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ESOPHAGUS  Normally, a reflex relaxation of the gastroesophageal musculature

precedes the antiperistaltic contractile wave associated with vomiting. This


Esophageal Obstruction fails during prolonged vomiting, and refluxing gastric contents overwhelm
- Esophageal dysmotility interferes with the process of peristaltic contraction, and the gastric inlet and cause the esophageal wall to stretch and tear.
can take several forms:  Tears usually cross the gastroesophageal junction but may also be located
 High amplitude esophageal contractions in which the OL layer of smooth in the proximal gastric mucosa.
muscle contracts before the IC layer occurs in some patients.  Up to 10% of upper GI bleeding, which presents as hematemesis, is
 Nutcracker esophagus: periodic short-lived esophageal obstruction associated with Mallory-Weiss syndrome.
 Other motor disorders include diffuse esophageal spasm, which can also  These generally do not require surgical intervention, and healing tends to
result in functional obstruction. be rapid and complete.
 Increases esophageal wall stress  formation of small diverticulae  In contrast, Boerhaave syndrome, characterized by distal esophageal
(pseudodiverticulae because they lack a true muscularis), although rupture and mediastinitis, occurs rarely and is a catastrophic event.
uncommonly due to the dense, continuous esophageal musculature - Chemical and Infectious Esophagitis
 Zenker diverticulum (pharyngoesophageal diverticulum):  The stratified squamous mucosa of the esophagus may be damaged by a
located immediately above the upper esophageal sphincter variety of irritants including alcohol, corrosive acids or alkalis, excessively
o May reach several cm in size and accumulate food, hot fluids and heavy smoking.
producing a mass and symptoms like regurgitation  May also happen when medicinal pills lodge and dissolve in the
 Traction diverticulum: occurs near the midpoint of the esophagus rather than passing into the stomach intact (pill-induced
esophagus esophagitis)
 Epiphrenic diverticulum: immediately above the lower  Esophagitis due to chemical injury generally only causes self-limited pain,
esophageal sphincter particularly dysphagia. Hemorrhage, stricture or perforation may occur in
- Esophageal stenosis (narrowing of the lumen) severe cases.
 Generally caused by fibrous thickening of the submucosa  Iatrogenic esophageal injury may be caused by cytotoxic chemotherapy,
 Associated with atrophy of the muscularis propria as well as secondary radiation therapy or GVHD.
epithelial damage  Infections are most frequent in those who are immunocompromised. In
 Although occasionally congenital, stenosis is most often due to these patients, infection by HSV, CMV or fungal organisms is common.
inflammation and scarring that may be caused by chronic  Among fungi, candidiasis is most common, although mucormycosis
gastroesophageal reflux, irradiation or caustic injury. and aspergillosis may occur.
 Associated dysphagia is usually progressive, first affecting ability to eat  The esophagus may also be involved by the desquamative skin diseases
solids, and liquids later on. bullous pemphigoid and epidermolysis bullosa and, rarely, Crohn disease,
 Patients may subconsciously modify their diet to favor soft foods and  Morphology:
liquids and be unaware of their condition until obstruction is  Varies with etiology
complete.  Dense infiltrates of neutrophils are present in most cases but may
- Esophageal mucosal webs be absent following injury induced by chemicals (lye, acids,
 Uncommon ledge-like protrusions of mucosa that may cause obstruction detergent), which may result in outright necrosis of the esophageal
 Encountered most frequently in women over age 40 wall.
 Often associated with gastroesophageal reflux, chronic GVHD or blistering  Pill-induced esophagitis frequently occurs at the site of strictures.
skin diseases  When present, ulceration is accompanied by superficial necrosis
 Upper esophageal webs accompanied by IDA, glossitis and cheilosis are with granulation tissue and eventual fibrosis.
part of the Patterson-Brown-Kelly or Plummer-Vinson syndrome.  Esophageal irradiation causes intimal proliferation and luminal
 Webs are most common in the upper esophagus, where they are generally narrowing of submucosal and mural blood vessels. Mucosal damage
semicircumferential, eccentric lesions that protrude less than 5 mm and is, in part, due to radiation-induced vascular injury.
have a thickness of 2-4 mm.  Infection by fungi or bacteria can either cause damage or complicate
 Microscopically, webs are composed of a fibrovascular connective tissue a preexisting ulcer. Nonpathogenic oral bacteria are frequently found
and overlying epithelium. in ulcer beds, while pathogenic organisms may invade the lamina
 Main symptom is dysphagia associated with incompletely chewed food. propria and cause necrosis of overlying mucosa.
- Esophageal rings (Schatzki rings)  Candidiasis, when advanced, is characterized by adherent,
 Similar to webs, but are circumferential and thicker gray-white pseudomembranes composed of densely matted
 Include mucosa, submucosa and, in some cases, hypertrophic muscularis hyphae and inflammatory cells covering the mucosa.
propria  Endoscopy often provides a clue as to the infectious agent in viral
 When present in the distal esophagus above the gastroesophageal esophagitis.
junction, they are termed A rings and are covered by squamous mucosa  Herpesviruses typically cause punched-out ulcers. Biopsy
 Those located at the squamocolumnar junction of the lower esophagus are specimens demonstrate nuclear viral inclusions within a ri of
designated B rings and may have gastric cardia-type mucosa on their degenerating epithelial cells at the margin of the ulcer.
undersurface  CMV causes shallower ulcerations and characteristic nuclear
- Achalasia and cytoplasmic inclusions within capillary endothelium and
 Increased tone of the lower esophageal sphincter (LES), as a result of stromal cells.
impaired smooth muscle relaxation  Although histologic appearance is characteristic,
 Release of nitric oxide and vasoactive intestinal polypeptide from inhibitory immunohistochemical stains for virus-specific antigens are a
neurons, along with interruption of normal cholinergic signaling allows the sensitive and specific ancillary diagnostic tool.
LES to relax during swallowing  Histologic features of esophageal GVHD are similar to those in skin,
 Achalasia is characterized by the triad of incomplete LES relaxation, and include:
increased LES tone, and aperistalsis of the esophagus.  Basal epithelial cell apoptosis
 Primary achalasia is caused by failure of distal esophageal inhibitory  Mucosal atrophy
neurons and is, by inhibition, idiopathic.  Submucosal fibrosis without significant acute inflammatory
 Degenerative changes in neural innervations, either intrinsic to the infiltrates
esophagus or within the extraesophageal vagus nerve or the dorsal  Microscopic appearances of esophageal involvement in bullous
motor nucleus of the vagus, may also occur. pemphigoid, epidermolysis bullosa and Crohn disease are similar to
 Secondary achalasia may arise in Chagas disease, in which Trypanosoma those in the skin.
cruzi infection causes destruction of the myenteric plexus, failure of - Reflux Esophagitis
peristalsis and esophageal dilatation.  The stratified squamous epithelium of the esophagus is resistant to
 Duodenal, colonic and ureteric myenteric plexi can also be affected abrasion from foods but is sensitive to acid.
in Chagas disease.  Submucosal glands, most abundant in the proximal and distal
 Achalasia-like disease may be caused by: esophagus, secrete mucin and bicarbonate for protection
 Diabetic autonomic neuropathy  More importantly, constant lower esophageal sphincter tone
 Infiltrative disorders (malignancy, amyloidosis, sarcoidosis) prevents reflux of acidic gastric contents, which are under positive
 Lesions of dorsal motor nuclei, particularly polio or surgical ablation pressure and would otherwise enter the esophagus
 Reflux of gastric contents into the lower esophagus is the most common
Esophagitis outpatient GI diagnosis in the US. The associated clinical condition is
- Lacerations called GERD.
 Longitudinal tears in the esophagus near the gastroesophageal junction  Pathogenesis:
(Mallory-Weiss tears) are most often associated with severe retching or  Reflux of gastric juices leads to mucosal injury in GERD.
vomiting secondary to acute alcohol intoxication
 In severe cases, reflux of bile from the duodenum may exacerbate  Intramucosal carcinoma is characterized by invasion of neoplastic
the damage. epithelial cells into the lamina propria.
 Conditions that decrease LES tone or increase abdominal pressure
contribute to GERD Esophageal Varices
 Alcohol and tobacco use - Diseases that impede the portal venous circulation cause portal hypertension
 Obesity and can lead to the development of esophageal varices, an important cause of
 CNS depressants esophageal bleeding.
 Pregnancy - Pathogenesis:
 Hiatal hernia (separation of the diaphragmatic crura and  Portal hypertension results in the development of collateral channels at
protrusion of the stomach into the thorax through the resulting sites where the portal and caval systems communicate.
gap)  Although allowing some drainage, they lead to the development of a
 Delayed gastric emptying congested subepithelial and submucosal venous plexus within the distal
 Increased gastric volume. esophagus.
 In many cases, no definitive cause is identified.  Varices develop in 90% of cirrhotic patients, most commonly in association
 Morphology with alcoholic liver disease.
 Simple hyperemia, evident as redness on endoscopy, may be the  Hepatic schistosomiasis is the second most common cause.
only alteration. - Morphology:
 In mild GERD, the mucosal histology is often unremarkable.  Varices can be detected by venogram, and appear as tortuous dilated
 With more significant disease, eosinophils are recruited into the veins lying primarily within the submucosa of the distal esophagus and
squamous mucosa followed by neutrophils, which are usually proximal stomach
associated with more severe injury.  Venous channels directly beneath the esophageal epithelium may also
 Basal zone hyperplasia exceeding 20% of the total epithelial become dilated
thickness and elongation of the lamina propria papillae, such that  Varices may not be grossly obvious in surgical or postmortem specimens
they extend into the upper third of the epithelium, may also be because they collapse in the absence of blood flow and, when they are not
present. ruptured, the overlying mucosa is intact.
- Eosinophilic Esophagitis  Variceal rupture results in hemorrhage into the lumen or esophageal wall,
 Symptoms: in which case the overlying mucosa appears ulcerated and necrotic.
 If rupture has occurred in the past, venous thrombosis, inflammation and
 Food impaction and dysphagia in adults
evidence of prior therapy may also be present.
 Feeding intolerance or GERD-like symptoms in children
- Factors leading to rupture:
 Cardinal histologic feature: large numbers of intraepithelial eosinophils,
 Inflammatory erosion of thinned overlying mucosa
particularly superficially
 Increased tension in progressively dilated veins
 Their abundance can help to differentiate it from GERD, Crohn  Increased vascular hydrostatic pressure associated with vomiting
disease and other causes of esophagitis
 Clinical characteristics (also necessary for diagnosis) Esophageal Tumors
 Failure of high-dose PPI treatment - Adenocarcinoma
 Absence of acid reflux  Typically arises in a background of Barrett esophagus and long-standing
 Majority of patients are atopic. Many have atopic dermatitis, allergic GERD
rhinitis, asthma or modest peripheral eosinophilia.  Risk is greater in those with documented dysplasia and is further
increased by tobacco use, obesity and prior radiation therapy
Barrett Esopagus  Risk is reduced by diets rich in fresh fruits and vegetables
- Complication of chronic GERD  Some H. pylori serotypes are associated with a decreased risk of
- Characterized by intestinal metaplasia within the esophageal squamous mucosa adenocarcinoma, perhaps by causing gastric atrophy and reducing acid
- Most common in white males; typically presents between 40 and 60 years of age reflux.
- Greatest concern: confers an increased risk of esophageal adenocarcinoma (i.e.  Occurs most frequently in Caucasians, and is much more common in men
Barrett esophagus is a pre-malignant condition)  Pathogenesis:
- Epithelial dysplasia is seen in persons with Barrett esophagus  Progression of Barrett esophagus to adenocarcinoma occurs over
- Although the vast majority of esophageal adenocarcinomas are associated with an extended period through the stepwise acquisition of genetic and
Barrett esophagus, it is important to remember that most individuals with Barrett epigenetic changes.
esophagus do not develop esophageal tumors.  Morphology:
- Morphology:  Usually occurs in the distal third of the esophagus and may invade
 Barrett esophagus can be recognized as one or several tongues or the adjacent gastric cardia
patches of red, velvety mucosa extending upward from the
 Initially appears as flat or raised patches in otherwise intact mucosa
gastroesophageal junction.
 Alternatively, tumors may infiltrate diffusely or ulcerate and invade
 This metaplastic mucosa alternates with residual smooth, pale
deeply
squamous (esophageal) mucosa and interfaces with light-brown
 Microscopically, Barrett esophagus is frequently present adjacent to
columnar (gastric) mucosa distally
the tumor.
 Subclassification:
 Tumors most commonly produce mucin and form glands, often with
 Long segment – 3 cm or more of esophagus is involved
intestinal-type morphology
 Short segment – less than 3 cm is involved
 Less frequently, tumors are composed of diffusely infiltrative signet-
 Unclear whether the risk of dysplasia in short segment disease is less
ring cells (similar to those seen in diffuse gastric cancers) or, in rare
 Diagnosis required endoscopic evidence of abnormal mucosa above the
cases, small poorly differentiated cells (similar to small-cell
gastroesophageal junction and histologically documented interstinal
carcinoma of the lung)
metaplasia.
 By the time symptoms (dysphagia, weight loss, hematemesis, chest pain)
 Goblet cells, which have distinct mucous vacuoles that stain pale
appear, the tumor has usually spread to the submucosal lymphatic vessels
blue by H&E, are necessary for diagnosis
- Squamous Cell Carcinoma
 Requirement for intestinal metaplasia reflects the fact that this  In the US, it occurs in adults over age 45 and affects males more often
feature correlates with neoplastic risk  Risk factors:
 Foveolar mucus cells, which do not have the distinct mucous  Alcohol and tobacco use
vacuoles, are insufficient for diagnosis.
 Poverty
 The requirement for an endoscopic abnormality helps to prevent
 Caustic esophageal injury
misdiagnosis if metaplastic goblet cells within the cardia are
 Achalasia
included in the biopsy.
 When dysplasia is present, it is classified as low grade or high grade.  Tylosis
 Increased epithelial proliferation, often with atypical mitoses, nuclear  Plummer-Vinson Syndrome
hyperchromasia and stratification, irregularly clumped chromatin,  Frequent consumption of very hot beverages
increased nuclear-to-cytoplasmic ratio, and a failure of epithelial  Previous radiation therapy to the mediastinum
cells to mature as they migrate to the esophageal surface are  Pathogenesis
present in both grades.  Apart from alcohol and tobacco use, nutritional deficiencies, as well
 Gland architecture is frequently abnormal, and is characterized by as polycyclic hydrocarbons, nitrosamines and other mutagenic
budding, irregular shapes and cellular crowding. compounds (ex. those found in fungus-contaminated foods) must
 High-grade dysplasia exhibits more severe cytologic and also be considered.
architectural changes.  HPV infection has been implicated in high-risk areas,
 Molecular pathogenesis remains incompletely defined, but loss of  Uremic patients and/or patients infected with urease-secreting H.
several tumor suppressor genes is involved. pylori  inhibition of gastric bicarbonate transporters by ammonium
 Morphology ions
 In contrast to adenocarcinoma, half of the squamous cell  Ingestion of harsh chemicals, particularly acid or bases  direct
carcinomas occur in the middle third of the esophagus injury to mucosal epithelial and stromal cells
 Squamous cell carcinoma begins as an in situ lesion termed  Direct cellular injury also implicated in gastritis due to excessive
squamous dysplasia (this lesion is referred to as intraepithelial alcohol consumption, NSAIDs, radiation therapy and chemotherapy
neoplasia or carcinoma in situ at other sites)  Since the entire gastric mucosal surface is replaced every 2-6
 Early lesions appear as small, gray-white, plaque-like thickenings. days, mitotic inhibitors, including those used in cancer
 Over months to years, they grow into tumor masses that may be chemotherapy, cause generalized mucosal damage due to
polyploid or exophytic and protrude into and obstruct the lumen insufficient epithelial regeneration
 Other tumors are either ulcerated or diffusely infiltrative lesions that  Decreased oxygen delivery at high altitudes may also contribute to
spread within the esophageal wall and cause thickening, rigidity and acute gastritis
luminal narrowing. - Morphology:
 These may invade surrounding structures including the  Mild acute gastritis may be difficult to recognize, since the lamina propria
respiratory tree, causing pneumonia; the aorta, causing shows only moderate edema and slight vascular congestion
catastrophic exsanguinations; or the mediastinum and  Surface epithelium is intact, although scattered neutrophils may be present
pericardium. among the epithelial cells or within mucosal glands.
 Most squamous cell carcinomas are moderately to well-  In contrast, an abundance of lymphocytes or plasma cells suggests
differentiated. chronic disease.
 Less common histologic variants:  The presence of neutrophils above the basement membrane in direct
 Verrucous squamous cell carcinoma contact with epithelial cells is abnormal in all parts of the GI tract and
 Spindle cell carcinoma signifies active inflammation.
 Basaloid squamous cell carcinoma  Active inflammation may be present in both acute and chronic
 Regardless of histology, symptomatic tumors are generally very disease states.
large at diagnosis and have already invaded the esophageal wall.  With more severe mucosal damage, erosions and hemorrhage develop.
 The rich submucosal lymphatic network promotes circumferential  Erosion denotes loss of the superficial epithelium, generating a
and longitudinal spread, and intramural tumor nodules may be defect in the mucosa that is limited to the lamina propria.
present several centimeters away from the principal mass.  Accompanied by a pronounced neutrophilic infiltrate within the
 Sites of lymph node metastases vary with tumor location mucosa and a fibrin-containing purulent exudates in the lumen
 Cancers in the upper third favor cervical lymph nodes  Hemorrhage may occur and cause dark punctae in an otherwise
 Those in the middle third favor mediastinal, paratracheal, and hyperemic mucosa.
tracheobronchial nodes  Concurrent erosion and hemorrhage is termed acute erosive
 Those in the lower third spread to gastric and celiac nodes hemorrhagic gastritis.
- Uncommon Esophageal Tumors  Large areas of the gastric surface may be denuded, although the
 Other malignancies of the esophagus include unusual forms of involvement is typically superficial.
adenocarcinoma, undifferentiated carcinoma, carcinoid tumor, melanoma,  When erosions extend deeply, they may progress to ulcers.
lymphoma and sarcoma. - Acute Gastric Ulceration
 Benign tumors are generally mesenchymal in origin and arise within the  Focal, acutely developing gastric mucosal defects are a complication of
esophageal wall. NSAID therapy. They also appear after severe physiologic stress.
 Tumors of smooth muscle origin, leiomyomas, are most common  Stress ulcers: most common in individuals with shock, sepsis or
 Fibromas, lipomas, hemangiomas, neurofibromas and severe trauma
lymphangiomas also occur  Curling ulcers: occur in the proximal duodenum, and are associated
 Some benign tumors take the form of mucosal polyps with severe burns or trauma
 These are usually composed of fibrous and vascular tissue, or  Cushing ulcers: gastric, duodenal and esophageal ulcers arising in
adipose tissue, and are known as fibrovascular polyps or persons with intracranial disease; high incidence of perforation
pedunculated lipomas, respectively.  Pathogenesis
 Squamous papillomas are sessile lesions with a central core of connective  NSAID-induced ulcers are related to COX inhibition  prevents
tissue and a hyperplastic papilliform squamous mucosa. synthesis of prostaglandins, which enhance bicarbonate secretion,
 Uncommonly, papillomas are associated with HPV infection, in which case inhibit acid secretion, promote mucin synthesis and increase
the term condyloma applies. vascular perfusion
 In rare instances, a mass of inflamed granulation tissue, growing either as  Cushing ulcers are caused by direct stimulation of vagal nuclei,
an inflammatory polyp or an infiltrative mass in the wall of the esophagus, which causes hypersecretion of gastric acid. Systemic acidosis
may resemble a malignant lesion. These are called inflammatory found in these settings may also lower intracellular pH of mucosal
pseudotumors. cells
 Hypoxia and reduced blood flow caused by stress-induced
splanchnic vasoconstriction also contribute to pathogenesis.
STOMACH  Morphology
 Range in depth from superficial epithelial damage to deeper lesions
Acute Gastritis that penetrate the depth of the mucosa
- Transient mucosal inflammatory process that may be asymptomatic or cause  Acute ulcers are rounded and less than 1 cm in diameter. The ulcer
variable degrees of epigastric pain, nausea and vomiting. base is frequently stained brown to black by acid digestion of
- In more severe cases, there may be mucosal erosion, ulceration, hemorrhage, extravasated blood and may be associated with transmural
hematemesis, melena, or, rarely, massive blood loss. inflammation and local serositis.
- Pathogenesis:  Unlike peptic ulcers, which arise in the setting of chronic injury,
 Gastric lumen is strongly acidic acute stress ulcers are found anywhere in the stomach.
 Mechanisms exist to protect the gastric mucosa:  Gastric rugal folds are essentially normal, and the margins and base
 Mucin secreted by the surface foveolar cells prevents large food of the ulcers are not indurated.
particles from directly touching the epithelium  While ulcers may occur singly, more often there are multiple ulcers
 Mucus layer also promotes formation of an “unstirred” layer of fluid throughout the stomach and duodenum.
over the epithelium that protects the mucosa and has a neutral pH  Microscopically, acute stress ulcers are sharply demarcated, with
as a result of bicarbonate ion secretion by surface epithelial cells essentially normal adjacent mucosa.
 Rich vascular supply to the gastric mucosa delivers oxygen,  Depending on the duration of ulceration, there may be a suffusion of
bicarbonate and nutrients while washing away acid that has back- blood into the mucosa and submucosa and some inflammatory
diffused into the lamina propria. reaction.
 Acute or chronic gastritis can occur following disruption of any of the  Conspicuously absent are the scarring and thickening of blood
protective mechanisms. vessels that characterize chronic peptic ulcers.
 Reduced mucin synthesis in the elderly  increased susceptibility  Healing with complete re-epithelialization occurs after the injurious
to gastritis factors are removed.
 NSAIDs interfere with cytoprotection normally provided by
prostaglandins or reduce bicarbonate secretion  increased Chronic Gastritis
susceptibility of the gastric mucosa to injury - Symptoms are less severe, but more persistent. Hematemesis is uncommon.
- Most common cause is infection with H. pylori.
- Autoimmune gastritis is the most common cause of atrophic gastritis, but  Characterized by:
represents less than 10% of cases of chronic gastritis. It is the most common  Antibodies to parietal cells and intrinsic factor that can be detected
form in patients without H. pylori infection. in serum and gastric secretions
- Less common etiologies include radiation injury, chronic bile reflux, mechanical  Reduced serum pepsinogen I concentration
injury, and involvement by systemic disease such as Crohn disease, amyloidosis  Antral endocrine cell hyperplasia
or GVHD.  Vitamin B12 deficiency
- Helicobacter pylori Gastritis  Defective gastric acid secretion (achlorhydria)
 These spiral-shaped or curved bacilli are present in gastric biopsy  Pathogenesis
specimens of almost all patients with duodenal ulcers and the majority of  Associated with loss of parietal cells, which are responsible for
individuals with gastric ulcers or chronic gastritis. secretion of gastric acid and IF
 Acute H. pylori infection does not produce sufficient symptoms to require  Absence of acid stimulates gastrin release  hypergastrinemia and
medical attention; it is chronic gastritis that causes the individual to seek hyperplasia of antral gastrin-producing G cells
treatment.
 Lack of IF  disables ileal vitamin B12 absorption  B12
 Organisms are present in 90% of individuals with chronic gastritis affecting
deficiency and pernicious anemia
the antrum
 Reduced serum pepsinogen I results from chief cell destruction
 The increased acid secretion that occurs in H. pylori gastritis may result in
peptic ulcer disease, and H. pylori infection also confers increased risk of  Although H. pylori can cause hypochlorhydria, it is not associated
gastric cancer. with achlorhydria or pernicious anemia because the parietal and
 Pathogenesis: chief cell damage is not as severe as in autoimmune gastritis
 Disease most often presents as a predominantly antral gastritis with  CD4+ T cells directed against parietal cell components, including the
high acid production, despite hypogastrinemia H+,K+-ATPase are the principal agents of injury
 Risk of duodenal ulcer is increased in these patients and, in most,  No evidence of autoimmune reaction to chief cells, suggesting that
gastritis is limited to the antrum with occasional involvement of the these are lost through gastric gland destruction during autoimmune
cardia attack on parietal cells
 Pangastritis is associated with multifocal mucosal atrophy, reduced  If destruction is controlled by immunosuppression, the glands can
acid secretion, intestinal metaplasia and increased risk of gastric repopulate, demonstrating that gastric stem cells survive and are
adenocarcinoma. able to differentiate into parietal and chief cells.
 Morphology
 H. pylori has adapted to the ecologic niche provided by gastric
mucus. Although it may invade the gastric mucosa, this is not  Characterized by diffuse mucosal damage of the oxyntic (acid-
evident histologically. producing) mucosa within the body and fundus
 Four features linked to its virulence:  Damage to the antrum and cardia is typically absent or mild
1. Flagella – allow the bacteria to be motile in viscous mucus  With diffuse atrophy, the oxyntic mucosa of the body and fundus
2. Urease – generates ammonia from endogenous urea, thereby appears markedly thinned, and rugal folds are lost.
elevating local gastric pH  If B12 deficiency is severe, nuclear enlargement (megaloblastic
3. Adhesins – enhance their bacterial adherence to surface change) occurs within epithelial cells.
foveolar cells  Neutrophils may be present, but the inflammatory infiltrate is more
4. Toxins, such as CagA – may be involved in ulcer or cancer often composed of lymphocytes, macrophages and plasma cells.
development Lymphoid aggregates may be present.
 Infection results in increased acid production and disruption of  The superficial lamina propria plasma cells of H. pylori gastritis are
normal gastric and duodenal protective mechanism. typically absent, and the inflammatory reaction is most often deep
 Gastritis is therefore the result of an imbalance between and centered on the gastric glands.
gastroduodenal mucosal defenses and damaging forces that  Loss of parietal and chief cells can be extensive.
overcome those defenses.  Small surface elevations may be apparent. These correlate with
 Over time, chronic antral gastritis may progress to pangastritis, areas of intestinal metaplasia, characterized by the presence of
resulting in multifocal atrophic gastritis. Progression may be due to goblet cells and columnar absorptive cells.
host and bacterium unteractions.  Antral endocrine cell (or enterochromaffin cell) hyperplasia parallels
 Morphology: the degree of mucosal atrophy, and is a physiologic response to
 Organism is concentrated within the superficial mucus overlying decreased acid production.
epithelial cells in the surface and neck region  Over time, hypergastrinemia can stimulate endocrine cell
 Distribution can be irregular, with areas of heavy colonization hyperplasia in the fundus and body. This rarely progresses to form
adjacent to those with few organisms low-grade neuroendocrine, or carcinoid, tumors
 In extreme cases, the organisms carpet the luminal surfaces of - Uncommon Forms of Gastritis
foveolar and mucous neck cells, and can extend into the gastric pits.  Reactive Gastropathy
 H. pylori shows tropism for gastric epithelia and is generally not  Marked by foveolar hyperplasia, glandular regenerative changes
found in association with gastric intestinal metaplasia or duodenal and mucosal edema
epithelium. However, it may be present in foci of pyloric metaplasia  Neutrophils are not abundant
within chronically injured duodenum or gastric-type mucosa within  Causes include chemical injury, NSAID use, bile reflux and mucosal
Barrett esophagus. trauma secondary to prolapse.
 Within the stomach, organisms are typically found in the antrum.  Commonly seen after gastric surgeries that bypass the pylorus
Infection of the cardia occurs at somewhat lower rates.  Gastric antral trauma induces a grossly characteristic lesion referred
 H. pylori are uncommon in oxyntic (acid-producing) mucosa of the to as gastric antral vascular ectasia (GAVE)
fundus and body except in heavy colonization.  Endoscopy: longitudinal stripes of edematous erythematous mucosa
 Antral biopsy is preferred for evaluation of H. pylori gastritis. alternating with less severely injured mucosa (watermelon stomach)
 On endoscopy, antral mucosa is usually erythematous, and has a  Histologically, the antral mucosa shows reactive gastropathy with
coarse or nodular appearance. dilated capillaries containing fibrin thrombi
 The inflammatory infiltrate generally includes variable numbers of  Eosinophilic Gastritis
neutrophils within the lamina propria, including some that cross the  Characterized by tissue damage associated with dense infiltrates of
basement membrane to assume an intraepithelial location and eosinophils in the mucosa and muscularis, usually in the antral or
accumulate in the lumen of gastric pits to create pit abscesses. pyloric region
 Superficial lamina propria includes large numbers of plasma cells  Often present in other areas of the GI tract, and is associated with
and increased numbers of lymphocytes and macrophages. peripheral eosinophilia and increased serum IgE levels
 Intraepithelial neutrophils and subepithelial plasma cells are  Allergic reactions are one cause: cow’s milk and soy protein in
characteristic of H. pylori gastritis. children; drugs in adults and children
 When intense, inflammatory infiltrates may create thickened rugal  Parasitic and H. pylori infections are other causes.
folds, mimicking early infiltrative lesions.  Lymphocytic Gastritis
 Lymphoid aggregates, some with germinal centers, are frequently  Preferentially affects women
present and represent an induced form of mucosa-associated  Produces nonspecific symptoms
lymphoid tissue that has the potential to transform into lymphoma.  Idiopathic, but approximately 40% of cases are associated with
- Autoimmune Gastritis celiac disease, suggesting immune-mediated pathogenesis
 Unlike H. pylori gastritis, it typically spares the antrum and includes
hypergastrinemia
 Also called varioliform gastritis based on its distinctive endoscopic Beneath this, active granulation tissue infiltrated with mononuclear
appearance (thickened folds covered by small nodules with central leukocytes and a fibrous or collagenous scar forms the ulcer base.
aphthous ulceration)  Vessel walls within the scarred area are typically thickened and are
 Entire stomach is affected in most cases occasionally thrombosed.
 Histologically, there is a marked increase in the number of  Ongoing bleeding within the ulcer base may cause life-threatening
intraepithelial T lymphocytes, mostly CD8+ T cells, within surface hemorrhage.
and pit regions  Scarring may involve the entire thickness of the wall and pucker the
 Granulomatous Gastritis surrounding mucosa into folds that radiate outward.
 Applied to any gastritis that contains granulomas or aggregates of  Size and location do not differentiate benign and malignant ulcers.
epithelioid histiocytes (tissue macrophages) However, the gross appearance of chronic peptic ulcers is virtually
 Correlation with clinical, endoscopic, radiologic and serologic data is diagnostic.
generally necessary for diagnosis.  Malignant transformation of peptic ulcers is very rare.
 Gastric involvement by Crohn disease is the most common specific - Mucosal Atrophy and Intestinal Metaplasia
cause. Sarcoidosis is the second, followed by a variety of infections.  Long-standing chronic gastritis that involves the body and fundus may
 Narrowing and rigidity of the gastric antrum may occur secondary to ultimately lead to significant loss of parietal cells mass.
transmural granulomatous inflammation  May be associated with intestinal metaplasia, recognized by
presence of goblet cells
Complications of Chronic Gastritis  Strongly associated with increased risk of gastric adenocarcinoma
- Peptic Ulcer Disease  Risk is greatest in autoimmune gastritis, because achlorhydria
 Most often associated with H. pylori gastritis permits overgrowth of bacteria that produce carcinogenic
 Presence of chronic gastritis can help to distinguish peptic ulcers from nitrosamines
acute erosive gastritis or stress ulcers, since the mucosa adjacent to the  Intestinal metaplasia also occurs in chronic H. pylori gastritis and may
ulcer is generally normal in the latter two conditions. regress after clearance of the organism.
 PUD may occur in any portion of the GI tract exposed to acidic gastric - Dysplasia
juices, but it is most common in the gastric antrum and first portion of the  Chronic gastritis exposes the epithelium to inflammation-related free
duodenum. radical damage and proliferative stimuli.
 PUD may also occur in the esophagus as a result of GERD or ectopic  Over time, this leads to accumulation of genetic alterations that
gastric mucosa. result in carcinoma.
 Gastric mucosa within a Meckel diverticulum can result in peptic ulceration  Pre-invasive in situ lesions are recognized histologically as
of adjacent mucosa. dysplasia
 Pathogenesis  Morphologic hallmarks of dysplasia:
 Imbalances of mucosal defenses and damaging forces that cause  Variations in epithelial size, shape and orientation
chronic gastritis  Coarse chromatin texture, hyperchromasia and nuclear enlargement
 Generally develops on a background of chronic gastritis  Distinction between dysplasia and regenerative epithelial changes induced
 H. pylori infection and NSAID use are the primary underlying by active inflammation is challenging, since increased epithelial
causes, and both compromise mucosal defense while causing proliferation and mitotic figures may be prominent in both.
mucosal damage  But, whereas reactive epithelial cells mature as they reach the
 The gastric hyperacidity that drives PUD may be caused by H. pylori mucosal surface, dysplastic lesions remain cytologically immature.
infection, parietal cell hyperplasia, excessive secretory responses or - Gastritis Cystica
impaired inhibition of stimulatory mechanisms such as gastrin  Refers to an exuberant reactive epithelial proliferation associated with
release. entrapment of epithelial-lined cysts
 For example, Zollinger-Ellison syndrome, in which there are  May be found in the submucosa (gastritis cystic polyposa) or deeper layers
multiple peptic ulcerations along the GIT, is caused by of the gastric wall (gastritis cystic profunda)
uncontrolled release of gastrin by a tumor and the resulting  Regenerative epithelial changes can be prominent in the entrapped
massive acid production epithelium  can mimic invasive adenocarcinoma
 Most common cofactors in peptic ulcerogenesis:
 Chronic NSAID use, which causes direct chemical irritation Hypertrophic Gastropathies
while suppressing PG synthesis - Uncommon diseases characterized by giant cerebriform enlargement of the rugal
 Cigarette smoking, which impairs mucosal blood flow and folds due to epithelial hyperplasia without inflammation
healing - Linked to excessive growth factor release
 High-dose corticosteroids, which suppress PG synthesis and - Ménétrier Disease
impair healing  Rare disorder caused by excessive secretion of TGF-a
 Duodenal ulcers are more frequent in individuals with alcoholic  Characterized by diffuse hyperplasia of the foveolar epithelium of the body
cirrhosis, COPD, chronic renal failure and hyperparathyroidism. and fundus, and hypoproteinemia due to protein-losing enteropathy
 In the latter two, hypercalcemia stimulates gastrin production  Symptoms and pathologic features in children are similar to those in
and therefore increases acid secretion adults, but pediatric disease is usually self-limited and often follows
 Self-imposed or exogenous psychologic stress may increase gastric respiratory infection.
acid production  Risk of gastric adenocarcinoma is increased in adults with this disease.
 Morphology  Morphology:
 Ulcers are four times more common in the proximal duodenum than  Irregular enlargement of the gastric rugae in the body and fundus
in the stomach  Antrum is generally spared
 Duodenal ulcers usually occur near the pyloric valve and involve the  Histologically, the most characteristic feature is hyperplasia of
anterior duodenal wall. foveolar mucous cells
 Gastric peptic ulcers are predominantly located along the lesser  Glands are elongated with a corkscrew-like appearance and cystic
curvature near the interface of the body and antrum. dilation is common
 The classic peptic ulcer is a round to oval, sharply punched-out  Inflammation is modest.
defect. The mucosal margin may overhang the base slightly,  Diffuse or patchy granular atrophy, evident as hypoplasia of parietal
particularly on the upstream side, but it is usually level with the and chief cells, is typical
surrounding mucosa. Heaped-up margins are more characteristic of - Zollinger-Ellison Syndrome
cancers.  Caused by gastrin-secreting tumors, gastrinomas, that are commonly
 The depth of ulcers may be limited by the thick gastric muscularis found in the small intestine or pancreas
propria or by adherent pancreas, omental fat or the liver.  Patients often present with duodenal ulcers or chronic diarrhea.
 Hemorrhage and fibrin deposition are often present on the gastric  Within the stomach, the most remarkable feature is a doubling of oxyntic
serosa. mucosal thickness due to a fivefold increase in the number of parietal cells
 Perforation into the peritoneal cavity is a surgical emergency that  Gastrin also induces hyperplasia of mucous neck cells, mucin
may be identified by the presence of free air under the diaphragm on hyperproduction, and proliferation of endocrine cells within oxyntic
upright radiographs of the abdomen. mucosa.
 The base of peptic ulcers is smooth and clean as a result of peptic  In some cases, these endocrine cells can form small dysplastic
digestion of exudates. Blood vessels may be evident. nodules or, rarely, true carcinoid tumors
 In active ulcers, the base may have a thin layer of fibrinoid debris
underlaid by a predominantly neutrophilic inflammatory infiltrate. Gastric Polyps and Tumors
- Polyps develop due to epithelial or stromal cell hyperplasia, ectopia or neoplasia.
- Inflammatory and Hyperplastic Polyps  Genetic variants of pro-inflammatory and immune response genes
 75% of polyps are associated with elevated risk of gastric cancer when
 Most common between ages 50 and 60 accompanied by H. pylori infection, and p53 mutations are present
 Usually develop in association with chronic gastritis, which initiates the in the majority of sporadic gastric cancers of both histologic types
injury and reactive hyperplasia that leads to polyp growth  This shows that chronic inflammation promotes neoplastic
 Among indibiduals with H. pylori gastritis, polyps may regress after progression
bacterial eradication.  Morphology
 Because of the risk of dysplasia correlates with size, polyps larger than 1.5  Gastric adenocarcinomas are classified according to location in the
cm should be resected and examined histologically. stomach, and most importantly, according to gross and histologic
 Morphology: morphology.
 Majority are smaller than 1 cm in diameter and are frequently  Most involve the gastric antrum. The lesser curvature is involved
multiple, particularly in individuals with atrophic gastritis more often than the greater curvature.
 Polyps are ovoid in shape and have a smooth surface, though  Gastric tumors with an intestinal morphology tend to form bulky
superficial erosions are common tumors composed of glandular structures.
 Microscopically, they have irregular, cystically dilated and elongated  Although intestinal-type adenocarcinomas may penetrate the
foveolar glands. The lamina propria is typically edematous, and gastric wall, they typically grow along broad cohesive fronts to
surface ulceration may be present. form either an exophytic mass or an ulcerated tumor
- Fundic Gland Polyps  Neoplastic cells often contain apical mucin vacuoles, and
 Occur sporadically and in individuals with familial adenomatous polyposis abundant mucin may be present in gland lumens
(FAP)  Diffuse gastric cancer is generally composed of discohesive cells
 Prevalence has increased with PPI therapy that do not form glands, but instead have large mucin vacuoles that
 This reflects increased gastrin secretion in response to reduced expand the cytoplasm and push the nucleus to the periphery,
gastric acidity, and the resulting glandular hyperplasia. creating a signet-ring cell morphology.
 Five times more common in women; discovered at an average age of 50  These cells permeate the mucosa and stomach wall
 May be asymptomatic or associated with nausea, vomiting, epigastric pain individually or in small clusters, which makes tumor cells easy
 Morphology: to confuse with inflammatory cells, such as macrophages, at
 Fundic gland polyps occur in the gastric body and fundus low magnification.
 Well-circumscribed lesions with a smooth surface  Extracellular mucin release in either type of gastric cancer can result
 May be single or multiple in formation of large mucin lakes that dissect tissue planes.
 Composed of cystically dilated, irregular glands lined by flattened  A mass may be difficult to appreciate in diffuse gastric cancer, but
parietal or chief cells these tumors often evoke a desmoplastic reaction that stiffens the
 Inflammation typically absent or minimal gastric wall, and may provide a valuable diagnostic clue.
- Gastric Adenoma  When there are large areas of infiltration, diffuse rugal flattening and
 Represent as many as 10% of all gastric polyps a rigid, thickened wall may impart a leather bottle appearance
 Incidence increases progressively with age termed linitis plastica.
 Patients are usually between 50 and 60 years of age  Breast and lung cancers that metastasize to the stomach may
 Males are affected three times more often also create a linitis plastica-like appearance.
 Incidence is increased in patients with FAP  Intestinal-type gastric cancer predominates in high-risk areas and
 Almost always occur on a background of chronic gastritis with atrophy and develops from precursor lesions including flat dysplasia and adenomas.
intestinal metaplasia Mean age of presentation is 55 years, and the male-to-female ratio is 2:1.
 Risk is related to size of the lesion, and is particularly elevated in lesions  Incidence of diffuse gastric cancer is relatively uniform across countries.
greater than 2 cm in diameter  Notably, the remarkable decrease in gastric cancer incidence applies only
 Carcinoma present in up to 30% of gastric carcinomas to the intestinal type, which is most closely associated with atrophic
 Morphology: gastritis and intestinal metaplasia. As a result, incidences of both types are
 Usually solitary lesions less than 2 cm in diameter, most commonly now similar.
located in the antrum  The depth of invasion and the extent of nodal and distant metastasis at the
 Majority are composed of intestinal-type columnar epithelium time of diagnosis remains the most powerful prognostic indicators for
 By definition, all GI adenomas have epithelial dysplasia that can be gastric cancer.
classified as low or high grade  In advanced cases, gastric carcinoma may first be detected as
 Both grades may include enlargement, elongation and metastases to the supraclavicular sentinel lymph node, also called
hyperchromasia of epithelial cell nuclei, epithelial crowding, Virchow’s node.
and pseudostratification  Gastric tumors can also metastasize to the periumbilical region to
 High-grade dysplasia is characterized by more severe form a subcutaneous nodule, termed a Sister Mary Joseph nodule.
cytologic atypia and irregular architecture, including grandular  Local invasion into the duodenum, pancreas and retroperitoneum is
budding and gland-within-gland, or cribriform, structures also characteristic.
- Gastric Adenocarcinoma - Lymphoma
 Most common malignancy of the stomach, comprising 90% of cancers  Although extra-nodal lymphomas can arise in virtually any tissue, they do
 Early symptoms resemble chronic gastritis so most commonly in the GI tract, particularly in the stomach
 Often discovered at advanced stages  In allogeneic bone marrow transplant and organ transplant recipients, the
 Gastric cancer is more common in lower socioeconomic groups and in bowel is also the most frequent site for EBV-positive B-cell
individuals with multifocal mucosal atrophy and intestinal metaplasia lymphoproliferations, because the deficits in T-cell function caused by oral
 PUD does not impart an increased risk of gastric cancer, but patients who immunosuppressive agents are greatest at intestinal sites of drug
have had partial gastrectomies for PUD have a slightly higher risk in the absorption.
residual gastric stump as a result of hypochlorhydria, bile reflux and  Most common: indolent extra-nodal marginal zone B-cell lymphomas
chronic gastritis.  In the gut, these tumors are often referred to as MALTomas.
 Although overall incidence of gastric adenocarcinoma is falling, cancer of  Second most common: diffuse large B-cell lymphoma
the gastric cardia is on the rise. This is related to Barrett esophagus and  Pathogenesis:
may reflect the increasing incidence of chronic GERD and obesity.  Extra-nodal marginal zone B-cell lymphomas usually arise at sites of
 Pathogenesis: chronic inflammation.
 While the majority of gastric cancers are not hereditary, some  They can originate in the GI tract at sites of preexisting MALT,
mutations have been identified in familial gastric cancer such as Peyer’s patches of the small intestine, but most
 Germline mutations in CDH1, which encodes E-cadherin, a commonly arise within tissues that are normally devoid of
protein that contributes to epithelial intercellular adhesion. organized lymphoid tissue.
Loss of function is a key step in the development of diffuse  Most common cause of pro-lymphomatous inflammation in the
gastric cancer. stomach is chronic H. pylori infection, which is found in
 Individuals with BRCA2 mutation are also at increased risk of association with most cases of gastric MALToma
developing diffuse gastric cancer.  As with other low-grade lymphomas, MALTomas can
 Increased risk of intestinal-type gastric cancer in individuals with transform into more aggressive tumors that are histologically
FAP, particularly in Japan  reflects the interaction between host identical to diffuse large B-cell lymphomas
genetic background and environmental factors  Eradication of H. pylori infection with antibiotics induces durable
 Mutations in B-catenin, a protein that binds to both E-cadherin remissions of MALTomas with low rates of recurrence.
and adenomatous polyopsis coli (APC)  Histologic features that predict antibiotic treatment failure
include transformation to large-cell lymphoma, tumor invasion
to the muscularis propria or beyond, and lymph node  Increased incidence of GIST in individuals with neurofibromatosis type 1
involvement.  Pathogenesis:
 Three genetic translocations are associated with gastric MALToma.  75-80% of all GISTs have oncogenic, gain-of-function mutations of
Each has the same net effect, the constitutive activation of NF-kB, a the gene encoding the tyrosine kinase c-KIT, which is the receptor
transcription factor that promotes B-cell growth and survival. for stem cell factor
 In tumors without the translocations, elimination of the  8% have mutations that activate a related tyrosine kinase, PDGFRA.
immune stimulus (H. pylori) down-regulated NF-kB, resulting  GISTs appear to arise from, or share a common stem cell with the
in tumor suppression. interstitial cells of Cajal, which are located in the muscularis propria
 In contrast, NF-kB is constitutively active in tumors bearing and serve as pacemaker cells for gut peristalsis
translocations, and as a result the elimination of H. pylori has  Constitutively active c-KIT and PDGFRA receptor tyrosine kinases
no effect. produce intracellular signals that activate RAS and PI3K/AKT
 Morphology: pathways and thereby promote tumor cell proliferation and survival
 Histologically, gastric MALToma takes the form of a dense  Morphology:
lymphocytic infiltrate in the lamina propria  Primary gastric GISTs can be quite large, as much as 30 cm in
 Characteristically, the neoplastic lymphocytes infiltrate the gastric diameter.
glands focally to create diagnostic lymphoepithelial lesions  They usually form a solitary, well-circumscribed, fleshy mass
 Reactive-appearing B-cell follicles may be present, and, in about covered by ulcerated or intact mucosa, but can also project outward
40% of tumors, plasmacytic differentiation is observed. toward the serosa.
 Occasionally, the tumor cells accumulate large amounts of pale  Metastases may take the form of multiple serosal nodules
cytoplasm (monocytoid change) throughout the peritoneal cavity or as one or more nodules in the
 Like other tumors of mature B cells, MALTomas express the B-cell liver.
markers CD19 and CD20. They do not express CD5 and CD10, and  Spread outside the abdomen is uncommon.
are positive for CD43 in 25% of cases.  GISTs composed of thin elongated cells are classified as spindle cell
- Carcinoid Tumor type, whereas tumors dominated by epithelial appearing cells are
 Arise from the diffuse components of the endocrine system termed epithelioid type. Mixtures may occur.
 Majority are found in the GI tract, and more than 40% occur in the small  The most useful diagnostic marker is c-KIT, which is
intestine. The tracheobronchial tree and lungs are the next most commonly immunohistochemically detectable in 95% of cases.
involved sites.  Prognosis correlates with tumor size, mitotic index and location, with
 Gastric carcinoids may be associated with endocrine cell hyperplasia, gastric GISTs being somewhat less aggressive than those arising in the
chronic atrophic gastritis and Zollinger-Ellison syndrome. small intestine.
 More indolent course than GI carcinomas  Recurrence or metastasis is rare for gastric GISTs under 5 cm, but
 Best considered to be well-differentiated neuroendocrine carcinomas common for mitotically active tumors larger than 10 cm.
 Carcinoids within the GI tract arise from the endocrine cells that release
peptide and nonpeptide hormones to coordinate gut function.
 Morphology:
 Grossly, they are intramural or submucosal masses that create
small polyploidy lesions
 Overlying mucosa may be intact or ulcerated, and the tumors may
invade deeply to involve the mesentery.
 Tend to be yellow or tan in color, and are very firm as a
consequence of an intense desmoplatic reaction, which may cause
kinking of the bowel and obstruction.
 Histologically, composed of islands, trabeculae, strands, glands or
sheets of uniform cells with scant, pink granular cytoplasm and a
round to oval stippled nucleus
 In most, there is minimal pleomorphism, but anaplasia, mitotic
activity, and necrosis may be present in rare cases.
 Immunohistochemical stains are typically positive for endocrine
granular markers, such as synaptophysin and chromogranin A.
 Peak incidence in the sixth decade, but may appear at any age
 Symptoms determined by the hormones produced
 Carcinoid syndrome – caused by vasoactive substances secreted by the
tumor into the systemic circulation
 The most important prognostic factor for GI carcinoid tumors is location.
 Foregut carcinoid tumors (stomach, duodenum proximal to ligament
of Treitz, esophagus)  rarely metastasize and are generally cured
by resection.
 This is particularly true for gastric carcinoid tumors that arise
in association with atrophic gastritis, while gastric carcinoid
tumors without predisposing factors are more aggressive.
 Midgut carcinoid tumors (jejunum and ileum)  often multiple, and
tend to be aggressive.
 Greater depth of local invasion, increased size, and presence
of necrosis and mitosis are associated with poor outcome.
 Hindgut carcinoids (appendix and colorectum)  discovered
incidentally
 Those in the appendix occur at any age, and are generally
located at the tip. These are rarely more than 2 cm in
diameter, and are almost uniformly benign.
 Rectal carcinoid tumors tend to produce polypeptide
hormones and, when symptomatic, present with abdominal
pain and weight loss. Metastasis is uncommon.
 Tumors of the proximal colon are uncommon, but may grow to
large size and metastasize.
- Gastrointestinal Stromal Tumor
 Most common mesenchymal tumor of the abdomen. More than half of
these occur in the stomach.
 Slightly more common in males. Peak age of diagnosis in the stomach is
60 years.
 Of the uncommon GISTs in children, some are related to the Carney triad,
a nonhereditary syndrome seen primarily in young females that includes
gastric GIST, paraganglioma and pulmonary chondroma.

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