been reports of PS in the newborn as well as in infants aged 4 months (14
). PS is a common condition, seen in 1 of 200 infant boys. The male-to-female ratio is 5:1 or greater, and white, firstborn boys are at greatest risk. An increased concordance rate in twins and increased recurrence rate in siblings have been reported (15
). Neurons supplying the circular muscle layer of the pylorus lack activity of the enzyme nitric oxide synthase. The circular muscle layer undergoes hypertrophy and elongation, and gastric outlet obstruction ensues. Progressive nonbilious vomiting, the primary manifestation, commences at 2 to 6 weeks of age in an otherwise healthy infant. The diagnosis is suggested when the hypertrophic pyloric muscle mass, approximately the size of an olive, is palpated in the right upper quadrant after a feeding. Abdominal x-ray films show marked gaseous distension of the stomach, and barium studies demonstrate a narrow and elongated pyloric channel (“string sign”). Treatment is surgical. At operation, the hypertrophic pyloric muscle appears as an elongated sphere (“olive”), approximately 2.5 cm long and 1.5 cm in diameter. A longitudinal surgical incision of the hypertrophic muscle down to the submucosa (pyloromyotomy) immediately and efficaciously relieves the obstruction. Occasional postmortem observations indicate that the circular layer of muscularis propria is hypertrophic, hyperplastic, and disorganized in appearance. The outer, longitudinal muscle layer is attenuated and of variable thickness.
A very unusual cause of gastric outlet obstruction in young infants is an antral web (antral diaphragm) of fibrous tissue and gastric mucosa obstructing the antrum a few centimeters proximal to the pylorus. A small, central aperture, usually no more than several millimeters in diameter, permits passage of some stomach contents; variability in the size of the opening explains the variability in age at presentation. The diagnosis is made by barium studies, and endoscopy is often difficult.
Gastric duplication presents as a cystic mass on the greater curvature or at the pylorus and may present with bleeding, rupture, or obstruction. The pathologic features are similar to those of the more commonly encountered small-intestinal duplication. The mucosa of a gastric duplication resembles stomach mucosa in most cases, but primitive or simplified gut epithelium or intestinal mucosa is also encountered.
Pancreatic Heterotopia and Pancreatic Acinar Metaplasia
Heterotopic pancreatic tissue is most commonly noted in the stomach and proximal small bowel, although it can be seen in the liver, spleen, umbilicus, and other sites. Heterotopic pancreatic tissue also affects small-bowel stenoses, duplications, and diverticula. It is often detected incidentally on imaging studies or at autopsy. The majority of patients are asymptomatic. It usually forms a sessile mass in the antrum; a central depression may be seen, corresponding to the opening of the pancreatic duct draining the heterotopic tissue. It consists histologically of acinar and endocrine pancreas. The term adenomyoma
has been applied to a variant characterized by a predominance of pancreatic duct structures interlaced with smooth muscle bundles but without pancreatic parenchyma. Occasionally, ulceration develops in the overlying mucosa and causes epigastric pain. More commonly in our experience, is the usually incidental histologic finding of clusters or small lobules of pancreatic acinar cells located in the deep gastric antral mucosa, which has been called pancreatic acinar metaplasia.
This lesion is distinct from pancreatic heterotopia in that it is a histologic finding without an associated mass or recognizable endoscopic features and does not include pancreatic ducts or endocrine tissue. It has been associated with chronic gastritis in adults, whereas there are no distinct clinical or endoscopic features in children (16
Spontaneous Gastric Perforation in the Neonate
Spontaneous perforation of the body of the stomach is a rare but frequently fatal condition that can occur in both preterm and term infants, especially those under intensive care (17
). The cause of the perforation is inapparent, although it often occurs in an area of hemorrhagic or coagulative necrosis and may be ischemic or traumatic in origin. The usual presentation is sudden abdominal distension and pneumoperitoneum.
A list of the types of gastritis in children is much shorter than a similar list in adults because of the absence of many of the atrophic, metaplastic, and dysplastic conditions of the adult stomach. However, it is clear that gastritis occurs with considerable frequency in children and adolescents. Numerous classification schemes exist, but for practical purposes, gastritis is categorized by etiology if apparent.
Hemorrhagic and Erosive Gastritis
The etiology of acute hemorrhagic gastritis is multifactorial, with ischemia, stress, and drug therapy playing contributory roles. Drugs known to damage the gastric mucosa include aspirin, corticosteroids, alcohol, and nonsteroidal anti-inflammatory drugs (NSAIDs), such as indomethacin. The ingestion of corrosive substances also causes a similar picture. At endoscopy, a diffusely injected and edematous mucosa, often with petechial hemorrhages and small erosions, is seen. In severe cases, which usually occur in very ill children hospitalized for sepsis, hemorrhagic shock, major surgery, burns, central nervous system disorders, or other severe illness, the changes are most severe in the gastric body and fundus.
Biopsies are usually not obtained in these severely ill patients, and therefore, this condition is usually seen at the time of autopsy. The histologic changes essentially represent a chemical injury to the gastric mucosa caused by reduced host defense against the injurious action of gastric acid and digestive enzymes. Hemorrhage and mucosal edema dominate the histologic picture. Significant inflammation is not present except directly adjacent to areas of ulceration (eFigure 14-3A, B).
Helicobacter pylori Gastritis
Since the early 1980s, it has been recognized that diffuse antral gastritis is caused by infection with H. pylori, a small coccoid or spirillar gram-negative bacillus. This organism, which is the pathogen responsible for the associated symptoms and pathologic changes, is not an opportunist or a commensal. Children with H. pylori infection usually present with nausea, vomiting, and epigastric pain. Endoscopy shows erythema, particularly in the antrum, and, in the more severe cases, erosion, antral nodularity, and thickened gastric folds. However, there is no good correlation between the endoscopic and histologic findings of gastritis. That is, in many cases where endoscopic findings of gastric mucosal erythema, granularity, or erosion are described, biopsies are entirely unremarkable. Conversely, in many cases where the gastric mucosa is described as endoscopically normal, gastritis may be evident histologically.
According to guidelines recently published by the North American and the European Societies for Pediatric Gastroenterology Hepatology and Nutrition (NASPGHAN and ESPGHAN), the initial diagnosis of H. pylori
infection should be based on endoscopy with gastric biopsies (one each from the antrum and corpus) plus either a positive rapid urease test or a positive culture (18
). The rapid urease or CLO (for Campylobacter
-like organism) test is inexpensive and sensitive, and is based on the production of urease by the organism, which causes a change in the color of the test solution. Serologic studies are also sensitive, but positivity may persist for some time after eradication of the organism. On biopsy, the organisms are most reliably found in the antrum, although the fundus and cardia of the stomach may also be affected. The bacilli can be seen faintly on ordinary preparations stained with hematoxylin and eosin, but they are more easily seen with Giemsa, Genta, Warthin-Starry, or immunoperoxidase staining; they appear as small curved or slightly twisted rods, 4 to 5 µm in length, within the mucous coat overlying the surface or superficial foveolar epithelium (Figure 14-10
). The presence of the organisms is almost invariably accompanied by neutrophils.
The antral mucosa exhibits a diffuse superficial infiltrate composed primarily of plasma cells and lymphocytes. Active foci of neutrophilic infiltration may be seen in the lamina propria or in glandular or surface epithelium. Although lymphoid aggregates are normal in the gastric mucosa, the
presence of lymphoid follicles with germinal centers is highly suggestive of past or current H. pylori
infection. In patients on a proton pump inhibitor for dyspepsia or symptoms of GER, the H. pylori
organism may migrate to cause active gastritis of the gastric body mucosa, resulting in an inactive appearance of the antral gastritis.
FIGURE 14-10 • Helicobacter pylori organisms over antral mucosa (Warthin-Starry stain, 400×).
Eradication of the organism is recommended for children with H. pylori
-positive peptic ulcer disease and is based on the use of a proton pump inhibitor in combination with two antibiotics for 7 to 14 days (18
). This typically results in prompt disappearance of the organisms and the neutrophilic component of the mucosal inflammatory cell infiltrates. By contrast, it may take many months for the lymphocytic and plasma cell infiltrates to disappear. Biopsies obtained during this period may be diagnosed as inactive gastritis. The diagnosis of inactive gastritis can be difficult, as there are a number of lamina propria lymphocytes and plasma cells in the gastric mucosa normally (19
). As a general rule of thumb, when the density of plasma cells is such that they are clustered and touching each other, this can be regarded as indicative of inactive gastritis. In some patients with inactive antral gastritis, there may not be an antecedent diagnosis of H. pylori
gastritis, as the infection may have been treated incidentally during antibiotic treatment of infection elsewhere (e.g., otitis media). Treatment failure is not uncommon and is usually related to antibiotic resistance, and options for these children usually include repeat EGD with culture and antibiotic susceptibility testing (18
FIGURE 14-11 • Eosinophilic gastritis. A: A pure infiltrate of abundant eosinophils 200×. B: Eosinophils infiltrate the surface epithelium 400×.
Even though H. pylori causes duodenal ulcers, the organism is not found in duodenal mucosa except in instances of gastric metaplasia of the duodenum, which is rare in children. The mechanism of duodenal ulcer formation in H. pylori infection is thought to involve increased acid secretion as a response to the gastric infection, as well as direct damage by the organism in the areas of duodenal gastric foveolar metaplasia.
In addition to the immediate morbidity of gastritis and ulcer disease in children and adults, infection with H. pylori is known to carry a risk for future adenocarcinoma of the stomach and gastric lymphoma arising in mucosa-associated lymphoid tissue (MALT).
The histologic differential diagnosis of H. pylori
gastritis includes a small number of unusual conditions of the stomach with distinctive clinical and histologic findings, including involvement by eosinophilic gastroenteritis (EG) (Figure 14-11
), CD, chronic granulomatous disease (CGD), and Henoch-Schönlein purpura (HSP). Lymphocytic gastritis, defined as greater than 25 lymphocytes for every 100 epithelial cells in the gastric mucosa (20
), is most frequently associated with celiac disease in children (eFigure 14-4). It is not likely to be associated with H. pylori
infection unless neutrophils are also present (21
Helicobacter heilmannii (Gastrospirillum hominis) Gastritis
infection of the stomach is more rare and not as serious or chronic a disease as is H. pylori
gastritis. The clinical presentation and histologic features are similar except that H. heilmannii
gastritis is more focal and less intense compared to H. pylori
). In addition, H. heilmannii
is a larger organism than H. pylori
, more obviously spiraled, and more readily seen on sections stained with hematoxylin and eosin (Figure 14-12
). Helicobacter heilmannii
and H. pylori
may coexist; the treatment is similar.
FIGURE 14-12 • Helicobacter heilmannii organisms over antral mucosa (Giemsa stain, 1000×).
Peptic Ulcer Disease
Peptic ulcers are of two types: acute (stress) and chronic. They are also classified as primary and secondary, the latter associated with systemic disease. Nearly all peptic ulcers occur in the stomach and duodenum, but they may occur in any location where acid- and pepsin-secreting gastric mucosa is found, including Meckel diverticulum.
Most cases of childhood and adult chronic ulcers have been shown to be caused by infection with H. pylori
, though it has been more recently recognized that a significant proportion of chronic duodenal ulcers (20% to 40%) are not related to H. pylori
, drugs, or any other identifiable cause (23
). Chronic (or primary) peptic ulceration in children is the same acid peptic disease that is so common in adults. This condition can develop in children as young as 4 or 5 years old, although it is more common in preadolescents and adolescents of either sex. It is most common in adolescent boys. Duodenal ulcer is more common than is gastric ulcer. Chronic abdominal pain is the most frequent presenting symptom. More than 50% of the patients have hematemesis, melena, or occult bleeding at the time of presentation. At endoscopy, chronic peptic ulcers are usually round to oval, less than 2 cm in diameter, well delineated from the surrounding mucosa by sharp margins, and covered by exudate at the base.
Microscopically, granulation tissue and scar tissue form the ulcer base, which often extends deep into the muscularis propria. The stomach invariably shows active antral gastritis, and H. pylori
is usually identified. If the ulcer is duodenal, active duodenitis is usually present in surrounding, nonulcerated mucosa. Chronic peptic ulcers usually heal with a medical regimen. Other causes of peptic ulcer disease in children include the Zollinger-Ellison syndrome, cystic fibrosis, short bowel syndrome, and hyperparathyroidism. The Zollinger-Ellison syndrome is rare, occurs mainly in middle-aged adults but has been reported in children, and is characterized by peptic ulceration resistant to therapy, giant gastric rugal folds, and increased serum levels of gastrin. Ulceration due to mucosal injury caused by NSAIDs or other medications is also a diagnostic consideration in older children. Among 360 children with gastritis studied by Dohil et al. (24
), 55% had no detectable cause.
Ménétrier disease is found primarily in adults but is known to occur in children. Though similarities exist, the clinical course and etiology are different. In adults, the cause is unknown and the disease is usually severe and often requires gastrectomy. Childhood cases are often self-limited, and most are caused by CMV infection. Classic Ménétrier disease presents with epigastric or abdominal pain and weight loss. In contrast to adults, children often also present with complications of protein-losing gastropathy, such as ascites, pleural effusions, and periorbital or peripheral edema.
Unlike the adult form, Ménétrier disease in children does not spare the antrum, and hypertrophic gastric folds can be seen throughout the stomach. Histologic features include mucous cell hyperplasia, pronounced elongation and tortuosity of the usually short gastric pits (foveolae), glandular atrophy, and reversal of the usual pit-to-gland ratio. Cysts lined by superficial mucous cells are found deep in the mucosa. Inflammation is more prominent in children than in adults, reflecting the infectious etiology in most children. CMV inclusions are often evident in biopsy material in children. Gastric and urine cultures, serology, polymerase chain reaction and immunohistochemistry, and/or in situ hybridization may be useful ancillary tests. Other associations have included allergy, autoimmunity, and other infections, such as Campylobacter and herpes.
Ménétrier disease is difficult to diagnose in superficial mucosal biopsy specimens. The differential diagnosis includes other causes of large gastric folds: H. pylori gastritis, EG, chronic varioliform gastritis, lymphoma, lymphangiectasia, and other infectious gastritides such as tuberculosis, syphilis, and histoplasmosis.
Foveolar hyperplasia of the antrum in neonates may be caused by prostaglandin therapy administered to maintain patency of the ductus arteriosus in certain forms of congenital heart disease (25
). Usually, the clinical setting, antral location, and presence of hypoalbuminemia make it possible to distinguish this group of neonates from those with Ménétrier disease.
Ectors et al. (26
) presented the spectrum of causes or associations of granulomatous gastritis in 71 adults. CD constituted 52%; isolated idiopathic granulomatous gastritis, 25%; foreign body granulomas, 10%; and the remainder were
related to tumors, sarcoidosis, Whipple disease, vasculitis, or unclassifiable. In our experience, CD is by far the most common cause in children followed remotely by CGD. CGD, an inherited defect of granulocytes, may lead to pyloric outlet obstruction. Endoscopically, in such patients, the antral mucosa is thickened and irregular, and surgical specimens have inflamed mucosa, submucosa, and muscularis. The infiltrate contains mononuclear inflammatory cells, multinucleate histiocytes, and eosinophils. Some have granulomas and foci of necrosis.
Crohn Disease of the Stomach
Involvement of the stomach by CD usually occurs in association with disease in the more common locations—the distal ileum and colon. In a review of 230 children with CD by Lenaerts et al. (27
), 30% had lesions of the esophagus, stomach, and duodenum. On occasion, the initial presentation of CD is as a gastroduodenal process. In such cases, the antrum is usually involved, often in continuity with the proximal duodenum. Obstruction of the gastric outlet is a feature shared with EG and some cases of H. pylori
gastritis. The histology of gastric CD is similar to that in other sites. Particularly suggestive of gastroduodenal CD is the combination of distinctly focal acute inflammation causing destruction of glandular epithelium plus spotty chronic inflammation similar to the characteristic focal involvement of the distal gastrointestinal tract in CD. This focally enhanced pattern of active gastritis in CD is usually distinct from the more diffuse, superficial and plasma cell predominant pattern of gastritis due to H. pylori
infection. In a retrospective study of 238 children with upper gastrointestinal biopsies, focal gastritis was present in 65% of patients with CD and in 20.8% of patients with ulcerative colitis (UC), compared to 2.3% of controls without IBD and one of 39 with H. pylori
). The presence of granulomas is very helpful in addition to these nonspecific inflammatory features. Pascasio reviewed 438 consecutive biopsies in children with gastritis looking for histologic markers for CD such as granulomas and focal glandulitis (29
). Of 58 patients diagnosed as having CD by colonic biopsy and other standard criteria, 34 (77%) were predicted to have CD by gastric biopsy alone. Eosinophils were a significant component in many of the inflammatory foci. In their experience, none of the focal glandulitis biopsies had a history of UC.
Polyps and Tumors of the Stomach
Gastric polyps are rare in children. Juvenile polyps and Peutz-Jeghers polyps may occur in the stomach as part of a generalized polyposis syndrome. Gastric hyperplastic polyps are rare in children but can occur in the setting of H. pylori
gastritis. Fundic gland polyps are a more common clinically insignificant consequence of chronic administration of proton pump inhibitors used to treat GERD and dyspepsia. They are usually small and often multiple and are restricted to the oxyntic mucosa of the proximal stomach. Histologically, they can be difficult to distinguish from normal gastric fundic mucosa as the histologic features can be subtle, despite the endoscopic appearance of a polypoid lesion. The diagnostic histologic features include dilatation of the fundic glands and parietal cells with cytoplasmic protrusions extending into the glandular lumina. Cytoplasmic vacuolization of parietal cells is also common. The complete absence of lamina propria inflammation and edema is a striking feature of these polyps (eFigure 14-5). The surrounding flat fundic mucosa often exhibits histologic features similar to but not as pronounced as those evident in the polyps. Fundic gland polyps also develop commonly in patients with familial polyposis coli. Thus, if a fundic gland polyp is identified in a young patient not taking a proton pump inhibitor, colonoscopy to exclude colonic polyposis may be indicated. Dysplasia does occur in fundic gland polyps associated with familial polyposis coli but is exceedingly rare in the sporadic setting (30
). For this reason, it is not necessary to remove multiple sporadic fundic gland polyps.
Gastric teratomas are large, bulky multicystic masses that project into the gastric lumen or outward into the peritoneal space. Heterotopic pancreatic tissue should be considered in the differential diagnosis of gastric tumors.
Malignant tumors of the stomach are quite rare in children. MALT lymphomas associated with H. pylori
infection and Burkitt lymphomas are the most common types of lymphoma reported (31
). Adenocarcinoma of the stomach is distinctly rare but has been reported in otherwise normal children. It is also known to occur in ataxia-telangiectasia and other primary immunodeficiency disorders. Rare examples of inflammatory myofibroblastic tumor and rhabdomyosarcoma have also been reported.
Gastrointestinal Stromal Tumors
Gastrointestinal stromal tumors (GISTs) occur mainly in middle-aged and older patients, with an estimated incidence of about 5000 cases annually in the United States (32
). Approximately 85% occur in the stomach, with most of the remainder occurring in the small bowel. Presentation elsewhere in the gastrointestinal tract is unusual. About 1% of GISTs present in children, either as sporadic tumors or in the setting of a syndrome. The vast majority of, but not all, GISTs in children occur in the stomach. Iron deficiency anemia is the most common presenting symptom in sporadic cases, while abdominal pain, a palpable mass, or vomiting occurs rarely (33
). Two closely related syndromes feature GIST: the Carney triad and the Carney-Stratakis syndrome. Carney triad is used to describe patients with paragangliomas, pulmonary chondromas, and GIST. About 85% of patients with Carney triad are female, and the GISTs are often multifocal, which is unusual for sporadic tumors. Despite extensive molecular analysis, a specific underlying genetic defect has not been identified in patients with Carney triad (34
) Carney-Stratakis syndrome designates a separate group of patients with GISTs and paragangliomas but no pulmonary chondromas. In these patients, autosomal dominant
transmission has been demonstrated and germ-line mutations in any of three mitochondrial complex II succinate dehydrogenase (SDH) enzyme subunits (SDHB, SDHC, or SDHD) have been documented (35
). GISTs can also develop in individuals with neurofibromatosis type 1, although usually not in childhood.
GISTs are presumed to develop from the interstitial cells of Cajal, which are thought to represent the pacemaker cells throughout the gastrointestinal tract. These cells are normally located within the myenteric plexus and the muscularis propria and have an important role in the regulation of peristalsis. In adults, approximately 90% of GISTs are associated with gain-of-function mutations of the KIT or PDGFR genes. In contrast, these mutations are only present in 15% of pediatric GISTs (32
). Thus, the molecular pathogenesis of pediatric GIST is distinct from the adult counterparts, and the underlying mechanisms are currently undefined.
Pediatric GISTs can be of spindle cell or epithelioid morphology, and mixed forms are also common. Among sporadic tumors, epithelioid tumors are more common overall, but spindle cell morphology is more common in boys. The epithelioid tumors are composed of round to polygonal cells, which may have little or abundant cytoplasm. Cytoplasmic vacuolization is common in these tumors and sometimes can be so prominent as to produce a signet ring cell-like appearance (Figure 14-13A, B
). The vacuoles do not stain for mucosubstances, glycogen, or fat and appear to represent an artifact of formalin fixation. The spindle cell variant of the tumor resembles smooth muscle tumors (SMT), but the cells are usually not as long and slender. Areas of hyaline fibrosis are common in both spindle cell and epithelioid variants of the tumor (see Chapter 25
The diagnosis of GIST is confirmed by immunohistologic detection of cytoplasmic reactivity in tumor cells with the c-kit antibody. Even in pediatric tumors where 15% or less of the tumors have mutations in either the c-kit or PDGFRA genes, most of the tumors still express c-kit by immunohistochemistry. In adults, immunohistologic detection utilizing a recently developed antibody-designated DOG1 has been reported as highly sensitive and specific for the diagnosis of GISTs, including those that are nonreactive with the c-kit antibody (36
). The antigen detected by the DOG1 antibody is uniformly present in Cajal cells throughout the gastrointestinal tract, but not in mast cells, unlike the c-kit protein (37
). In one study, 9 of 11 pediatric GISTs were reactive with the DOG1 antibody (38
FIGURE 14-13 • Gastric gastrointestinal stromal tumor. A: This example demonstrates epithelioid histology, which is more common in the pediatric age group 100×. B: Cytoplasmic vacuoles are sometimes prominent, as seen here 200×.
In the pediatric population, the differential diagnosis of GIST includes leiomyoma, inflammatory myofibroblastic tumor, desmoid fibromatosis, and monophasic synovial sarcoma. In addition to the greater degree of spindle cell eosinophilia, leiomyoma can be excluded based on immunohistochemical negativity for CD117 and DOG1. Prognostic stratification for GISTs has relied primarily on tumor size and mitotic rate (mitotic figures per 50 HPFs) (39
). Management recommendations for pediatric GIST depend on KIT and PDGFRA mutation status as it is presumed that pediatric GIST carrying a KIT or PDGFRA mutation will have a similar evolution and response as adult GIST. In these cases, the mainstay of treatment is imatinib mesylate, an inhibitor that binds to the intracellular portion of KIT and inhibits intracellular signaling. For the majority of children with mutation-negative tumors, the primary treatment is complete surgical resection with the goal of obtaining negative margins, which usually means either a total gastrectomy or a local wedge resection. Adjuvant imatinib is not recommended in mutation-negative GIST as it is not believed to be effective. In the St Jude experience, the incidence of local recurrence was high after primary resection (70%), and greater than 80% after re-resection, with most recurrences manifesting as small peritoneal nodules (35
). Because of the usually indolent nature of GISTs in children, surveillance without therapy is recommended for asymptomatic patients with unresectable or metastatic disease.
Hirschsprung disease (HSCR, aganglionosis) is characterized by an absence of intramural parasympathetic ganglion cells in the distal gastrointestinal tract resulting in persistent contraction of the affected segment and subsequent colonic obstruction. HSCR is a congenital disorder with an incidence of one per 5000 live births. The condition results from defective craniocaudal migration of vagal neural crest cells
(the progenitors of ganglion cells), which populate the entire length of the bowel by the 7th week of gestation. Mutation of one or more HSCR susceptibility genes is the major basis of the disorder (58
). More than a dozen genes have been associated with HSCR, the major one being the RET gene, a protooncogene, which codes for a transmembrane receptor, which has also been identified as disease causing in MEN 2A and which maps to chromosome 10q11.2.
More than 90% of patients with Hirschsprung disease are born at full term with a normal birth weight. Presenting symptoms in neonates include delayed passage of meconium (>48 hours), vomiting, abdominal distension, and, in some cases, enterocolitis. In most cases, Hirschsprung disease is an isolated congenital anomaly (70% of patients), but associations have been noted with Down syndrome (10% of patients with Hirschsprung disease have Down syndrome) and other syndromes such as Bardet-Biedl, Mowat-Wilson, multiple endocrine neoplasia (MEN type 2A), Smith-Lemli-Opitz, Waardenburg, and central hypoventilation syndrome (Haddad or Ondine syndrome).
The aganglionic segment in Hirschsprung disease begins at the anal sphincter and extends proximally (Figure 14-21A to E
). In 80% of cases, aganglionosis is limited to the rectum and distal sigmoid colon, referred to as short-segment disease. In the remaining patients, the aganglionic segment is longer (long-segment Hirschsprung disease) and extends as far proximally as the splenic flexure or transverse colon in 10% and the cecum in 5% (total colonic aganglionosis or Zuelzer-Wilson disease). In rare cases, aganglionosis extends into the small intestine and may reach as far as the proximal duodenum. Short-segment disease is 5.5 times more common in males, is less likely to recur in siblings, and has features suggestive of multifactorial inheritance. By contrast, long-segment aganglionosis shows a significantly lower male gender bias, higher recurrence rate, and genetic properties suggestive of dominant inheritance with incomplete penetrance (58
). In the usual case, barium enema shows a narrow rectum and rectosigmoid colon with a proximal funneling transition to a dilated sigmoid colon. Neonates and infants with long aganglionic segments do not have this diagnostic radiologic picture. Anal manometry is another valuable diagnostic tool used in certain clinical settings. Despite the relative rarity of Hirschsprung disease, it enters into the differential diagnosis of many other conditions because of its
varied modes of presentation and the common occurrence of functional constipation in children.
FIGURE 14-21 • Distribution of affected colon in Hirschsprung disease (stippled area). A: Rectosigmoid aganglionosis. B: Ultrashort Hirschsprung disease affected the distal rectum near the anal sphincter. C: Long-segment Hirschsprung disease with involvement of the hepatic flexure. D: Total colonic aganglionosis. E: Aganglionosis involving the entire colon and the distal small bowel (in exceptional cases, the distal duodenum may be involved).
FIGURE 14-22 • Normal submucosal ganglion cells. A: In this 7-month-old child, ganglion cells are easy to identify 400×. B: In this 8-day-old infant, the ganglion cells are immature appearing and therefore more difficult to identify 400×. (Courtesy of Dr. Eduardo Ruchelli, The Children’s Hospital of Philadelphia.)
Although radiographic and manometric studies are routine diagnostic screening procedures, microscopic evaluation of rectal biopsies is the gold standard for the diagnosis of this disorder. The biopsy should be performed at least 1 to 1.5 cm above the dentate line in order to avoid the normal zone of hypoganglionic distal rectum (59
). Thus, the first task of the surgical pathologist is to assess the adequacy of the biopsy material. A biopsy that contains squamous or anal transitional epithelium should be reported as inadequate and the absence of ganglion cells in such a specimen is disregarded.
The biopsy must also contain an adequate thickness of submucosa in order to evaluate for loss of ganglion cells. An accepted rule of thumb is that in a well-oriented biopsy, the portion of submucosa sampled should be at least onethird the total cross-sectional area of the biopsy (58
). The absence of ganglion cells in an adequate biopsy is diagnostic of HSCR. However, careful examination of a large number of serial sections of each biopsy (75
) is necessary before a diagnosis of Hirschsprung disease is made. As the average distance between submucosal ganglia may be up to 500 µm, a few sections 3 to 5 µm in thickness may miss the ganglia and result in a false diagnosis of aganglionosis. Further, ganglion cells in neonates can have an immature morphology that can be difficult to recognize in H&E sections, particularly in the submucosa (Meissner plexus), and confusion between endothelial cells and neuronal cells may lead to a false-negative diagnosis (Figure 14-22A, B
). One useful feature present in most, but not all, patients with HSCR is the presence of multiple submucosal hypertrophic extrinsic nerve fibers; the presence of nerve fibers with a diameter greater than 40 mm is reported to be characteristic of HSCR (Figure 14-23
). Thick submucosal nerve fibers are reportedly less common in short-segment Hirschsprung disease and in total colonic aganglionosis.
Histochemical demonstration of acetylcholinesterasepositive cholinergic nerve fibers within the lamina propria with the presence of thick ropey fibers in the muscularis mucosa provides supportive evidence for the diagnosis of Hirschsprung disease, since they are not present in normal individuals (Figure 14-24
). However, this change may not be always evident in patients under the age of 6 months, particularly in short-segment Hirschsprung disease. In addition, this technique can only be performed on frozen sections, requiring the clinician to obtain extra biopsies, and the staining procedure must be followed meticulously using freshly prepared reagents.
Immunohistochemical staining with calretinin has recently become a reliable alternate ancillary method to acetylcholinesterase staining. Calretinin is a calcium-binding protein that is expressed by a subset of submucosal and myenteric ganglion cells, some of which extend neurites into the mucosa.
The observation was made that patients with Hirschsprung disease lacked calretinin-immunoreactive submucosal nerve fibers in the aganglionic segment of the colon (61
). Absence of calretinin-immunoreactive small nerves or neurites in the lamina propria and muscularis mucosae, with appropriate positive and negative control sections, has now been shown to be the equivalent of AChE histochemistry as a confirmative finding in HSCR (62
) (Figure 14-25
). A clear advantage is that calretinin immunostaining can be performed on formalin-fixed paraffin-embedded sections, obviating the need for additional biopsies or frozen sections. An important caveat that remains to be confirmed in further studies is the presence of calretinin-immunoreactive fibers extending into very short segment of aganglionic colon, complicating the diagnosis of very short segment HSCR (64
FIGURE 14-23 • Hypertrophic submucosal nerve fibers in a patient with Hirschsprung disease 100×.
FIGURE 14-24 • Acetylcholinesterase stain of a rectal biopsy in a patient with Hirschsprung disease. Note the presence of abnormal ropey nerve fibers in the muscularis mucosae and lamina propria 400×.
FIGURE 14-25 • Calretinin immunostains performed on sections from suction rectal biopsies. A: In a normal infant, calretinin reactive submucosal nerve fibers and neurites in the lamina propria are prominent 200×. B: In an infant with Hirschsprung disease, there is no reactivity in the submucosa or lamina propria in the aganglionic segment 200×.
A number of different histochemical stains (using lactic dehydrogenase, alpha-naphthyl esterase, and NADPH-diaphorase on frozen sections) and different antibodies (S-100, NSE, bcl-2, bone morphogenic protein 1A, and RET) to detect ganglion cells in paraffin sections have been proposed over the years but are not superior to H&E coupled with either acetylcholinesterase or calretinin and thus have not found widespread clinical use.
The definitive treatment of HSCR is surgical, and a number of different operations can be performed. The Swenson and Soave procedures involve removal of the aganglionic segment (in the case of the Soave procedure the mucosa and submucosa of the aganglionic segment are stripped) with creation of a ganglionated neorectum using normally innervated bowel, in either a one-step or two-step procedure with an intervening ostomy. On the other hand, in the Duhamel procedure, ganglionated bowel is brought down and anastomosed directly to the aganglionic segment. In either case, intraoperative seromuscular biopsies for examination of the myenteric (Auerbach) plexus are required mainly to identify normally ganglionated bowel for the anastomosis or ostomy. Seromuscular biopsies should be a minimum of 5 mm in length and require proper orientation and sectioning perpendicular to the serosa to visualize both layers of the muscularis propria to confirm the presence or absence of ganglion cells within the myenteric plexus. Ideally, the specimen should present a shrimplike or C-shaped profile. The myenteric plexus and ganglion cells within seromuscular biopsies are larger and easier to interpret than those in the submucosal plexus, provided the biopsy is adequate and there are no artifacts. In HSCR, nerves are present, usually thicker than normal, and ganglion cells are completely absent. Frozen sections performed above the grossly narrowed segment, to confirm that normal numbers of ganglion cells are present, allow the surgeon to identify the proper
level at which to transect the colon. An important point to remember when examining these frozen sections is that colonic segments from patients with HSCR usually contain a transition zone of variable length, with some degree of hypoganglionosis and hypertrophic nerves, immediately proximal to the aganglionic segment. As definitive anastomosis in this zone is associated with continuing postoperative constipation, intraoperative frozen sections must ensure that the segment of bowel used for anastomosis has a normal complement of ganglion cells and normal-caliber nerves (65
Finally, examination of the resected bowel in HSCR is done to confirm the diagnosis of aganglionosis, determine the length of the aganglionic segment, map the transition zone, and verify the integrity of the innervation of the proximal margin. The latter is best accomplished by examining a complete full-thickness circumference of the margin.
(HAEC) is a dreaded complication of this disorder and a major cause of morbidity. It can occur before surgical treatment and from 3 weeks to 20 months after the pull-through operation (66
) and can develop in aganglionic and ganglionated bowel. Several factors have been associated with an increased risk of developing HAEC: delay in diagnosis, increased length of the aganglionic segment, and trisomy 21. In one series, 45% of patients with trisomy 21 and Hirschsprung disease had enterocolitis (67
Patients with HAEC present with abdominal distension, vomiting, fever, lethargy, and shock; abdominal radiographs reveal a distended proximal colon and absence of air in the rectosigmoid region, a useful feature, which has been termed the “cutoff” sign (66
). Pathologic features can vary from a mild acute cryptitis to a full-blown mucosal ischemic necrosis; some cases may have a pseudomembranous appearance. A grading system for the histopathologic findings has been proposed (68
). Neonates may present with a picture suggesting necrotizing enterocolitis (NEC) with pneumatosis intestinalis (69
The mortality rates vary from 0% to 30%, with lower rates observed in more recent studies (70
). It requires aggressive management including antibiotics (71
). In cases of repeated enterocolitis, the possibility of persistent obstruction should be investigated, including rectal biopsies to rule out residual aganglionosis.
Chronic Intestinal Pseudo-Obstruction
The term intestinal pseudo-obstruction denotes greatly impaired or absent peristalsis without mechanical obstruction to luminal flow. Pseudo-obstruction is a clinical syndrome, not a pathologic diagnosis, and encompasses a wide spectrum of entities. A classification of these disorders was published recently, the major subclasses of which are neurogenic and myopathic (Table 14-4
). The guidelines proposed by this working group also offer diagnostic criteria for these various entities, using both H&E and immunohistochemistry (72
essentially fall into two main groups: quantitative disorders, where there is an abnormality in the number of enteric neural cells (absent, as in Hirschsprung disease; hypoganglionosis; and hyperganglionosis), and qualitative disorders, where there is a cytomorphologic abnormality. The latter include acquired disorders such as inflammatory and degenerative neuropathies (Chagas disease, lymphocytic and eosinophilic ganglionitis, laxative-induced neurotoxicity) and cytologic abnormalities such as intraneuronal nuclear inclusions, an inherited disorder. The diagnosis of a quantitative abnormality such as hypoganglionosis is less easily accomplished because of a lack of robust quantitative data from normal controls (73
). Values for neuronal density appear to vary with age, the region of bowel sampled, the degree of intestinal dilatation, and the methodology. Hypoganglionosis
is encountered most frequently in the transition zone proximal to an aganglionic segment. A recent systematic review of isolated hypoganglionosis (not in association with HSCR) identified only 92 published cases, the diagnosis of which remains uncertain given the differences in methodologic workup. Most reported patients presented with some form of slow transit constipation and the outcome has been variable (74
). The authors also concluded that diagnosis required
full-thickness biopsies. Other techniques have tried to detect abnormalities in the myenteric plexus not otherwise observable on routine H&E sections. For example, silver staining of thick sections of muscularis propria embedded flat to view the myenteric plexus have resulted in the description of a number of rare abnormalities but have not found wide application in clinical diagnosis (75
). More modern techniques including confocal microscopy and digitalization with three-dimensional viewing of the enteric nervous system offer the possibility of a better understanding of these conditions.
TABLE 14-4 CLINICAL CLASSIFICATION OF PEDIATRIC INTESTINAL PSEUDO-OBSTRUCTION
Aganglionosis (Hirschsprung disease)
Intestinal neuronal dysplasia
Retarded neuronal maturation
Diffuse abnormal layering of small-intestinal smooth muscle
Segmental additional smooth muscle coat
Focal absence of smooth muscle
Degenerative visceral myopathy
Visceral involvement in muscular dystrophies
Megacystis-microcolon-intestinal hypoperistalsis syndrome
IDIOPATHIC (NO DIAGNOSTIC PATHOLOGY)
From Kapur R. Motor disorders. In: Russo P, Ruchelli E, Piccoli D, eds. Pathology of Pediatric Gastrointestinal and Liver Disease. Heidelberg, Germany: Springer Verlag; 2014a:249-317, with permission.
can be encountered mainly in two situations: ganglioneuromas and intestinal neuronal dysplasia (IND). Ganglioneuromas can occur anywhere in the alimentary tract but are most commonly seen in the colon and rectum. The most common form is the isolated polypoid ganglioneuroma, which occurs more frequently in children. These can be sessile or pedunculated, may be grossly indistinguishable from juvenile or hamartomatous polyps, and are usually not associated with disturbances in intestinal motility, neurofibromatosis, or MEN syndromes. On histologic examination, the lamina propria is expanded by a proliferation of ganglion cells and Schwann cells. Multiple ganglioneuromatous polyps (ganglioneuromatous polyposis) are associated with juvenile polyposis and Cowden syndrome (CS). The diffuse form of ganglioneuromatosis is characterized by a proliferation of ganglioneuromatous tissue extensively involving submucosal and myenteric plexuses, which can produce structural thickening along the bowel wall (77
). The latter is associated with multiple endocrine neoplasia type 2B (MEN2B), CS, and neurofibromatosis.
has been described in association with Hirschsprung disease and as an isolated form. The latter is a controversial entity, with histologic diagnostic criteria that have varied since its initial description 40 years ago, and is neither well described nor widely accepted in the English medical literature. It has been divided into two forms by its proponents: IND-A, the rarest form, and IND-B. Patients with IND-A have been reported to present with constipation since early infancy. Histopathologic descriptions feature hypoplasia of the sympathetic innervation of the myenteric plexus, detected by catecholamine immunofluorescence on frozen sections, in association with hyperplasia of myenteric ganglion cells and increased acetylcholinesterase staining in the lamina propria (78
). IND-B, on the other hand, is characterized by the presence of “giant” (>8 ganglion cells) submucosal ganglia (Figure 14-26
). There may be associated increased acetylcholinesterase staining of the lamina propria. However, since it is now recognized that giant ganglia are more numerous in premature infants and neonates, this criterion is felt to be diagnostic only in patients older than 4 years of age. Current criteria rely on histoenzymologic stains for dehydrogenases to highlight ganglion cells on 15-µm-thick frozen sections, with “giant” ganglia involving a minimum of 20% of all submucosal ganglia (79
). The applicability of these criteria to the evaluation of H&E-stained 4 µm-thick paraffin sections is uncertain. The clinical significance of these findings is equally unclear, and conservative management is considered sufficient, without the need for surgical resection (79
). The reproducibility of the histologic diagnosis of IND-B remains poor, and some investigators believe these features may represent a normal variant of postnatal development rather than a pathologic process (80
FIGURE 14-26 • Giant ganglion in a patient with intestinal neuronal dysplasia 400×.
can usually be appreciated by conventional microscopy, although full-thickness specimens of intestinal wall are necessary because the abnormalities are in the muscularis propria. Degeneration, atrophy, and sometimes fibrosis of intestinal smooth muscle are revealed by hematoxylin and eosin stain and enhanced by Masson trichrome stain. The outer, longitudinal layer of the muscularis propria is almost always more affected than the inner, circular layer. Most patients, except those with congenital megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS), present later in childhood or adolescence. MMIHS is a congenital disorder with possible autosomal recessive inheritance diagnosed at birth or by prenatal ultrasonography. Affected infants present with abdominal distension, vomiting, microcolon, and markedly distended bladder and/or ureters. According to a recent review of more than 200 cases, mortality is high, with survivors maintained by parenteral nutrition or bowel transplant (81
). Smooth muscle degenerative changes also occur secondarily in the muscular dystrophies, particularly Duchenne muscular dystrophy, in whom esophageal and gastric dysmotility are more common than intestinal pseudo-obstruction. Major pathologic changes include atrophy and fibrosis of the muscularis propria and muscularis mucosa, though few descriptions
). Intestinal dysmotility can also be a key feature of mitochondriopathies, which include mitochondrial neurogastrointestinal encephalomyopathy (MNGIE); mitochondrial myopathy, epilepsy, lactic acidosis, and strokelike episodes (MELAS); and Alpers disease. Pathologic features include patchy atrophy of the muscularis externa and eosinophilic cytoplasmic inclusions in enteric ganglion cells (83
). Diffuse abnormal layering of the intestinal smooth muscle is a relatively recently described X-linked disorder with distinctive pathologic features characterized by a trilaminar arrangement of the muscularis propria (84
). Other alterations of the visceral smooth muscle include the “brown bowel syndrome,” due to lipofuscin deposition in the muscularis propria resulting from vitamin E deficiency (85
) and disorders such as myocyte hypertrophy with honeycomb fibrosis, alpha smooth muscle actin deficiency, and loss of the pacemaker cells of Cajal [reviewed in (58
Intussusception, or the invagination of a portion of the intestine into itself, is a relatively common pediatric surgical problem. Infants, particularly those between 5 and 9 months of age, are most commonly affected. More than 90% of cases of childhood intussusception begin at the ileocecal valve, and the intussusceptum may reach as far as the descending colon or rectum. Progressive compression of the blood supply of the invaginated bowel causes edema, hemorrhage, and ischemic necrosis. In the classic case, severe, intermittent, colicky pain begins suddenly in an infant, followed after a few hours by vomiting and the passage of blood and mucus from the rectum. Barium enema is both diagnostic and therapeutic. The obstructing mass of invaginated bowel can be recognized, and if the congestion and edema are not too advanced, the application of hydrostatic pressure by the radiologist reduces the intussusception. Operative reduction is required if barium enema reduction fails, as happens in 20% to 30% of cases (86
FIGURE 14-27 • Small-bowel intussusception in an infant due to adenovirus infection. A: Histologic section from the lead point of the intussusception demonstrating lymphoid hyperplasia 20×. B: High power demonstrates smudgy intranuclear inclusion within enterocytes 200×. C: Immunostain utilizing an adenovirus antibody confirms the diagnosis 200×.
Gangrene of a portion of the intussusceptum necessitates segmental intestinal resection in approximately 10% of cases. These specimens exhibit edema, congestion, and coagulative and hemorrhagic necrosis indicative of combined ischemia and venous outflow obstruction.
In most cases, the cause is unknown. Large Peyer patches have been proposed as the possible lead point in many cases. Lymphoid hyperplasia due to adenovirus infection has been implicated in a subset of patients (Figure 14-27A to C
). Use of the first commercially available oral rotavirus vaccine was associated with an increased risk of intussusception in children,
leading to withdrawal of the vaccine from the market (87
). Newer-generation vaccines do not appear to have this risk (88
Approximately 10% of cases of childhood intussusception do not conform to the typical picture. In children past infancy and in atypically located intussusceptions (i.e., those not in the ileocecal valve region), a discrete lead point is usually identified. Meckel diverticulum, Peutz-Jeghers polyps, juvenile polyps, small-intestinal duplications, and Burkitt lymphoma have been implicated.
TABLE 14-5 PEDIATRIC GASTROINTESTINAL INFECTIONS
Means of Diagnosis
Stomach, especially antrum
Epigastric abdominal pain in surface
Active chronic nonspecific gastritis; organisms visible mucous coat
Histologic identification of bacilli on biopsy, culture of endoscopic biopsy
Salmonella (S. enteritidis, S. typhi, S. choleraesuis)
Distal SI, especially ileum, colon
Gastroenteritis; inflammatory, bloody, mucoid stools; enteric (typhoid) fever
Acute enteritis with exudation, hemorrhage, focal ulceration; acute infective colitis; hypertrophy, necrosis, and macrophage infiltration of Peyer patches, mesenteric LN
Stool culture, blood culture (S. typhi)
Colon, distal SI
Bloody, mucoid stools, diarrhea, cramps, fever, convulsions
Acute infective colitis
Massive watery diarrhea and dehydration
Enteritis; may show villous atrophy
Stool culture and serotyping
Watery diarrhea, traveler’s diarrhea
Stool culture and serotyping
Distal SI, colon
Bloody, mucoid diarrhea
Acute infective colitis
Stool culture and serotyping
Colon, distal SI
Bloody diarrhea, hemolytic uremic syndrome
Acute infective colitis
Stool culture on selective medium, serotyping, toxin assay
Abdominal pain, diarrhea, bloody stools
Acute enteritis, acute infective colitis, acute appendicitis, mesenteric adenitis
Entire GI tract especially ileum, appendix, colon
Diarrhea, abdominal pain, fever
Enteritis with ulcerations and microabscesses; terminal ileitis mimicking Crohn disease; necrotizing appendicitis; acute infective colitis with aphthoid ulceration; mesenteric adenitis
Pseudomembranous colitis, antibioticassociated diarrhea
Pseudomembranous colitis, acute colitis
Toxin assay on stools
SI, colon; systemic spread in immuno-suppressed
ND for GI tract
Stool culture, rectal swab on selective media
Acute watery diarrhea; dysenteric-like illness, colitis
Mycobacterium avium complex
Diarrhea, abdominal pain, malabsorption in AIDS
Acid-fast bacilli in macrophages throughout lamina propria
Identification of acidfast bacilli in macrophages in lamina propria of intestinal biopsy
All GI tract
Depends on location
Pseudohyphae and yeast forms with acute inflammation
Fungal stain on biopsy
Diarrhea, malabsorption, failure to thrive
Proximal SI changes range from minimal change to chronic inflammation and villous atrophy. Organisms on H&E
Stool examination for cysts; mucus smears of intestinal biopsy; identification visible of trophozoites on proximal SI biopsy
Small intestine in normal hosts; stomach, SI, and colon in AIDS patients
Minimal change or mild, nonspecific enteritis; organisms visible on H&E
Stool examination for cysts; identification by histologic examination of proximal SI biopsy
Hematochezia, diarrhea, bloody, mucoid diarrhea
Diffuse acute colitis, microulcerations, deep ulcers undermining mucosa, organism visible on H&E
Stool examination for trophozoites and cysts; identification of trophozoites on histologic examination of colonic biopsy; serology; identification of organism on biopsy
Watery diarrhea, vomiting
Enterocyte necrosis, partial villous atrophy, mononuclear inflammation
Watery diarrhea, vomiting
Stool ELISA, PCR on stool
Inclusions in surface epithelium
Identification of inclusions on biopsy
ELISA on stool
All parts of GI tract
GI bleeding, hemorrhagic colitis, esophagitis
Focal necrotizing colitis, esophagitis, gastritis; inclusions visible in endothelium and mesenchymal cells
Identification of inclusions on endoscopic biopsy, culture of biopsy or stool, and IHC
Small focal (aphthous) ulcerations, inclusion in epithelium
Identification of inclusions on biopsy, culture of biopsy, and IHC
GI, gastrointestinal; H&E, hematoxylin and eosin; LN, lymph node; SI, small intestine; ND, not described; ELISA, enzymelinked immunosorbent assay; RT-PCR, reverse transcriptase polymerase chain reaction; IHC, immunohistochemistry.
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