Introduction
The conventional approach to teaching inflammatory disorders of the gastrointestinal (GI) tract is to describe clinical and histologic features of individual disease entities. Unfortunately, mucosal biopsies of the GI tract are not normally given a specific diagnosis. Therefore, it is incumbent on the pathologist to evaluate all of the clinical, endoscopic, and histologic features in each case to establish a specific diagnosis. One of the biggest challenges in mucosal biopsy pathology is to recognize a specific morphologic pattern of injury. Use of standardized terminology is critical because each discrete morphologic pattern of injury has well-defined etiologic associations and therapeutic implications. For instance, a diagnosis of “Barrett’s esophagus” or “inflammatory bowel disease” leads to lifelong endoscopic surveillance of the patient and imposes a significant burden on patients and on the health care system. Use of nonstandardized terms such as “nonspecific esophagitis” or “nonspecific colitis” is misleading and, therefore, not helpful for patient management.
The purpose of this chapter is to outline a simple algorithmic approach to the diagnosis of common inflammatory disorders of the GI tract in mucosal biopsies. The process begins by dividing biopsies into one of several broad categories (e.g., normal, inflammatory, neoplastic) and is followed by a systematic evaluation of morphologic features to determine a specific morphologic pattern of injury. This approach often implies a fairly standard etiologic differential diagnosis.
Esophagus
Esophageal biopsies can be broadly categorized as normal, inflammatory, or neoplastic ( Fig. 13.1 ). Normal esophageal mucosa is composed of nonkeratinizing squamous epithelium with a basal zone that is one to three cell layers thick, papillae that are confined to the lower half of the mucosa, and lamina propria that is composed of loose connective tissue without inflammatory cells ( Fig. 13.2 ). The presence of surface keratinization, parakeratosis, spongiosis, or inflammatory cells in the epithelium is a sign of mucosal injury and should lead to further evaluation of the biopsy specimen for a specific morphologic pattern of injury.
If a biopsy is considered inflammatory, the next step is to evaluate the dominant inflammatory cell type. Inflammation in the esophagus may be dominated by eosinophils, neutrophils, lymphocytes, granulomas, or a combination of these cells, and each of these categories has well-defined etiologic associations (see Fig. 13.1 ). Disorders with prominent eosinophilic and/or neutrophilic patterns of inflammation are classified as active esophagitis and are further graded as mild, moderate, or severe based on the severity of inflammation. As illustrated in Figure 13.1 , gastroesophageal reflux disease (GERD) and infections may be associated with more than one pattern of inflammation; for that reason, they are always in the differential diagnosis of inflamed (or even near-normal) esophageal biopsies. However, endoscopic or histologic evidence of esophagitis is present in only approximately 40% of patients with well-established GERD.
Eosinophil-Predominant Esophagitis
Intraepithelial eosinophilic infiltration is the most common pattern of inflammatory injury in esophageal biopsies. GERD and eosinophilic esophagitis (EoE) are the diseases most commonly associated with this pattern of injury. The presence of eosinophils in esophageal mucosa is not necessarily diagnostic of primary EoE, a well-defined clinicopathologic disorder which is discussed in detail in Chapter 14 . No single clinical, endoscopic, histologic, or treatment parameter allows for absolute distinction of GERD from EoE. EoE is a clinicopathologic diagnosis and requires correlation with patient symptoms; endoscopic features; the density, pattern, and gradient of eosinophilic infiltration in mucosal biopsies; and treatment response. Some of the salient features that help distinguish GERD from EoE are summarized in Table 13.1 and illustrated in Fig. 13.3 . Eosinophilic infiltration in esophageal mucosa may also be present in disorders other than GERD and EoE. A list of these disorders and the clinical or morphologic features that are helpful in making these diagnoses is presented in Table 13.2 .
| Features | Reflux Esophagitis | Eosinophilic Esophagitis |
|---|---|---|
| Clinical History | ||
| Allergy/asthma | Low incidence | High incidence |
| Food impaction | Uncommon | Common |
| Symptoms | ||
| GERD symptoms | Typical | May be present |
| Dysphagia | May be present | Common |
| Endoscopy | ||
| Rings | Uncommon | Typical |
| Linear furrows | Uncommon | Typical |
| Erosions/ulcers | Typical | Uncommon |
| pH/impedance | Abnormal | Normal |
| Pathology | ||
| Inflammation gradient | Distal >> Mid/upper | Mid/upper >> Distal |
| Eosinophilic infiltrate | ||
| Maximum no. | <10/HPF | >15/HPF |
| Clusters | No | Yes |
| Superficial aggregates | No | Yes |
| Microabscesses | No | Yes |
| BCH/spongiosis | Mild | Severe |
| Therapy | ||
| Response to PPIs | Yes | No |
| Response to steroids | No | Yes |
| Diagnosis | Diagnostic Features |
|---|---|
| Infections | Viral inclusions/parasites on biopsy |
| Eosinophilic gastroenteritis | Gastric/SI involvement |
| Achalasia | Motility studies |
| Hypereosinophilic syndrome | Peripheral blood hypereosinophilia |
| Crohn’s disease | Granulomas, colon/SI involvement |
| GVHD | Apoptosis, history of BMT |
| Drug hypersensitivity | Clinical history |
Neutrophil-Predominant Esophagitis
A neutrophil-predominant inflammatory pattern of injury may be associated with infections, GERD, pill esophagitis, or corrosive mucosal injury ( Fig. 13.4 ), among other causes. The presence of surface hyperkeratosis in association with a neutrophilic inflammation should prompt a search for fungi, such as Candida . Yeast and pseudohyphae may, at times, be confined to surface keratinous debris and may be associated with either minimal or no inflammation in the epithelium or lamina propria. Cytomegalovirus (CMV) and herpes esophagitis may also be associated with a neutrophil-predominant pattern of inflammation, and these infections may be diagnosed when typical viral inclusions are demonstrated in the biopsy. A diagnosis of pill esophagitis should be considered when the inflammation, or ulcer, is present in the upper and middle levels of the esophagus. This diagnosis requires correlation with the patient’s medication history. Similarly, the presence of active esophagitis containing scattered atypical cells with large, hyperchromatic epithelial and/or stromal nuclei may be indicative of radiation esophagitis. Corrosive mucosal injury often leads to necrosis of the upper half of the squamous epithelium, and a band of neutrophils may be present between the superficial necrotic and deeper viable mucosa.
Lymphocyte-Predominant Esophagitis
Intraepithelial lymphocytosis of variable severity is not an uncommon finding in esophageal biopsies. When it is associated with basal cell hyperplasia and scattered eosinophils and/or neutrophils, it is most likely a result of GERD. The presence of hyperkeratosis and scattered neutrophils should always raise suspicion for Candida esophagitis. The presence of a severe (and pure) lymphocytic infiltrate, particularly in the peripapillary epithelium, is diagnostic for lymphocytic esophagitis ( Fig. 13.5 ). Lymphocytic esophagitis is a poorly defined entity with myriad etiologic associations; the most notable are motility disorders and Crohn’s disease. Crohn’s disease manifests in the esophagus with a lymphocytic esophagitis pattern of injury more often in pediatric patients than in adults. Other disorders that cause intraepithelial lymphocytosis in the esophagus are listed in Box 13.1 . When the lymphocytic infiltrate is distributed predominantly at the epithelial lamina propria interface and scattered necrotic keratinocytes are present, the possibility of a dermatologic disorder such as lichen planus should be considered.
Crohn’s disease (particularly in pediatric age group)
GERD
Infections
Motility disorders
Allergy/asthma
Autoimmune diseases
Immunodeficiency (HIV, CVID)
Celiac disease
Esophageal involvement in dermatologic disorders
CVID , Common variable immunodeficiency; GERD , gastroesophageal reflux disease; HIV , human immunodeficiency virus.
Granulomas
Granulomatous esophagitis ( Fig. 13.6 ) is associated with Crohn’s disease or sarcoidosis in almost all cases. Rare causes of granulomatous esophagitis include mycobacterial or fungal infection, vasculitis, and drug-induced mucosal injury.
Pauciinflammatory Esophagitis
A list of pauciinflammatory disorders is shown in Table 13.3 . Graft-versus-host disease (GVHD) is the disorder that most frequently manifests with this pattern of mucosal injury ( Fig. 13.7 ). Apoptosis and necrosis in the absence of inflammation, characteristic of GVHD, overlaps with mycophenolate-induced mucosal injury. Infections in immunocompromised patients also may lack an inflammatory response. Amyloidosis is another disorder that may be easily missed because the mucosa is typically completely normal and the diagnostic changes are subtle, usually confined to the blood vessels in the lamina propria and superficial submucosa.
| Diagnosis | Features |
|---|---|
| CMV, HSV | Viral inclusions |
| GVHD, mycophenolate | Increased apoptosis |
| Corrosive injury | Superficial necrosis |
| Taxol, colchicine toxicity | Mitotic arrest |
| Skin disorders (pemphigus) | Vesicles, bullae |
| Scleroderma | Submucosal fibrosis |
| Amyloidosis | Perivascular deposits |
Ulcers
In some instances, one may see ulcerated granulation tissue, without viable mucosa, in a biopsy of the esophagus. A specific diagnosis cannot be rendered in most of these cases. However, biopsies with this pattern of injury should be evaluated for viral inclusions, pill fragments, and neoplastic cells before they are dismissed as “nonspecific.”
Gastroesophageal Junction
The anatomic gastroesophageal junction (GEJ) is defined, endoscopically, as the proximal limit of the gastric rugal folds. The squamocolumnar junction (SCJ) represents the point of transition from pearly-gray squamous mucosa of the esophagus to salmon-red columnar mucosa of the proximal stomach (or the distal esophagus in cases of Barrett’s esophagus). In healthy individuals, the SCJ is located at the GEJ, whereas in patients with Barrett’s esophagus (BE), the SCJ is located proximal to the anatomic GEJ. When an endoscopic biopsy is submitted with a question of BE, it is imperative for the pathologist to know the precise location of the biopsy, even before histologic evaluation is performed. Biopsies labeled as “GEJ,” “SCJ,” or “Z-line” cannot be definitely labeled as BE, even when goblet cells are identified in the biopsy, unless there are morphologic features in the biopsy specimen that help determine that the columnar epithelium is located in the anatomic esophagus. These features include multilayered epithelium, mucosal or submucosal glands or ducts ( Fig. 13.8 ), subsquamous (“buried”) glands, or hybrid epithelium. A definite diagnosis of BE can be rendered only in biopsies obtained from (and confined to) the distal esophagus and in which goblet cells are identified in the columnar epithelium.
Ultimately, the differential diagnosis of goblet cells in a GEJ biopsy includes BE and carditis with intestinal metaplasia. Distinction between these two conditions is important, because patients with BE require lifelong surveillance with biopsies for early detection of dysplasia or cancer. Carditis with intestinal metaplasia is most often caused by Helicobacter pylori infection, whereas BE is a complication of long-standing GERD. The epidemiologic, clinical, and pathologic differences between these two conditions and the methods of distinguishing them in mucosal biopsies from the GEJ region are discussed in Chapter 14 .
Stomach
General Comments
Gastric mucosal biopsies may be broadly categorized on morphologic evaluation as either normal, inflammatory, or neoplastic. Another category consists of lamina propria infiltrates or pigment deposition in the absence of significant lymphoplasmacytic, neutrophilic, or eosinophilic inflammation ( Fig. 13.9 ). Normal gastric corpus mucosa is composed of closely packed oxyntic glands, whereas the antrum is composed of pure mucus glands ( Fig. 13.10 ). In older children and young adults, both compartments show minimal intervening stroma and few or no scattered plasma cells in the lamina propria. However, with advancing patient age, a mild lymphocytic or plasma cell infiltrate is considered “normal” if not associated with epithelial injury or repair. Primary lymphoid follicles without active germinal centers are normally present at the base of gastric corpus mucosa and should not be considered a manifestation of chronic gastritis. However, lymphoid aggregates in the antrum, lymphoid aggregates with active germinal centers, and the presence of a band-like lymphoplasmacytic infiltrate beneath the surface epithelium are all features of chronic gastritis.
Gastritis
Determination of the predominant inflammatory cell type in the lamina propria is the first step in diagnosing gastritis (see Fig. 13.9 ). A lymphoplasmacytic infiltrate is by far the most common type of inflammatory reaction seen in gastric biopsies in routine practice. This pattern (also broadly referred to as chronic gastritis ) includes several well-defined clinicopathologic entities. This pattern of inflammation should be evaluated for pattern of injury (focal versus diffuse), region of the stomach predominantly involved (antrum versus corpus or both), location in the mucosa (superficial versus deep), degree of active inflammation, presence or absence of microorganisms, atrophy of oxyntic glands, endocrine cell hyperplasia, intraepithelial lymphocytes (IELs), and subepithelial collagen layer, among others features ( Table 13.4 ).
| Feature | Helicobacter | Other Infectious | Autoimmune | Lymphocytic | Collagenous | Eosinophilic |
|---|---|---|---|---|---|---|
| Lymphoplasmacytic infiltrate | +++ | ++ | ++ | ++ | ++ | + |
| Antral predominance | +++ | − | − | ± | ± | − |
| Superficial bandlike infiltrate | +++ | ± | − | ± | ± | − |
| Microorganisms or viral inclusions | + | + | − | − | − | − |
| Oxyntic gland atrophy | ± | ± | +++ | − | − | − |
| Endocrine cell hyperplasia | − | − | +++ | − | − | − |
| Increased IELs | ± | − | − | +++ | ± | − |
| Thick subepithelial collagen layer | − | − | − | − | +++ | − |
| Eosinophil clusters, aggregates, and epithelial damage | − | ± | − | − | ± | +++ |
Focal Gastritis
Focal active gastritis may be a gastric manifestation of inflammatory bowel disease (IBD), particularly in pediatric patients ( Fig. 13.11 ). It may also be seen in children with autism. The etiologic associations of focal active gastritis in adults are diverse, and the association with IBD is weak. Infections such as CMV and adenovirus, Helicobacter heilmannii, and drug reactions can also cause focal active gastritis.
Diffuse Gastritis
Lymphoplasmacytic
The two diseases most commonly encountered in routine clinical practice in association with diffuse chronic gastritis with lymphoplasmacytic inflammation are H. pylori infection and autoimmune gastritis ( Fig. 13.12 ). The presence of a neutrophilic infiltrate should always raise suspicion of H. pylori gastritis, but an active inflammatory component may be present in almost any type of chronic gastritis, such as autoimmune, environmental, drug-induced, lymphocytic, or collagenous gastritis. Helicobacter gastritis is an antral-predominant gastritis with a superficial bandlike inflammatory infiltrate beneath the surface foveolar epithelium. It is associated with a variable active (neutrophilic) component. The latter finding may be mild in cases of H. heilmannii gastritis. Autoimmune gastritis involves the corpus, causing atrophy of the oxyntic glands, and leads to intestinal metaplasia, endocrine cell hyperplasia, and eventually gastric carcinoids.
Intraepithelial Lymphocytes
Increased IELs (>25 per 100 epithelial cells) in the absence of other significant pathologic changes is diagnostic of lymphocytic gastritis ( Fig. 13.13 ). This condition usually manifests as pangastritis, but the disease may be patchy in some cases. Common etiologic associations of this pattern of mucosal injury include celiac disease, hypersensitivity response to H. pylori infection, human immunodeficiency virus (HIV) infection, and drugs (e.g., ticlopidine).
Thick Subepithelial Collagen
Thickening of the subepithelial collagen layer is rarely seen in gastric biopsies, but this pattern of injury encompasses two distinct clinical disorders. Collagenous gastritis in pediatric patients usually involves only the stomach, whereas in adults it typically occurs in association with involvement of the small intestine (collagenous sprue) or colon (collagenous colitis) or both. The inflammatory component in collagenous gastritis may be dominated by IELs or eosinophils in the lamina propria and some cases may be misdiagnosed as “lymphocytic” or “eosinophilic” gastritis if attention is not paid to the character of the subepithelial collagen layer.
Increased Eosinophils
Eosinophilic gastritis is characterized by an eosinophil-predominant infiltrate ( Fig. 13.14 ). It is composed of large clusters and aggregates of eosinophils in the lamina propria and epithelium. A clinical history of asthma, food allergies, connective tissue disorder, or drug intake is typically present. Rarely, parasitic infection may lead to eosinophilic gastritis.
