Stomach and Proximal Duodenum: Inflammatory and Miscellaneous

13
Stomach and
Proximal Duodenum:
Inflammatory and
Miscellaneous Disorders
Chapter Outline
CLASSIFICATION OF GASTRITIS
AND GASTROPATHY
Current Classification of Gastritis
GASTRITIS
Distinctive (Specific) Types
of Gastropathies
Reactive (Predominant Epithelial) Changes
Reactive gastropathy
Toxic gastropathy
Reactive Changes with Erosions in
Helicobacter—One or Two Diseases?
Distinction of Reactive Changes from
Dysplasia
Reactive changes in intestinal metaplasia
Alcoholic gastropathy
Caustic-induced injury
Graft versus host disease
Chemotherapy and radiation
Ischemia
Predominantly Vascular Changes
Gastric antral vascular ectasia
Portal hypertension (congestive gastropathy)
Hemorrhagic gastropathy (“gastritis”)
and “Curling’s ulcer”
Distinctive (Specific) Types of Gastritis
Infections
A H. pylori infection
Histology of H. pylori–associated gastritis
H. pylori diagnosis
Noninvasive methods
Invasive methods
Atrophic gastritis and gastric atrophy
Staging gastric atrophy
Disorders associated with H. pylori gastritis
Gastroduodenal erosions and ulcers
(“peptic ulcers”)
Pathogenetic factors
Epidemiology
Atypical clinical presentations
Endoscopic appearance of peptic
erosions and ulcers
“PEPTIC DISEASES” OF THE DUODENAL
BULB AND THE PROXIMAL DUODENUM
Pathogenesis and Clinical Features of
Duodenitis
Duodenal ulcer
Clinical features
Pathology of Duodenitis and Duodenal
Erosions and Ulcer
Gross pathology
Histology
Differential diagnosis of duodenitis
Healing and healed ulcers
Complications of gastroduodenal ulcers
Treatment
The role of the pathologist and clinical
implications
Autoimmune Gastritis
Pathogenesis
Subtypes of autoimmune gastritis (AIG)
and their ­etiology
Clinical features
Pathology
LYMPHOCYTIC GASTRITIS
Morphologic Separation of Etiologies
GRANULOMATOUS GASTRITIS
CARDITIS
NON–H. PYLORI BACTERIAL INFECTIONS
Non–H. pylori Helicobacter Species
(NHPH)/“Helicobacter heilmannii”
Gastric disease associated with
non–H. pylori Helicobacter
species/“Helicobacter heilmannii”
Diagnosis
Tuberculosis
Syphilis
Enterococcal Gastritis
Phlegmonous and Emphysematous
Gastritis
VIRAL INFECTIONS
Cytomegalovirus Infection (HHV-5)
Herpes Viruses (HHV-1,2)
Epstein–Barr Virus (EBV—HHV-4)
Other HHV Viruses
Other Viruses
FUNGAL INFECTIONS
Candida albicans
Histoplasmosis
Mucormycosis (Zygomycosis)
Aspergillosis
PARASITES AND NEMATODES
Cryptosporidium
Anisakiasis
Other Parasites and Nematodes
OTHER GASTRITIDES
Clinical features
Endoscopic features
Histologic features
Eosinophilic Gastritis
Eosinophilic gastritis as part of gastric
involvement in eosinophilic gastroenteritis
Differential diagnosis
Collagenous Gastritis
Diffuse collagenous gastroenterocolitis
Gastric Malakoplakia
Drug- and Chemotherapy-induced
Gastritis
HYPERTROPHIC GASTROPATHIES
AND MÉNÉTRIER’S DISEASE
Primary/Idiopathic Ménétrier’s Disease
Clinical Presentation
Pathology of Primary Ménétrier’s Disease
Carcinoma Complicating Ménétrier’s
Disease
Secondary Ménétrier’s Disease
HYPERTROPHIC GASTROPATHYASSOCIATED WITH PROTEIN LOSS
Cytomegalovirus-associated
Hypertrophic Gastropathy
Hypertrophic Lymphocytic Gastritis
Helicobacter pylori–associated
Hypertrophic Gastritis
HIV-associated Hypertrophic Gastritis
Large Gastric Folds Associated with
Other Conditions
Other Types of Large Gastric Folds
DISTINCTIVE ENDOSCOPIC ENTITIEs
MISCELLANEOUS DISORDERS OF THE
STOMACH
Gastric Calcinosis
Gastric Glandular Siderosis
Approach to the Interpretation of
Gastric Biopsies
Surface epithelium
HISTOLOGY
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Chapter 13 Stomach and Proximal Duodenum: Inflammatory and Miscellaneous Disorders
CLASSIFICATION OF GASTRITIS
AND GASTROPATHY
Though no classification of gastritis satisfies everyone,
the overall goal of any classification is to help clear
thinking and be clinically useful. Inevitably much of
the early thinking regarding gastritis was centered on
“peptic ulcer disease” (PUD). Ignorance regarding the
role of both Helicobacter and medications gave rise
to theories that were to some extent flawed, yet they
still dominate traditional teaching. Gastritis was considered physiologic and intestinal metaplasia an aging
phenomenon. We also need to recall that
1.Gastritis originally meant “redness”—which now is
usually associated with a gastropathy rather than
gastritis; conversely, most histologic gastritis has a
normal endoscopic appearance.
2.Many disorders that are characterized by abnormal endoscopy also have a typical biopsy appearance. From a classification viewpoint are these best
considered from an endoscopic or histologic viewpoint? Most classifications can only be viewed from
one vantage point.
3.From a clinical viewpoint, “ulcers” have played a
major role in gastric disease because of the symptoms with which they or their complications are associated (pain, bleeding, perforation, and ­obstruction/
stenosis). However, the term “peptic ulcer disease”
has been in common parlance for decades, with
the implication that this is associated with acid, the
“proof” being that symptoms are markedly ameliorated with therapy, whether antacids, H2-receptor
antagonists, or proton pump inhibitors (PPIs). In the
early 1980s, it was ultimately shown that some ulcer
disease, especially in the duodenum, was related to
Helicobacter pylori, so that its eradication virtually
guaranteed that duodenal ulcer, the archetypal peptic ulcer, would not recur. Thus PUD changed from
being primarily acid related to primarily bacterial,
or a combination of both.
4.
Nonsteroidal anti-inflammatory drugs (NSAIDs),
aspirin (acetylsalicylic acid—ASA), and other medications now play a huge role in gastric pathology.
While the introduction of NSAIDs around 1970 was
a major step forward therapeutically, it came at a
price that included numerous gastrointestinal (GI)
side effects. Prior to this time, ASA had been “the”
analgesic and antipyretic of choice. Bayer introduced ASA in the market around 1900, and within
a decade or two this “wonderdrug” was present
in virtually every household in the more developed countries, and used widely for ­numerous ailments—colds, coughs, headaches, migraines, and all
arthritides. Yet the erosive, ulcerative, and bleeding
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571
diathesis associated with this drug was not widely
appreciated. In retrospect, from about 1900 on,
many “peptic ulcers” may well have been as much
ASA associated as Helicobacter associated, and this
association even creeps, almost inadvertently, into
case reports back in the 1950s.1 So while we typically
think of “peptic ulcer disease” historically as unrecognized Helicobacter infection, ASA was very likely a
major contributor. This continued until acetaminophen/paracetamol/Tylenol came into the market
in to the 1960s. Further, it is now well recognized
that, especially in the very young2,3 and elderly,4 not
only that NSAIDs are likely “the” culprit irrespective of the presence of H. pylori, but that the risk of
complications such as bleeding (and therefore the
erosions and ulcers that bleed) can be largely prevented using PPIs. Thus, historically, the disease we
consider to be “peptic ulcer disease” may have been
as much NSAID/ASA associated as Helicobacter associated, especially in the presence of abundant acid.
5.Historically, alcohol, which not only has a social
role in many societies but is also an analgesic in
large doses, has been around much longer than any
other gastric damaging agent except for Helicobacter,
and produces histologic changes similar to NSAIDs
(i.e., a chemical/reactive gastropathy). From around
1900 on when aspirin became available, the big
three, became Helicobacter, alcohol, and ASA, and
from 1970 on, NSAIDs was added to these.
6.The notion of “peptic ulcer disease” and “no acid—
no ulcer” is therefore likely true in that in the major
causes of gastroduodenal erosions and ulcers, namely,
Helicobacter and NSAIDs/ASA, and other medications or chemicals, especially alcohol, the presence of
acid facilitated the development of injury caused by
these agents. Although the nature of the interaction of
these common causes of peptic ulcer is still unclear, it
would make most sense if, when antral-predominant
H. pylori is present, that the risk of NSAID/ASA and
alcohol-induced damage was increased, but that
when the organism spread proximally, resulting in
a decrease in acid output, that there may well be a
degree of protection from NSAID/ASA, and possibly
alcohol-associated damage (Table 13-1).
Current Classification of Gastritis
Chapter 13
Until the early 1970s, chronic gastritis was classified into three main varieties (superficial, atrophic,
and hypertrophic) as suggested by Schindler in 19395
(Table 13-2). Wood as well as Schindler later concluded
that chronic hypertrophic gastritis is a variation of
normal mucosal function.6,7 Thus, chronic gastritis
was classified as superficial or atrophic.
Whitehead’s classification was the first to understand the importance of noting location, and grading
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Lewin, Weinstein, and Riddell’s Gastrointestinal Pathology and Its Clinical Implications
Table 13-1 ABC Classification
of Gastritis
Autoimmune
Bacterial
Chemical
Drug-associated/
Iatrogenic
Eosinophilic
Focal
Granulomatous
Hypertrophic (big folds)
Idiopathic
Juvenile (pediatric)
Lymphocytic
Multifocal intestinal
metaplasia with/
without atrophic
front
Pernicious anemia
Bugs including post-Rx effects:
Helicobacter pylori
Enterococcus
Syphilis
Bile reflux
NSAIDs/ASA
Anti-platelet medications
Chemotherapy/GVHD
Iron
Alcohol
Eosinophilic gastritis/­
gastroenteritis
Food allergies, medications
Crohn’s disease
Tuberculosis
Sarcoid
Crohn’s disease
Foreign body
Helicobacter pylori
“Ménétrier’s disease”
Lymphocytic gastritis
Eosinophilic gastritis
Gastric varices
Gastritis cystica profunda
Lymphoma (MALT)
Gastric adenocarcinoma
Helicobacter pylori gastritis
(lymphocytic), CMV
Zollinger–Ellison syndrome
Multiple polyps/polyposis
Follicular with H. pylori, CMV
Helicobacter pylori, celiac
disease
Chronic erosive (varioliform)
gastritis
In atrophic gastritis, isolated
Modified from Wyatt JI, Dixon MF. Chronic gastritis—a pathogenetic
approach. J Pathol. 1988;154(2):113–124.
the depth and degree of inflammation and the presence or absence of both intestinal and pseudopyloric
metaplasia, separating them from atrophic changes8
(Table 13-2). This really formed the basis of all subsequent morphologic classifications of gastritis. In 1973,
Strickland and Mackay classified gastritis based on
detecting parietal cell (PC) antibodies, clarifying the
etiology of autoimmune gastritis (AIG) (type A) despite
the fact that these can develop in Helicobacter infected
patients. It is associated with atrophic changes in body
and fundic (oxyntic) mucosa. Antral predominant gastritis was type B. Glass and Pitchumon added type AB into
Strickland–Mackay classification to encompass cases
that did not fit type A or type B, essentially pangastritis.
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With the rediscovery of H. pylori (originally Campylobacter pylori) by Warren and Marshall in the early
1980s,9 it became clear that H. pylori is a principal
component of most gastritides. In 1988, two classification systems emerged. That by Wyatt and Dixon incorporated reactive gastropathy (then called chemical
gastritis/gastropathy) as the “C” of the ABC classification system, A being autoimmune and B being bacterial (=Helicobacter but, at that time, C. pylori).10 The
same year, Correa proposed classifying gastritis based
on clinical and etiopathogenetic information. He classified chronic gastritis into superficial gastritis, diffuse
antral gastritis (DAG), usually Helicobacter associated
and related to duodenal ulcer disease, diffuse corporal atrophic gastritis (autoimmune), and multifocal
atrophic gastritis (MAG—considered to be “environmental”). MAG was related to intestinal-type adenocarcinoma and gastric ulcer, and intestinal metaplasia
in the antrum and body.11 Diffuse corporal atrophic
gastritis was often related to AIG and pernicious anemia, with inflammation and atrophy in the corpus and
relative sparing of the antrum11,12 (Fig. 13-1).
The Sydney system is the basis of most contemporary classifications of gastritis. Proposed by a group of
European pathologists and clinicians (World Congress
of Gastroenterology, Sydney, August 1990),12 it recommended incorporating the topography of gastric
mucosal changes with the immunology and microbiology of the disease. The classification depends on
separate assessment of the antrum and corpus by taking a minimum of two biopsies from the anterior and
posterior walls of the respective gastric compartments
as well as any specific lesions identified. An important feature is a standard three-tier grade of mild,
moderate, and severe applicable to a selected number of morphologic variables. As a broad guideline,
each successive grade represents an increment in
severity of about one-third. Graded variables included
inflammation (acute and chronic), atrophy, metaplasia, and density of H. pylori. The Sydney system also
expanded previous classifications by adding a variety
of other “special forms” of gastritides (collagenous,
eosinophilic, granulomatous, lymphocytic, etc.).
The Sydney classification was updated in 1994,13
which expanded the section on specific entities (special forms) and includes a 4-point visual analog (equivalent to none, mild, moderate, and severe) to aid with
morphologic grading of inflammation and atrophy.13
Gastric atrophy is loss of normal glands, often with
replacement by an epithelium that could be either
native or metaplastic (Table 13-3). The score is an
average from each region’s biopsies. Antral atrophy
was the average score for atrophy from all antral biopsies and corpus atrophy (the average score for atrophy
from all corpus biopsies).13 The updated Sydney classification depends on the separate assessment of the
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Table 13-2 Gastritis Classification “Historical Prospective”
YEAR, AUTHOR
CLASSIFICATION
1942, Schindler
Gastritis
Superficial
Atrophic
Hypertrophic (later dropped as Schindler and others concluded
­hypertrophy is normal function ­variation)
Mucosa type
Gastritis grade
Metaplasia
Pyloric
Superficial
Body
Quiescent
Pseudopyloric
Cardiac
Active
Transitional
Atrophic (used synonymous with deep
Intestinal
­inflammation).
Indeterminate
Mild (quiescent or active)
Moderate (quiescent or active)
Severe (quiescent or active)
Type A or autoimmune gastric atrophy of pernicious anemia
Type B—nonautoimmune (pyloro-cardial extension type in connection with PUD (Kimura, 1972181)
Type A (autoimmune)
Type B (antrum)
Type AB (cases that did not fit Type A or Type B)
Morphologic
Mechanistic
Synonyms
Not atrophic
Superficial
Initial stage of other types?
Simple?
Diffuse antral (DAG)
Hypersecretory?
Antral
Psychosomatic?
Type B
Infectious? (C. pylori)
Atrophic
Postgastrectomy
Reflux
Chemical
Diffuse corporal
Autoimmune
Type A
Multifocal
Dietary?
Environmental
Type B
Type AB
Pangastritis
1972, Whitehead et al.8
1973, Strickland and
Mackay828
1976, Glass and Pitchumoni
modification of Strickland
and Mackay829
1988, Correa11
GASTRITIS
Figure 13-1. Prototypes of gastritis pattern predict disease outcome. In practice, all tend to have some degree of both antral and
corpus inflammation. Top left: Duodenal ulcer (DU) patients have
antral predominant inflammation with little corpus inflammation.
­Bottom left: Pangastritis is seen in gastric ulcer (GU) patients.
Corpus mucosa is inflamed and often extends into the specialized mucosa but still tends to be antral predominant. Top right:
­Pangastritis with atrophy is seen in patients with the intestinal type
of gastric adenocarcinoma (CA). Bottom right: Corpus-predominant
gastritis is usually seen in AIG or end-stage Helicobacter infection.
Riddell_Chap13.indd 573
Gastritis (in its broadest sense) and its complications account for millions of doctors’ office visits
each year. Symptoms are often associated with acute
changes or complications described as mild upper
abdominal discomfort, indigestion, heartburn, coated
tongue, foul breath, and bad taste to more ominous
symptoms such as loss of appetite, nausea, vomiting
blood or coffee-ground material, diarrhea, and dark
stools. Most patients with chronic gastritis have no
symptoms. Even so, these symptoms are not specific and include broad differentials such as H. pylori
infection, other infections, bile reflux, inflammatory
Chapter 13
antrum and corpus. It needs a minimum of two biopsies from the lesser and greater curvature of the respective gastric compartments as well as the incisura and
any specific lesions identified (Fig. 13-2).13 On all occasions accurate grading depends on correctly oriented
full-thickness mucosal biopsies. In practice, other
than for academic studies, grading is rarely required.
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Lewin, Weinstein, and Riddell’s Gastrointestinal Pathology and Its Clinical Implications
Table 13-3 Gastritis Classification “Sydney System”
1996, Updated
Sydney13
GASTRITIS TYPE
ETIOLOGY
SYNONYMS
Non-atrophic
Helicobacter pylori
? Other factors
Superficial
Diffuse antral,
Chronic atrophic
Interstitial—follicular
Hypersecretory
Type B
Autoimmunity
Type A
Diffuse corporal
Pernicious-anaemia associated
Type B
Type AB
Environmental
Metaplastic
Atrophic
Autoimmune
Multifocal
Special forms
Chemical
Radiation
Lymphocytic
Noninfectious
granulomatous
Eosinophilic
Other ­infectious
gastritis
Helicobacter pylori
Dietary
? Environmental
Chemical irritation:
Bile
NSAIDs/Antiplatelet
Other medications
Radiation injury
Idiopathic? Immune ­mechanism
Gluten
Drug (ticlopidine)
? H. pylori
Crohn’s disease
Sarcoidosis
Wegener’s granulomatosis and
other vasculitides
Idiopathic
Food sensitivity, drugs, Churg-Straus
Bacteria (other than H. pylori)
Viruses
Fungi
Parasites
Reactive, Reflux
NSAID
Type C
Varioliform (endoscopic)
Celiac disease–associated
Isolated granulomatous
Allergic
Phlegmonous
bowel disease (IBD), and side effects of medications
(Table 13-4). As treatment depends on the cause, it is
important to know the cause for appropriate management. Occasionally, it may be necessary to list possible etiologies for gastric inflammation, rather that
reporting “nonspecific chronic inflammation”—which
is an unnecessarily complex term as all inflammation
is “nonspecific,” so these words can always be omitted
from reports without deleterious effect. If it is specific, the cause (e.g., Helicobacter) should be stated.
Distinctive (Specific) Types
of Gastropathies
Figure 13-2. The updated Sydney biopsy protocol requires a
minimum of two biopsies from the lesser and greater curvature
of the respective gastric compartments as well as the incisura and
any specific lesions identified. This identifies all of the patterns of
gastritis illustrated in Figure 13-1, as well as estimating the extent
of atrophy present, which often starts at the incisura/angulus (IA),
affects the antrum (A1, A2), and then extends proximally to the
oxyntic zone (B1, B2), so that, as antral inflammation extends proximally, biopsy site B1 is first affected, and B2 is the last site affected.
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Gastropathies are biopsies in which epithelial (noninflammatory) changes predominate. The mucosa is
often mucin depleted, causing it to appear red endoscopically (invariably interpreted by endoscopists as
“gastritis” rather than areas of redness). They include
biopsies with primary epithelial reactive changes
(such as chemical/reflux (bile) gastropathy, chemotherapy effect) and a smaller subset of biopsies with
predominant vascular pathology (such as gastric antral
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Table 13-4 Classification by Predominant Histologic Change
SUBCATEGORY
Gastropathy
­(predominantly
noninflammatory)
Predominant epithelial
changes
Predominant vascular
pathology
Gastritis
­(predominant
­inflammatory)
Infectious
Noninfectious
Endoscopic
­gastropathies
Part of systemic
involvement
Distinctive
­macroscopic
­(endoscopic)
appearance
with appropriate
­histology
(a) Medications/reflux (bile) gastropathy
(b) Alcoholic gastropathy
(c) Caustic-induced injury
(d) GVHD
(e) Radiation/chemotherapy
(f) Ischemia
(a) GAVE
(b) Portal hypertension
(c) Hemorrhagic/shock gastropathy
1. Bacterial
(a) Helicobacter pylori bacterial infection (autoimmune gastritis,
­lymphocytic ­gastritis, granulomatous gastritis, carditis)
(b) NHPH infections—“H. heilmanii”
Other bacteria—TB, syphilis, phlegmonous and emphysematous
gastritis
2. Viral (CMV, Herpes)
3. Fungal (Candida, histoplasma, ­mucormycosis, Aspergillosis)
4. Parasitic (Cryptosporidium, Anisadikosis, other parasites, and
­nematodes)
1. IBD (endoscopic, histologic features, clinical implication)
2. Eosinophilic gastroenteritis
1. GVHD
2. Vasculitis (including Churg–Strauss)
1. Erosive and hemorrhagic
Varioliform gastritis
Watermelon stomach (GAVE)
Portal gastropathy
Hemorrhagic gastritis/gastropathy
2. Nonerosive
Nodular gastritis, children
Atrophic front, adults
3. Distinctive hypertrophic gastropathy
vascular ectasia [GAVE], portal hypertension gastropathy, Dieulafoy, and hemorrhagic/shock) (Table 13-4).
Graft versus host disease (GVHD) is usually normal
endoscopically.
Reactive (Predominant Epithelial) Changes
­ eactive (chemical/reflux-associated) gastropathy
R
is a reaction to noninfectious irritants. This can be
due to protracted exposure to bile and pancreatic
juice (especially postgastric surgery14). The most infamous of irritants are NSAIDs, which include overthe-­counter drugs such as aspirin and ibuprofen, and
many prescription medicines. Other medications—
such as bisphosphonates used for osteopenia, iron
pills and irritants in food such as capsaicin in peppers
and chilies and alcohol—can all cause this lesion.15
These irritants usually cause no clinical problems
when taken for the short term, although endoscopic
damage can be seen even with short-term use. However, regular (or e
­xcessive) use can lead to a more
severe ­
gastropathy as well as erosions and ulcers.
With the increasing use of aspirin and other NSAIDs,
Riddell_Chap13.indd 575
and decreasing prevalence of H
­ elicobacter, chemical/
reactive gastropathy is increasingly seen in gastric
biopsies, and may co-exist. Anti-platelet mediations
also cause similar injury.
Pathogenesis: Aspirin is the best-studied NSAID,
the mechanism of injury is inhibition of prostaglandin synthesis by inhibiting cyclooxygenase (COX)
1 and 2.16 Aspirin also changes the ability of the
mucosa to maintain a pH gradient causing gastric
acid back-diffusion with resultant mucosal injury.16
Further, its anticoagulant properties increase the
risk of bleeding once erosions or ulcers are present.
Conversely, some other NSAIDs have antiplatelet
properties but do not possess this therapeutic anticoagulant effect. NSAIDs produce mucosal injury
by both local and systemic effects.16 Newer NSAIDs
are predominantly COX-2 inhibitors, which make
them less likely to cause gastric injury and the risk
of gastric (or duodenal) injury is reduced, but not
abolished. A variety of antiplatelet medications are
increasingly being implicated causing similar injury.
Histology: The histology of reactive gastropathies has both an acute and a chronic phase, although
Chapter 13
CATEGORY
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