Double-Contrast Upper Gastrointestinal Radiography: A

Note: This copy is for your personal, non-commercial use only. To order presentation-ready copies for distribution to your colleagues or clients, use the Radiology Reprints form at the end of this article. EIW N COMMENTARY AND REVIEWS Double-Contrast Upper Gastrointestinal Radiography: A

Pattern Approach for Diseases of the Ⅲ Stomach1 RESIDENTS FOR REVIEW

Stephen E. Rubesin, MD The double-contrast upper gastrointestinal series is a valu- Marc S. Levine, MD able diagnostic test for evaluating structural and functional Igor Laufer, MD abnormalities of the stomach. This article will review the normal radiographic anatomy of the stomach. The principles of analyzing double-contrast images will be discussed. A pattern approach for the diagnosis of gastric abnormalities will also be presented, focusing on abnormal mucosal patterns, depressed lesions, protruded lesions, thickened folds, and gastric narrowing.

௠ RSNA, 2008

1 From the Department of Radiology, Hospital of the Uni- versity of Pennsylvania, 3400 Spruce St, Philadelphia, PA 19104. Received July 18, 2006; revision requested Sep- tember 20; revision received October 5; accepted Novem- ber 2; ﬁnal version accepted January 2, 2007; ﬁnal review by M.S.L. June 19. S.E.R. and M.S.L. are paid consultants for E-Z-Em, Westbury, NY. Address correspondence to M.S.L. (e-mail: [email protected] .edu ).

஽ RSNA, 2008

Radiology: Volume 246: Number 1—January 2008 33 REVIEW FOR RESIDENTS: Double-Contrast Upper Gastrointestinal Radiography Rubesin et al

his article presents a pattern ap- ples of double-contrast image interpre- more undulating on the greater curva- proach for the diagnosis of dis- tation, we will consider abnormal sur- ture. The thickness of the rugal folds Teases of the stomach at double- face patterns of the mucosa, depressed varies with the degree of gastric disten- contrast upper gastrointestinal radi- lesions (erosions and ulcers), protruded tion (5). ography. After describing the normal lesions (polyps, submucosal masses, appearance of the stomach on double- and other tumors), thickened folds, and Areae Gastricae contrast barium studies and the princi- gastric narrowing. The mucosal surface of the stomach consists of flat polygonal-shaped tufts of mucosa, known as areae gastricae, sep- Essentials Normal Stomach arated by narrow grooves (6,7). The Ⅲ Protruded lesions (eg, polyps and areae gastricae are recognized on dou- cancers) on the dependent wall of Gastric Configuration and Rugal Folds ble-contrast studies as a reticular net- the stomach may appear as radi- The normal stomach is a J-shaped work of barium-coated white lines when olucent filling defects in the bar- pouch that lies in the left upper quad- barium fills the grooves between these ium pool, whereas protruded le- rant (Fig 1). The stomach has a fixed mucosal tufts (Fig 3). Individual muco- sions on the nondependent wall configuration created by the greater sal tufts of areae gastricae normally may appear as barium-coated length of the longitudinal muscle layer have a diameter of 2–3 mm in the gas- “ring shadows” due to barium on its greater curvature. The lesser cur- tric antrum and of 3–5 mm in the gastric coating the edge of these lesions. vature of the stomach is suspended body and fundus (Fig 3) (6,8). Areae Ⅲ Multiple small, round, uniform nod- from the retroperitoneum by the hepa- gastricae are detected on double-con- ules in the stomach are usually togastric ligament, a portion of the trast studies in nearly 70% of patients caused by lymphoid hyperplasia lesser omentum. The gastrosplenic liga- and are observed with greater fre- associated with Helicobacter pylori ment and gastrocolic ligament (ie, the quency in the elderly (8,9). gastritis, whereas irregular nonuni- proximal portion of the greater omen- form nodules may be caused by tum) are attached to the greater curva- Comparison of Histologic Anatomy with low-grade B-cell mucosa-associated ture of the stomach. The gastric cardia Macroscopic Anatomy lymphoid tissue lymphoma. is attached to the diaphragm by the sur- Abasicunderstandingofthehistologic Ⅲ Aspirin and other nonsteroidal rounding phrenoesophageal membrane. anatomy of the stomach is helpful for antiinflammatory drugs (NSAIDs) The stomach is arbitrarily divided understanding peptic ulcer disease, as are by far the most common into five segments: the cardia, fundus, well as other gastric abnormalities cause of erosive gastritis, a condi- body, antrum, and pylorus. The gastric (5,10). The stomach contains several tion manifested on double-con- cardia is characterized on barium stud- types of mucosa: cardiac-type mucosa, trast studies as punctate or slitlike ies by three or four stellate folds that body/fundic-type mucosa, and antral/ erosions surrounded by radiolu- radiate to a central point at the gastro- pyloric-type mucosa. Gastric foveolae cent mounds of edema or, in esophageal junction, also known as the (or pits) are conical depressions in the some patients taking NSAIDs, by cardiac “rosette” (Fig 2) (1,2). The gas- mucosal surface that communicate linear or serpiginous erosions on tric fundus is defined as the portion of with gastric glands (4,10). The glands or near the greater curvature of the stomach craniad to the gastric car- are long, straight, and tightly packed the gastric antrum or body. dia. The gastric body is defined as the structures. The foveolae in all parts of Ⅲ H pylori gastritis is by far the portion of the stomach extending from the stomach are lined by surface fove- most common cause of focally or the gastric cardia to the smooth bend in olar mucous cells. The cardiac-type diffusely thickened gastric folds, the mid lesser curvature known as the mucosa comprises a short (1 cm in which can be so large and lobu- incisura angularis. The gastric antrum is length) segment of the gastric mucosa lated (eg, polypoid gastritis) that defined as the portion of the stomach adjacent to the gastroesophageal junc- the radiographic findings resem- extending from the incisura angularis to tion (4). The distinguishing feature of ble those of Menetrier disease or the pylorus (a structure created by a the body-type mucosa is the presence lymphoma. muscle sphincter shaped like a figure Ⅲ On barium studies, scirrhous carci- eight). nomas of the stomach may produce Rugal folds are most prominent in Published online alinitisplasticaappearancewith the gastric fundus and body, whereas 10.1148/radiol.2461061245 diffuse narrowing or long- or short- the gastric antrum is often devoid of Radiology 2008; 246:33–48 segment narrowing of any portion folds (Fig 1). Gastric rugae are change- of the stomach; metastatic breast able structures composed of mucosa Abbreviations: cancer and lymphoma occasionally and submucosa (3,4). The rugal folds MALT ϭ mucosa-associated lymphoid tissue NSAID ϭ nonsteroidal antiinflammatory drug may produce a similar radiographic are relatively straight on the lesser cur- appearance. vature of the stomach but larger and Authors stated no financial relationship to disclose.

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of parietal and chief cells in the glands. extending progressively higher on the (Fig 1). With air contrast, the luminal The parietal cells produce hydrochlo- lesser curvature. Peptic ulcers fre- contour appears as a smooth, continuous ric acid and intrinsic factor, and the quently develop on the lesser curva- barium-coated white line (Fig 1) (11). chief cells produce proteolytic en- ture at the transition zone (Fig 4). zymes. No parietal or chief cells are Barium Pool found in antral-type mucosa. The sur- The pool of high-density barium is the face foveolar mucous cells line both an- Principles of Image Analysis tool the radiologist uses to scrub and tral pits and glands. Body-type mucosa lines the ana- Appearance of the Stomach tomic gastric fundus and the gastric The radiologist ﬁrst examines the over- Figure 3 body and extends into the gastric an- all position, shape, and size of the stom- trum along the greater curvature (4). ach. The gastric fundus abuts the left Antral-type mucosa lines the antrum hemidiaphragm. The cardia has a mid- along the lesser curvature from the py- line location, abutting the crus of the left lorus to the incisura angularis, but only hemidiaphragm. The stomach curves to lines a small amount of antrum along the the right across the midline, with the greater curvature. Thus, the histologic distal gastric antrum and duodenum ex- division of the stomach into body- and tending to the right of the spine. There antral-type mucosa does not correlate is considerable variation in the size of with the anatomic and radiologic divi- the stomach, depending on the amount sion of the stomach into fundus, body, of barium and effervescent agent ad- and antrum (5). ministered. The transition zone between body- Figure 3: Double-contrast spot image of stom- and antral-type mucosa is a line that Luminal Contour ach with patient in left posterior oblique position extends from the incisura angularis to In the barium pool, the contour is de- shows normal areae gastricae pattern in antrum as the distal greater curvature. The transi- marcated by a smooth edge of barium 2–3-mm polygonally shaped radiolucent tufts of tion zone migrates proximally with age, mucosa outlined by barium in grooves. Areae Figure 2 gastricae are slightly larger in distal gastric body than in antrum. Figure 1

Figure 4

Figure 1: Normal stomach. Double-contrast spot image of stomach with patient supine shows distal gastric body (B) and antrum (A). Greater curvature (white arrows) and lesser curvature Figure 2: Double-contrast spot image of gas- (black arrows) are coated by barium. Rugal fold on tric fundus with patient in right-side-down posi- posterior wall of gastric body is depicted as tubu- tion shows normal gastric cardia with smooth lar, slightly undulating, radiolucent ﬁlling defect folds radiating to central point (white arrow) at Figure 4: Double-contrast spot image of stom- (black arrowheads) in shallow barium pool. Dense closed gastroesophageal junction, also known as ach with patient in supine position shows benign barium pool outlines contour (white arrowheads) cardiac rosette. Long, straight fold (arrowheads) lesser curvature gastric ulcer (U) as smooth, ovoid of gastric fundus (F). Mucosal surface and folds in extends inferiorly from cardia along lesser curva- collection of barium extending outside expected fundus are obscured by barium pool, and antrum ture. Black arrows denote normal extrinsic impres- luminal contour of gastric body. Smooth folds are is devoid of rugal folds. sion by adjacent spleen. seen radiating to edge of ulcer crater.

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coat the mucosal surface (12–15). Some dent wall usually appear as radiolucent thickness of barium in the grooves lesions are best shown in the barium filling defects in the barium pool (Fig 5) between the mucosal tufts in relation pool, whereas others are obscured by (16), whereas protruded lesions on the to the thickness of barium overlying even a small pool of high-density bar- nondependent wall appear as barium- the tufts (8,9). Thus, an increase in ium. Protruded lesions on the depen- coated “ring shadows” due to barium the height of the mucosal tufts or thin- coating the edge of these lesions (Fig 5). ning of the mucous gel layer in the Figure 5 When filled with barium, depressed le- stomach may cause the areae gastri- sions appear as barium collections on cae to become more visible or conspic- the dependent wall (Fig 4). When bar- uous. When viewed in profile, barium ium spills out of depressed lesions on in the grooves between areae gastri- the dependent wall, they may appear as cae may be manifested as tiny spike- ring shadows. like outpouchings, producing subtle spiculation of the luminal contour that En Face Mucosal Detail should not be mistaken for erosions. When viewed en face, the mucosal sur- In addition, the areae gastricae may face either has a smooth appearance be enlarged by conditions that in- (Fig 1) or is manifested as a reticular crease the size of the mucosal tufts network of barium-filled grooves be- beyond their normal diameter of 2–3 tween the areae gastricae (Fig 3). Dis- mm in the antrum and of 3–5 mm in ruption of the normal areae gastricae the body and fundus. Enlarged areae Figure 5: Double-contrast spot image of gas- pattern or the smooth mucosal surface gastricae have been reported in about tric body with patient in supine right posterior of the stomach by barium-coated lines is 50% of patients with Helicobacter py- oblique position shows multiple hyperplastic abnormal (Fig 5). lori gastritis (Fig 7) (18). In contrast, polyps on dependent, or posterior, wall as small small or even absent areae gastricae (Ͻ 1 cm in size), round or ovoid, finely lobulated have been reported in patients with radiolucent filling defects in barium pool (arrows). Pattern Approach for Double-Contrast severe atrophic gastritis and perni- In contrast, polyps on nondependent, or anterior, Diagnosis cious anemia (19). wall are coated by barium and appear as white Hpyloriis a curved or spiral-shaped, lines (arrowheads). Barium is seen to fill inter- Abnormal Mucosal Patterns gram-negative bacillus (20–22) that in- stices between lobules of some polyps. Striations.—Thin, barium-coated stria- fects the stomach in more than 50% of tions perpendicular to the longitudinal Americans over 50 years of age and in axis of the gastric antrum, also known nearly 100% of Japanese adults (23,24). as gastric “striae,” are sometimes seen H pylori most frequently involves the Figure 6 as a transient finding when the antrum gastric antrum (25). H pylori gastritis is slightly collapsed (Fig 6) (17). These can be documented in almost all pa- striae are a sign of chronic antral gastri- tients with duodenal ulcers and in about tis (16). 80% of patients with gastric ulcers (26). Conspicuous or enlarged areae gas- The mechanism by which H pylori tricae.—Visualization of the areae gas- causes ulceration is not fully under- tricae in the stomach depends on the stood. H pylori gastritis is also a major causative factor in the development of Figure 7 both gastric carcinoma (27,28) and gastric lymphoma (29,30). Uniform nodules.—Innumerable small (1–2 mm in size), round, uniform nodules disrupting the normal polygonal areae gastricae pattern are usually caused by lymphoid hyperplasia of the stomach resulting from chronic H pylori gastritis (Fig 8) (31–33). At birth, no Figure 6: Double-contrast spot image of an- lymphoid tissue is present in the stom- trum with patient in supine position shows gastric Figure 7: Double-contrast spot image of stomach. When H pylori infects the stomach, striae as transient finding due to barium filling ach with patient in supine position shows enlarged the organism colonizes the mucous delicate transverse grooves between thin radiolu- areae gastricae in patient with H pylori gastritis. layer and attaches to the membranes of cent folds traversing circumference of slightly Areae gastricae in antrum (white arrow) are larger the surface epithelial cells, resulting in collapsed gastric antrum. than those in distal gastric body (black arrow). the development of chronic gastritis

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Figure 8 Figure 9 (22). Repeated infections may eventually lead to lymphocytic infiltration of the stomach, followed by the formation of lymphoid aggregates and even true lymphoid follicles (34). Thus, when lymphoid hyperplasia is detected on double-contrast barium studies, these patients are almost always found to have chronic H pylori gastritis (33). Nonuniform nodules.—Irregular nodules disrupting the smooth mucosal surface or the polygonal areae gastricae pattern of the stomach may be caused by inflammation, metaplasia (alteration Figure 9: Double-contrast spot image of gas- of one form of epithelium to another), Figure 8: Double-contrast spot image of gastric body with patient in right posterior oblique or malignant tumor. The nodules are tric antrum with patient in left posterior oblique position shows nonuniform nodules disrupting nonuniform in size and shape and have position shows lymphoid hyperplasia with innu- normal surface pattern. Nodules (arrows) appear merable round, uniform, 1–2-mm nodules carpet- a patchy or diffuse distribution, involv- as round or lobulated, confluent protrusions varying mucosa and replacing normal polygonal areae ing a focal or large surface area of the ing from 3–6-mm in size. Endoscopic biopsy gastricae pattern. This patient had chronic H pylori stomach on barium studies. Nonuni- specimens revealed low-grade, B-cell, gastric gastritis. form mucosal nodularity is a worrisome MALT lymphoma in patient with chronic H pylori radiographic finding for gastric mucosa- gastritis. associated lymphoid tissue (MALT) lymphoma (Fig 9) or, rarely, superficial IIa (elevated), IIb (flat), or IIc (de- spreading carcinoma (Fig 10) (35). pressed) lesions (Fig 10); and ulcerated Gastric lymphomas usually arise EGCs that are more than 5 mm in depth from preexisting MALT in the stomach are type III lesions (42). Figure 10 associated with chronic H pylori gastritis. A lymphoid response to chronic in- Depressed Lesions fection by H pylori has been postulated Erosions.—An erosion is a focal area of as the precursor milieu for the develop- mucosal necrosis confined to the epithe- ment of low-grade B-cell gastric MALT lium or lamina propria without extend- lymphomas (36). These tumors are ing through the muscularis mucosae sometimes recognized on double-con- into the submucosa (5). In contrast, trast studies by the presence of innu- atrueulcernicheorcraterextends merable poorly defined, confluent mu- through the muscularis mucosae into cosal nodules of varying size (Fig 9) the deeper layers of the gastric wall (35). In such cases, endoscopic biopsy (4). The actual histologic depth of an specimens are required to rule out gas- ulcer cannot be determined on barium tric MALT lymphoma. studies. Instead, the radiographic size Figure 10: Double-contrast spot image of Because of mass screening of the and depth are used to distinguish an gastric fundus with patient in semiupright position adult population in Japan, early gastric erosion from an ulcer. When viewed shows superficial gastric carcinoma as focal area cancers (EGCs) constitute as many as in profile, a depressed lesion greater of slightly elevated, irregular radiolucent nodules 25%–46% of all gastric cancers de- than several millimeters in depth is (arrows) in shallow barium pool. Clubbed, irregu- tected in that country (37,38). In con- arbitrarily called an ulcer. lar folds (arrowheads) are seen radiating toward central area of mucosal nodularity. trast, EGCs constitute a much smaller Erosions are manifested on double- percentage of gastric cancers detected contrast studies as tiny, 1–2 mm in in the West, because endoscopy and depth collections of barium, usually in barium studies are performed predomi- the gastric antrum. Erosions may be turned from side to side, so a shallow nantly in symptomatic patients who al- punctate, round, linear, or stellate in pool of barium flows over the dependent ready have advanced lesions (39–41). In configuration and are often surrounded surface of the stomach (45). Erosions the Japanese classification system for by radiolucent halos of edematous mu- are defined as complete or varioliform if EGC, polypoid EGCs that protrude cosa (Fig 11) (43). Erosions are fre- surrounded by a radiolucent halo of more than 5 mm into the lumen are type quently seen to reside on the crests of edema and as incomplete if there is no I lesions; flat EGCs that appear as enlarged scalloped antral folds (44), surrounding edematous mound. Incom- plaques, nodules, or tiny ulcers are type particularly when the patient is slowly plete erosions are much less common,

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appearing as punctate or linear collec- the most common cause of gastric ero- eas of epithelial necrosis with hemor- tions of barium that may be difficult to sions (46). NSAID exposure causes rhage, edema, and vascular dilatation in differentiate from barium trapped be- breakdown of the mucosal barrier and the lamina propria (47). Because often tween areae gastricae or alongside rugal mucosal hypoxia, resulting in focal ar- there is relatively little inflammatory re- folds. sponse, the term NSAID gastropathy Aspirin and other nonsteroidal anti- rather than NSAID gastritis is favored inflammatory drugs (NSAIDs) are by far Figure 13 by some authors (10,48). NSAID-induced erosive gastritis is typically mani- Figure 11 fested as multiple varioliform erosions in the antrum or antrum and body of the stomach (18). Less frequently, these patients may have incomplete erosions that appear as linear or serpiginous barium collections (Fig 12), many of which are located on or near the greater curvature of the gastric body secondary to the effect of gravity (49). Other causes of gastric erosions include alcohol, viral infections, Crohn disease, hemorrhagic gastropathy, and iatrogenic trauma (4,50–55). Surpris- ingly, erosions are infrequently seen in patients with H pylori gastritis (18). Figure 13: Double-contrast spot image of Ulcers.—An ulcer is a focal area gastric body with patient in left posterior oblique of mucosal disruption that penetrates Figure 11: Double-contrast spot image of position shows gastric ulcer (U) as smooth, ovoid through the muscularis mucosae into distal gastric antrum with patient in left posterior collection of barium on posterior wall. Smooth, the deeper layers of the gastric wall. oblique position shows NSAID-induced erosive straight folds radiate directly to edge of ulcer cra- When viewed en face, most benign gas- ter. These are typical findings of a benign gastric antral gastritis. Multiple varioliform erosions are tric ulcers on the dependent wall are ulcer. seen as punctate (small white arrow) and linear manifested on double-contrast studies (large white arrow) collections of barium sur- as a smooth round or ovoid collection of rounded by radiolucent mounds of edema (black barium filling the ulcer crater (Fig 13). arrows). This patient was taking aspirin. Some shallow ulcers on the dependent Figure 14 wall and ulcers on the nondependent wall may be manifested as a circular or hemispheric ring due to barium coating Figure 12 the rim of the unfilled ulcer crater (Fig 14) (56). Most ulcers are round or ovoid, but some may have a linear, ser- pentine, rectangular, flame-shaped, or rod-shaped configuration (56–58). When viewed in profile, benign gastric ulcers may be recognized by a focal barium collection or barium-coated line extending outside the expected luminal contour (Fig 4) (11,59–61). Some ulcers Figure 14: Double-contrast spot image of have a smooth radiolucent rim of vari- gastric body with patient in supine position shows able thickness directly adjacent to the incompletely filled ulcer on dependent, or poste- ulcer crater, representing a collar of rior, wall as hemispheric ring shadow with two edema and inflammation, whereas oth- Figure 12: Double-contrast spot image of crescent-shaped barium-coated lines (arrows) ers have a thin radiolucent line (also gastric antrum with patient in left posterior oblique coating various portions of inferior rim of ulcer. known as a Hampton line) traversing position shows NSAID-induced linear and serpig- Smooth, straight folds radiate almost to edge of the base of the crater due to undermin- inous erosions (arrows). This patient was taking ulcer crater. The findings are characteristic of a ing of the submucosa (59). The pres- aspirin. Surgical clips in right upper quadrant are benign gastric ulcer with retraction of adjacent ence of a Hampton line is diagnostic of a from prior cholecystectomy. gastric wall. benign gastric ulcer. Chronic inflamma-

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Figure 15 Figure 16 tion and scarring may cause retraction of the adjacent gastric wall with the development of smooth, straight folds that radiate directly to the edge of the ulcer crater (Figs 13, 14). Although giant gastric ulcers are at greater risk for bleeding and perfora- tion (62), the size of the ulcer crater is not a useful criterion for differentiating benign and malignant gastric ulcers. Most benign gastric ulcers are located on the lesser curvature or posterior wall of the stomach at or near the transition zone between body- and antral-type mucosa (Fig 4). Some benign ulcers may be Figure 15: Double-contrast spot image of located on the greater curvature (al- gastric body with patient in supine position shows malignant gastric ulcer due to lymphoma. Large most all of these greater curvature ul- lobules of tumor (arrows) surround irregular cen- cers are caused by the use of aspirin or tral ulcer (U) filled with barium, although barium other NSAIDs) (14,63) or within hiatal Figure 16: List of radiographic features distin- pool is too dense to clearly delineate margins of guishing benign and malignant gastric ulcers. hernias, where the stomach traverses ulcer. the diaphragm (64). Thus, ulcer location also is not a useful criterion for differentiating benign and malignant nign radiographic appearance; virtually gastric ulcers. Radiologists therefore all of these unequivocally benign ulcers should ignore the size and location of are ultimately proved to be benign Figure 17 ulcers when assessing the risk of malig- (56,65). nancy; instead, they should focus on the In contrast, if an ulcer is associated morphologic features of these lesions. with nodularity of the adjacent mucosa, In general, malignant gastric ulcers mass effect, or radiating folds that are produce radiographic findings diametri- coarse, lobulated, or irregular (Figs 10, cally opposed to those of benign ulcers. 15), it fulfills the radiographic criteria With malignant ulcers, the ulcer crater for a malignant gastric ulcer, and endos- represents a focal area of necrosis and copy should be performed for a defini- excavation within a malignant tumor, tive diagnosis. Less than 5% of ulcers usually gastric carcinoma or lymphoma. have an unequivocally malignant radio- The surface of the ulcer and of the sur- graphic appearance; almost all of these rounding mucosa is therefore composed malignant-appearing ulcers are ulti- of nodules, irregular elevations, or mately proved to be malignant. irregular depressions of varying size Finally, one-fourth to one-third of within the tumor (Fig 15) (42). The gastric ulcers have an equivocal or in- folds adjoining a malignant ulcer may determinate appearance that does not have a coarse, lobulated, clubbed, or allow the radiologist to establish a penciled shape due to infiltration of the confident diagnosis of benignancy or Figure 17: Double-contrast spot image of folds by the tumor (Fig 10) (42). malignancy. An ulcer is classified as gastric body with patient in right posterior oblique Radiologists can often differentiate equivocal or indeterminate if there are position shows ulcer (U) on posterior wall filling benign and malignant gastric ulcers on coarse areae gastricae or moderate with barium. Small radiolucent nodules (arrow- the basis of the radiographic findings nodularity of the mucosa abutting the heads) are seen lateral to ulcer and larger nodules (Fig 16). If an ulcer has a smooth sur- ulcer (Fig 17), a nodular ulcer collar, (arrows) are seen just superior to ulcer. This nodu- face with smooth, straight folds radiat- or mildly irregular folds radiating to larity could be secondary to edema, inflammation, ing to the ulcer margin and no sur- the ulcer’s edge. In such cases, endos- metaplasia, dysplasia, or tumor; findings in this rounding mass effect or mucosal nodu- copy and biopsy are needed to rule out case do not meet radiographic criteria for a benign larity (Figs 4, 13, 14), it fulfills the malignant tumor. Nevertheless, the gastric ulcer, and lesion should be classified as radiographic criteria for a benign gas- majority of equivocal or indeterminate equivocal. Nevertheless, benign gastric ulcer was tric ulcer. About two-thirds of all gastric ulcers are ultimately proved to be be- confirmed at endoscopy and follow-up. Gastric metaplasia was found at the edge of the ulcer on ulcers diagnosed on double-contrast bar- nign. endoscopic biopsy specimens. ium studies have an unequivocally be- Some benign NSAID-induced greater

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curvature ulcers may have an indeter- the adjacent greater curvature (66). De- These tiny sacs are thought to represent minate appearance due to extensive spite a history of NSAID use, these the sequela of healed peptic ulcers. Par- surrounding mass effect and an appar- greater curvature ulcers therefore may tial antral diverticula are differentiated ent intraluminal location because of require endoscopy to rule out an ulcer- from true ulcers by their variable size spasm and inflammatory retraction of ated gastric carcinoma. Eventually, and shape at fluoroscopy and the ab- large NSAID-induced greater curvature sence of associated inflammatory changes. ulcers may penetrate inferiorly via the Figure 18 gastrocolic ligament into the superior Protruded Lesions border of the transverse colon, produc- Polyps.—A polyp is a small protrusion ing a gastrocolic fistula (67). from the mucosal surface, either sessile Diverticula.—Diverticula are un- or pedunculated. The term polyp does commonly found in the stomach. The not imply an adenomatous histology. In majority arise from the posterior wall of fact, a wide variety of benign and malig- the gastric fundus (68), presumably be- nant polypoid lesions may occur in the cause of a gap in the muscular layers of stomach. If polyps arise from the mu- the gastric wall in this location. Fundal cosa, they may have a smooth, nodular, diverticula are smoothly contoured, or lobulated surface on double-contrast broad-mouthed outpouchings, ranging studies, and when viewed in profile, from 1 to 10 cm in size (Fig 18). Rugal form acute angles with the adjacent gas- folds are not seen within the diverticula. tric wall (Fig 5) (70). In contrast, lesions These diverticula can be distinguished arising from the submucosa or muscu- from ulcers by their smooth contour, laris propria usually have a very smooth Figure 18: Double-contrast spot image with broad or shallow necks, and lack of surface and, when viewed in profile, patient in right decubitus position shows gastric diverticulum as smooth barium-coated outpouch- folds radiating to their margins. form right angles or slightly obtuse ing (arrow) extending from posterior wall of fun- A variant of a gastric diverticulum angles with the adjacent gastric wall dus. A small amount of barium is present in lumen may rarely be found on the greater cur- (Fig 19). Although large lesions that of diverticulum. vature of the distal antrum, also known have a smooth surface are usually sub- as a partial antral diverticulum (69). mucosal in origin, it is often difficult to determine whether protruded lesions less than 1–1.5 cm in diameter are mu- Figure 20 cosal or submucosal in origin, as small polyps originating in the mucosa may Figure 19 also have a smooth surface. Hyperplastic polyps are nonneoplas- tic proliferations of surface foveolar cells, consisting of elongated, distorted pits and numerous branching glands (4). These polyps are typically smooth or finely lobulated sessile lesions less than 1 cm in size (Fig 5). Occasionally, however, atypical hyperplastic polyps may be larger than 1 cm in diameter, pedunculated, and have a coarsely lobulated surface (Fig 20) (71–73). At least one-third of patients with hyperplastic polyps have multiple polyps, usually in the gastric body and fundus (Fig 5) (4). Figure 20: Double-contrast spot image of Although hyperplastic polyps have no gastric body with patient in supine position shows malignant potential, they usually arise in Figure 19: Double-contrast spot image of 1-cm in size, sessile, slightly lobulated polyp on the setting of chronic gastritis, the same fundus and upper body of stomach with patient in greater curvature as area of increased radiopacity milieu that results in gastric metaplasia semiupright position shows large submucosal coated by barium (arrow). Although radiographic and dysplasia. As a result, gastric ade- mass as smooth-surfaced hemispheric lesion findings are worrisome for an adenomatous polyp nomas and carcinomas have been re- (large arrows) forming right angles (small arrows) or even a small polypoid carcinoma, this lesion ported to occur with increased fre- with adjacent luminal contour. Surgery revealed was found to be a large hyperplastic polyp on en- quency in patients with hyperplastic benign gastrointestinal stromal tumor. doscopic biopsy specimens. polyps (4).

40 Radiology: Volume 246: Number 1—January 2008 REVIEW FOR RESIDENTS: Double-Contrast Upper Gastrointestinal Radiography Rubesin et al

Figure 21 Fundic gland polyps, the second in these patients. Atypical hyperplastic most common gastric polyps, are prolif- polyps that are unusually large or lobu- erations of the deep epithelial compart- lated (Fig 20) are indistinguishable from ment of body-type mucosa (4). These adenomatous polyps or even polypoid polyps consist of cystically dilated pits carcinomas (71–73). and glands lined by parietal and chief Retention polyps (juvenile polyps) cells. Fundic gland polyps are found may occur as solitary lesions or as mul- both sporadically and in patients with tiple lesions in Cronkite-Canada syn- familial adenomatous polyposis syndrome. drome (76). Xanthelasmas, isolated These polyps typically appear on dou- hamartomatous polyps, and inflamma- ble-contrast studies as smooth-sur- tory fibroid polyps are other benign pol- faced, sessile protrusions less than 1 cm yps occasionally encountered in the in size. Fundic gland polyps are usually stomach. A focal cluster of polyps may located in the fundus and upper body of also be seen in the gastric antrum or the stomach and are often multiple (74). body in patients with small carcinoid In patients with familial adenomatous tumors. polyposis syndrome, hundreds of small Masses.—For gastric masses larger (Ͻ 5 mm in size) fundic gland polyps than 2 cm in size, barium studies are Figure 21: Double-contrast spot image of may be found. extremely helpful for determining whether gastric body with patient in supine position shows Adenomatous polyps of the stomach the lesions arise from the mucosa, sub- barium outlining outer contour and interstices of a are a relatively uncommon macroscopic mucosa, or muscularis propria, or whether 3-cm sessile, multilobulated lesion (arrows). form of gastric dysplasia. Adenomas are they are extrinsic to the stomach. This Surgery revealed tubulovillous adenoma. (Re- classified as tubular, tubulovillous, or differentiation enables the radiologist to printed, with permission, from reference 15.) villous on the basis of their underlying suggest a specific diagnosis or differen- architecture. Gastric adenomas may tial diagnosis. In general, a mass origi- progress to gastric carcinoma by means nating in the mucosa has a nodular or of a polypoid adenoma to carcinoma se- lobulated surface, appearing en face on quence similar to that found in the co- double-contrast studies as a filling de- Figure 22 lon. In situ carcinoma or invasive carci- fect in the barium pool or as an area of noma is found in at least 50% of adeno- abnormal barium-coated lines, depend- matous polyps larger than 2 cm in size ing on whether it is on the dependent or (75). Most gastric dysplasias, however, nondependent walls (Fig 22) (11). Not are relatively flat macroscopically. In infrequently, irregular collections of fact, most gastric carcinomas arise from barium are trapped in the interstices of flat or slightly elevated or depressed the tumor (Fig 21) or in areas of ulcer- areas of dysplasia, not polypoid adeno- ation. Barium thus outlines multiple mas (4). round or ovoid nodules within the inter- In symptomatic patients, gastric ad- stices of the lesion. For example, a pol- enomas detected on double-contrast ypoid carcinoma may be manifested as a studies are usually larger than 1 cm in lobulated or fungating mass within the size (75). These adenomas can be sessile, expected luminal contour (Fig 22). lobulated, or pedunculated lesions In contrast, a submucosal mass may Figure 22: Double-contrast spot image of (Fig 21). Although most hyperplastic appear en face on double-contrast stud- upper gastric body with patient in supine position polyps are smaller than 1 cm and most ies as a round or ovoid, well-circum- shows multilobulated polypoid mass as confluent, adenomas are larger than 1 cm, it is not scribed, smooth or slightly lobulated lobulated radiolucent filling defects (black arrows) always possible to distinguish a hyper- area of increased radiopacity. When in barium pool with separate portion of lesion plastic polyp from an adenomatous viewed in profile, a submucosal mass outlined in white on greater curvature (white ar- polyp on barium studies. If a polyp is 1 may be manifested as a hemispheric in- row). Surgery revealed polypoid adenocarcinoma. cm or larger in size and has a finely traluminal projection that has a smooth nodular or lobulated surface, endoscopy surface and forms right angles or and biopsy therefore should be per- slightly oblique angles with the adjacent 23) (4). An ulcerated submucosal mass formed to exclude the possibility of an gastric wall (Figs 19, 23). Central ulcer- viewed en face produces a characteris- adenoma. Conversely, multiple rounded ation occurs in about 50% of submuco- tic “target” or “bull’s-eye” lesion, with a polyps 5 mm or smaller in size are al- sal masses due to central ischemia and central ulcer surrounded by a smooth, most always hyperplastic, so that en- necrosis of the tumor or pressure ne- well-defined mass (Fig 24). Gastrointes- doscopy and biopsy are not warranted crosis of the overlying epithelium (Fig tinal stromal tumors are by far the most

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common solitary submucosal masses in shape at fluoroscopy (78) and has fat An extrinsic mass that indents but the stomach (77). Lymphoma and soli- attenuation at computed tomography does not infiltrate the gastric serosa is tary metastases are other frequent sub- (79,80). Granular cell tumors usually manifested as a smooth, broad-based mucosal tumors. Lipoma is a submuco- appear as one or more small submuco- inbowing of the gastric wall (Fig 26). In sal lesion that may change in size and sal lesions. Most other mesenchymal tu- contrast, an extrinsic inflammatory or mors (eg, neurofibromas) are indistin- neoplastic mass that involves the serosa Figure 23 guishable from gastrointestinal stromal of the stomach may cause tethering of tumors. the gastric wall toward the extrinsic Ectopic pancreatic rest (ie, myoepi- process, resulting in spiculation of the thelial hamartoma) is an uncommon luminal contour. For example, omental submucosal lesion composed of varying metastases invading the greater curva- amounts of pancreatic tissue (including ture of the stomach through the gastro- ducts, acini, and islet cells), hypertro- colic ligament may cause spiculation phic smooth muscle fibers, and glandular and tethering of the greater curvature structures resembling Brunner glands (84). Extrinsic inflammatory or neoplas- (81,82). These lesions may be compli- tic processes that involve the gastric cated by pancreatitis, cysts, islet cell tu- wall or occlude gastric lymphatic or ve- mors, and even pancreatic carcinoma nous channels may also result in en- (4). Ectopic pancreatic rests usually larged gastric folds. For example, pan- appear on barium studies as small creatitis secondarily involving the stom- (1–2 cm), solitary, centrally umbilicated ach may be manifested as thickened submucosal masses, most often on the folds on the posterior gastric wall. greater curvature of the distal gastric The precise location of mass lesions antrum within 1–6 cm from the pylorus, in the stomach may help suggest the Figure 23: Double-contrast spot image of but can occasionally be located else- diagnosis in a small percentage of cases. gastric body with patient in supine position shows where in the stomach (Fig 25) (83). As previously discussed, a submucosal 4-cm smooth-surfaced submucosal mass out- lesion on the greater curvature of the lined in white by barium (arrows). Note central Figure 25 distal gastric antrum should suggest an triangular-shaped ulcer (arrowheads) in mass. ectopic pancreatic rest, whereas a sub- Surgery and clinical follow-up revealed a malig- mucosal defect extending from the nant gastrointestinal stromal tumor. lesser curvature of the distal antrum to the pylorus should suggest a hypertrophied antral-pyloric fold. In contrast, a smooth, undulating submucosal lesion Figure 24 on the medial aspect of the fundus near the gastric cardia should suggest a conglomerate mass of gastric varices (85). Multiplicity of lesions is another radiographic feature that may be helpful in suggesting a specific diagnosis or differential diagnosis. Numerous small (Ͻ 1 cm in size), smooth or finely lobulated, sessile protrusions are almost always hyperplastic polyps (Fig 5) or, if confined to the gastric body or fundus, fundic gland polyps. A cluster of polyps Figure 25: Double-contrast spot image of elsewhere in the stomach in patients gastric antrum with patient in left posterior oblique with chronic H pylori gastritis may rep- Figure 24: Double-contrast spot image of position shows smooth, 1-cm ovoid, radiolucent resent gastric carcinoid tumors due gastric body with patient in right posterior oblique filling defect (arrow) in barium pool with shallow to end-stage neuroendocrine hyperpla- position shows bull’s-eye or target lesion in stom- central umbilication containing trace amount of sia associated with hypogastrinemia ach as a 2-cm ovoid, smooth-surfaced, submuco- barium (arrowhead). Endoscopic biopsy speci- (5,10). Multiple large (Ͼ 1 cm in size) sal mass (black arrows) in barium pool containing mens revealed an ectopic pancreatic rest (myoepi- polypoid lesions may represent adeno- stellate central ulcer (white arrow). This patient thelial hamartoma). Ectopic pancreatic rests are matous polyps, atypical hyperplastic had breast cancer with hematogenous metastasis usually located on greater curvature of distal an- polyps, Peutz-Jeghers hamartomas, or to the stomach. trum, but this lesion was on posterior wall. even synchronous polypoid carcinomas.

42 Radiology: Volume 246: Number 1—January 2008 REVIEW FOR RESIDENTS: Double-Contrast Upper Gastrointestinal Radiography Rubesin et al

Figure 26 Finally, multiple submucosal masses or tal antrum to the pylorus or even centrally ulcerated bull’s-eye lesions may through the pylorus into the medial for- represent hematogenous metastases (such nix of the base of the duodenal bulb as metastatic melanoma), disseminated (Fig 27) (92). In most patients, a hyper- lymphoma, and, in patients with acquired trophied antral-pyloric fold can be dif- immunodeficiency syndrome, Kaposi sar- ferentiated from a neoplastic lesion by coma. its characteristic appearance and location (93). Another clue to the pres- Thickened Folds ence of a hypertrophied antral-pyloric Normal rugal folds are thicker in the fold is its variable size and shape at proximal stomach, have a smooth con- fluoroscopy, with palpation and peri- tour in profile, and taper distally (5). stalsis. Occasionally, however, a hy- Figure 26: Double-contrast spot image of Folds also are larger and more undulat- pertrophied fold may be unusually gastric antrum and body with patient in supine ing on the greater curvature than on the large or lobulated, so it can be mis- position shows smooth indentation on greater lesser curvature. Rugal folds become taken for a polypoid or plaquelike tu- curvature (black arrows) due to extrinsic mass straight and thinner with increasing gas- mor (93). lesion compressing stomach. Second barium- tric distention and can even disappear H pylori gastritis is by far the most coated line (white arrows) indicates that lumen is when the stomach is fully distended, common cause of focally or diffusely narrowed asymmetrically. Area of increased ra- particularly in the gastric antrum. Be- thickened folds in the stomach. Abnor- diopacity (D) also results from mass compressing lumen. These findings were caused by massive cause of these normal variations in fold mal folds are found in about 75% of retroperitoneal lymphoma. size, there are no reliable criteria for patients with H pylori gastritis (89). enlarged folds in the stomach. How- Fold enlargement in H pylori gastritis ever, rugal folds are much more likely to most commonly involves the gastric an- be abnormal when they have an irregu- trum and body but may involve the en- lar, lobulated, or scalloped contour or tire stomach or may even be confined to Figure 27 when they are enlarged or have an an- the gastric fundus. Most patients with H gled or transverse orientation in a well- pylori gastritis have mildly to moder- distended gastric antrum. Folds that are ately thickened gastric folds without larger on the lesser curvature than on substantial fold irregularity (Fig 28), so the greater curvature are also consid- that the radiographic findings are not ered to be abnormal. worrisome for Menetrier disease or Because rugal folds are composed of lymphoma. However, some patients mucosa and submucosa, any process with H pylori gastritis have such en- that infiltrates these layers of the gastric larged, lobulated folds (ie, polypoid gas- wall can increase the size of the folds. tritis) that the radiographic findings er- Enlarged folds may be caused by inflam- roneously suggest a malignant process. matory processes such as H pylori gas- Other patients with H pylori gastritis tritis (86–89), hyperplastic processes may have focally thickened polypoid such as Zollinger-Ellison syndrome (90) folds confined to the gastric antrum or and Menetrier disease (91), or malig- body that are mistaken radiographically nant tumors such as lymphoma and sub- for a polypoid or infiltrating neoplasm mucosally infiltrating adenocarcinoma. (88). Nevertheless, radiologists cannot Endoscopic biopsy specimens may be assume that all cases of enlarged folds required to differentiate these various are caused by this ubiquitous pathogen. causes of enlarged folds, particularly If the folds are markedly enlarged, lobu- when the folds are markedly thickened lated, or irregular (particularly if they and irregular. have a focal or segmental distribution), Antral gastritis (whether or not it is endoscopic biopsy specimens should Figure 27: Double-contrast spot image of associated with H pylori) is usually man- be obtained to exclude a malignant tu- gastric antrum with patient in supine left posterior ifested on barium studies as thickened, mor. oblique position shows ovoid, 1.5-cm smooth- scalloped folds that have a longitudinal In Menetrier disease, there is surfaced submucosal lesion (arrows) extending or transverse orientation. Antral gastri- marked hyperplasia of surface foveolar from lesser curvature of distal antrum to adjacent tis may lead to the development of a mucous cells (4,10), resulting in a pylorus. This lesion changed in size and shape at fluoroscopy with palpation and peristalsis. Find- hypertrophied antral-pyloric fold, seen marked increase in the height of the ings are characteristic of hypertrophied antral- as a smooth submucosal defect extend- foveolae and partial atrophy of the pyloric fold. ing from the lesser curvature of the dis- glands, with a corresponding loss of vol-

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ume of parietal and chief cell and subse- Although early reports stated that fold cause surface foveolar cells line the en- quent hypochlorhydria. The rugal folds enlargement predominantly involved tire stomach. may appear massively enlarged and lob- the gastric fundus and body (sparing the Portal hypertension sometimes may ulated on barium studies (Fig 29) (91). antrum) (94), later reports found that cause mucosal hyperemia with dilated Menetrier disease causes fold enlarge- submucosal vessels in the absence of Figure 28 ment throughout the stomach in at least true varices, a condition known as por- 50% of patients (91), presumably be- tal hypertensive gastropathy (95). This gastropathy can lead to acute or chronic Figure 30 gastrointestinal bleeding. Thickened, finely nodular folds are seen in the gastric fundus on barium studies (96). Gas- tric varices with associated esophageal varices are usually caused by portal hypertension, whereas isolated gastric varices (in the absence of esophageal varices) may be caused by portal hypertension or, less commonly, by splenic vein obstruction from pancreatic carcinoma, pancreatitis, or pancreatic pseudo- cysts (97,98). Gastric varices can be distinguished from the abnormal folds of portal hypertensive gastropathy by their undulating and tortuous configura- Figure 28: Double-contrast spot image of stom- tion and smooth contour (Fig 30) (97). ach with patient in supine position shows moderately Figure 30: Double-contrast spot image of In some patients, varices may also be thickened folds in gastric body due to chronic Hpy- gastric fundus with patient in right-side-down seen on double-contrast studies as mul- lori gastritis. Folds are considerably less thickened position shows smooth, undulating submucosal tiple smooth, round or ovoid nodules, and lobulated than in patient with Menetrier disease mass (arrows) on posterior wall of fundus extend- likened to the appearance of a bunch of (Fig 29). Note surgical clips from prior vagotomy. ing to cardia. This patient had portal hypertension grapes. In others, however, a conglom- with a conglomerate mass of gastric varices (also erate mass of gastric varices (also known as tumorous varices). Note surgical clips known as tumorous varices) may be from recent liver transplantation. manifested as a smooth, undulating sub- Figure 29 mucosal mass on the medial wall of the fundus near the gastric cardia (85). The normal gastric cardia is usu- Figure 31 ally manifested on double-contrast studies as a stellate collection of thin, smooth folds radiating to a central point at the gastroesophageal junction (Fig 2). Any lesion disrupting or oblit- erating the cardiac rosette with associated nodularity, mass effect, ulceration, or distorted folds in this region should be considered suspicious for carcinoma of the cardia (Fig 31). More advanced tumors at the cardia may appear as polypoid, ulcerated, or infiltrating lesions that can easily be visu- alized with a double-contrast tech- Figure 31: Double-contrast spot image of nique (Fig 31) (99–101). gastric fundus with patient in right-side-down Figure 29: Double-contrast spot image of position shows polypoid mass (arrows) that has Gastric Narrowing gastric body with patient in supine position shows obliterated and replaced normal cardiac rosette. Narrowing of the luminal contour of the markedly thickened, lobulated folds and diffuse Arrowheads denote areas of ulceration within tu- stomach may be caused by scarring, in- distortion of areae gastricae pattern in patient with mor. This patient had an advanced carcinoma of filtrating tumor, or extrinsic diseases Menetrier disease. cardia. secondarily affecting the stomach. Chronic

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Figure 32 Figure 33 scarring from peptic ulcer disease may produce asymmetric inbowing and retraction of one wall of the stomach, often associated with smooth, straight folds that radiate to the site of the healed ulcer. Other patients with peptic scarring have smooth, tapered narrowing of the gastric antrum or, less commonly, weblike antral narrowing (Fig 32). Scarring from ingestion of NSAIDs (ie, chronic NSAID gastropathy) can also result in the characteristic flattening of the greater curvature of the distal antrum (102). Long-segment narrowing of the stom- Figure 33: Double-contrast spot image of ach (either circumferential or confined gastric antrum and body with patient in supine to one wall) or diffuse narrowing of the Figure 32: Double-contrast spot image of position shows long segment of circumferential stomach is usually caused by an infiltrat- distal gastric antrum and duodenal bulb with pa- narrowing extending from mid gastric body to mid ing or scirrhous gastric carcinoma (103) tient in left posterior oblique position shows short gastric antrum (arrows denote limits of tumor). or metastatic breast cancer. The nar- segment of smooth, circumferential narrowing Although tumor surface is predominantly smooth, rowing with scirrhous carcinoma results (arrow) due to antral web related to scarring from focal areas of mucosal nodularity are seen in prox- from a desmoplastic reaction to tumor previous peptic ulcer disease. If mucosal nodular- imal end of lesion (arrowheads). This patient had cells infiltrating the submucosa, pro- ity or irregularity of luminal contour had been scirrhous gastric carcinoma producing a linitis ducing a linitis plastica appearance. present, endoscopy and biopsy would have been plastica appearance. Scirrhous carcinomas may be mani- required to rule out focal gastric cancer. fested as diffuse, long-segment, or even short-segment narrowing of any portion of the stomach (Fig 33) (103). be caused by antral scarring from Figure 34 The narrowed lumen is rigid and non- Crohn disease or, rarely, other granu- distensible at fluoroscopy, and gastric lomatous diseases such as sarcoidosis, peristalsis is obliterated in this region. syphilis, and tuberculosis. Occasion- The luminal contour may have a smooth, ally, antral narrowing may also result nodular, or finely ulcerated surface on from gastric atrophy related to the double-contrast studies (Fig 33). Occa- presence of a long-standing gastrojeju- sionally, scirrhous carcinomas of the nal anastomosis without an antrec- distal antrum may be very short, cir- tomy. cumferential lesions confined to the Atrophic gastritis is a condition in prepyloric region of the stomach (104). which body-type mucosal glands are re- It is important to recognize that en- placed by metaplastic cells resembling doscopy and biopsy have a poor sensi- pyloric- or intestinal-type epithelium tivity in depicting scirrhous carcino- (10). Most atrophic gastritis is related mas of the stomach, so that some pa- to chronic inflammation rather than au- Figure 34: Double-contrast spot image of tients with radiographically diagnosed toimmune phenomena. This form of gastric fundus and body with patient in right- lesions may require one or more re- atrophic gastritis is often patchy and side-down position shows smooth narrowing of peat endoscopic examinations to con- macroscopically flat, so that it is not fundus and body of stomach with absent rugal firm the diagnosis. recognizable on barium studies. In other folds and small, barely visible areae gastricae. In contrast, the narrowing with patients with the autoimmune form of These findings are characteristic of atrophic metastatic breast cancer results from atrophic gastritis, there is severe loss of gastritis. dense infiltration of the submucosa by parietal cell mass, resulting in inade- tumor. Severe scarring from previous quate secretion of intrinsic factor with caustic ingestion may cause diffuse an- the subsequent development of vitamin of gastric folds. More than 80% of pa- tral narrowing indistinguishable from B12 deficiency and, eventually, perni- tients with pernicious anemia have a antral carcinoma on barium studies, cious anemia. In the later stages of auto- diffusely narrowed stomach with a but the clinical history should suggest immune atrophic gastritis, decreased pari- smooth contour and decreased or ab- the correct diagnosis. Tapered nar- etal cell mass is manifested as a dimin- sent rugal folds on double-contrast rowing of the gastric antrum may also ished mucosal surface volume and loss studies (Fig 34).

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References 15. Rubesin SE, Levine MS. Principles for per- gastritis and primary B-cell gastric lym- 1. Freeny PC. Double-contrast gastrography forming a double contrast upper gastroin- phoma. Lancet 1991;338:1175–1176. testinal examination. Westbury, NY: E-Z- of the fundus and cardia: normal landmarks 30. Parsonnet J, Hansen S, Rodriguez L, et al. EM, 2000; 1–29. and their pathologic changes. AJR Am J Helicobacter pylori infection and gastric Roentgenol 1979;133:481–487. 16. Rubesin SE. Gallery of double contrast ter- lymphoma. N Engl J Med 1994;330:1267– 2. Herlinger H, Grossman R, Laufer I, Kressel minology. Gastroenterol Clin North Am 1271. 1995;24:259–288. HY, Och R. The gastric cardia in double– 31. Bahk YW, Ahn JR, Choi HJ. Lymphoid hy- contrast study: its dynamic image. AJR 17. Cho KC, Gold BM, Printz DA. Multiple perplasia of the stomach presenting as um- Am J Roentgenol 1980;135:21–29. transverse folds in the gastric antrum. Ra- bilicated polypoid lesions. Radiology 1971; 3. Toner PG, Cameron CHS. The gastric mu- diology 1987;164:339–341. 100:277–280. cosa. In: Whitehead R, ed. Gastrointestinal 18. Dheer S, Levine MS, Redfern RO, Metz 32. Sbeih F, Abdullach A, Sullican S, Meren- and oesophageal pathology. 2nd ed. Edin- DC, Rubesin SE, Laufer I. Antral gastritis kow Z. Antral nodularity, gastric lymphoid burgh, Scotland: Churchill Livingstone, radiographic findings in patients with and hyperplasia and Helicobacter pylori in 1995; 15–32. without Helicobacter pylori. Br J Radiol adults. J Clin Gastroenterol 1996;22:227– 2002;75:805–811. 230. 4. Fenoglio-Preiser CM, Noffsinger AE, Stemmermann GN, Lantz PE, Listrom MB. 19. Levine MS, Palman CL, Rubesin SE, Laufer 33. Torigian DA, Levine MS, Gill NS, et al. Gastrointestinal pathology: an atlas and I, Herlinger H. Atrophic gastritis in perni- Lymphoid hyperplasia of the stomach: ra- text. Philadelphia, Pa: Lippincott-Raven, cious anemia: diagnosis by double contrast diographic findings in five adult patients. 1999; 153–236. radiography. Gastrointest Radiol 1989;14: AJR Am J Roentgenol 2001;177:71–75. 215–219. 5. Rubesin SE, Furth EE, Levine MS. Gastritis 34. Genta RM, Hamner HW. The significance from NSAIDs to Helicobacter pylori. Ab- 20. Warren JR. Unidentified curved bacilli on of lymphoid follicles in the interpretation of dom Imaging 2005;30:142–159. gastric epithelium in chronic active gastri- gastric biopsy specimens. Arch Pathol Lab tis. Lancet 1983;1:1273–1275. Med 1994;118:740–743. 6. Mackintosh CE, Kreel L. Anatomy and radiology of the areae gastricae. Gut 1977;18: 21. Marshall BJ, Warren JR. Unidentified 35. Yoo CC, Levine MS, Furth EE, et al. Gastric 855–864. curved bacilli in the stomach of patients mucosa-associated lymphoid tissue lymphoma: with gastritis. Lancet 1984;1:1311–1315. radiographic findings in six patients. Radiology 7. Seaman WB. The areae gastricae. AJR 1998;208:239–243. Am J Roentgenol 1978;131:554. 22. Yardley JH, Hendrix TR. Gastritis, gastropathy, duodenitis, and associated ulcer- 36. Eidt S, Stolte M. Prevalence of lymphoid 8. Rubesin SE, Herlinger H. The effect of bar- ative lesions. In: Yamada Y, Alpers DH, follicles and aggregates in Helicobacter py- ium suspension viscosity on the delineation Laine L, Owyang C, Powell DW, eds. Text- lori gastritis in antral and body mucosa. of areae gastricae. AJR Am J Roentgenol book of gastroenterology. 3rd ed. Philadel- JClinPathol1993;46:832–835. 1986;146:35–38. phia, Pa: Lippincott Williams & Wilkins, 37. Kaneko E, Nakamura T, Umeda N, Fugino 9. Charagundla SR, Levine MS, Langlotz CP, 1999; 1463–1499. M, Niwa H. Outcome of gastric carcinoma Rubesin SE, Laufer I. Visualization of areae 23. Dooley CP, Cohen H, Fitzgibbons PL, et al. detected by gastric mass survey in Japan. gastricae on double-contrast gastrointestinal Prevalence of Helicobacter pylori infection Gut 1977;18:626–630. radiography: relationship to age of patients. and histologic gastritis in asymptomatic AJR Am J Roentgenol 2001;177:61–63. 38. Kaibara N, Kawaguchi H, Nishidoi H, et al. persons. N Engl J Med 1989;321:1562– Significance of mass survey for gastric can- 10. Appelman HD. Gastritis: terminology, eti- 1566. cer from the standpoint of surgery. Am J ology, and clinicopathologic correlations— 24. Graham DY, Go MF. Helicobacter pylori: Surg 1981;142:543–545. another biased view. Hum Pathol 1994;25: current status. Gastroenterology 1993;105: 1006–1019. 39. Montesi A, Graziani L, Pesaresi A, 279–282. DeNigris E, Bearzi I, Ranaldi R. Radio- 11. Laufer I, Kressel HY. Principles of double- 25. Bayerdorffer E, Lehn N, Hatz R, et al. Dif- logic diagnosis of early gastric cancer by contrast diagnosis. In: Levine MS, Rubesin ference in expression of Helicobacter pylori routine double-contrast examination. SE, Laufer I, eds. Double contrast gastroin- gastritis in antrum and body. Gastroenter- Gastrointest Radiol 1982;7:205–215. testinal radiology. 3rd ed. Philadelphia, Pa: ology 1992;102:1575–1582. Saunders, 2000; 8–46. 40. Gold RP, Green PH, O’Toole KM, Seaman 26. Dixon MF. Helicobacter pylori and peptic WB. Early gastric cancer: radiographic ex- 12. Laufer I. A simple method for routine dou- ulceration: histologic aspects. J Gastroen- perience. Radiology 1984;152:283–290. ble contrast study of the upper gastrointes- terol Hepatol 1991;6:125–130. tinal tract. Radiology 1975;117:513–518. 41. White RM, Levine MS, Enterline HT, 27. Parsonnet J, Friedman GD, Vandersteen Laufer I. Early gastric cancer: recent expe- 13. Shirakabe H, Kobayashi S, Maruyama M. DP, et al. Helicobacter pylori infection and rience. Radiology 1985;155:25–27. Principles and application of double con- the risk of gastric carcinoma. N Engl J Med trast radiography. In: Shirakabe H, Nish- 42. Shirakabe H, Nishizawa M, Maruyama M, 1991;325:1127–1131. izawa M, Maruyama S. Atlas of x-ray diag- Kobayashi S. Definition and classification of nosis of early gastric cancer. 2nd ed. To- 28. Hansson LE, Engstrand L, Nyren O, et al. early gastric cancer. In: Shirakabe H, Nish- kyo, Japan: Igaku-Shoin, 1982; 19–43. Helicobacter pylori infection: independent izawa M, Maruyama M, Kobayashi S, eds. risk indicator of gastric adenocarcinoma. Atlas of x-ray diagnosis of early gastric can- 14. Levine MS, Rubesin SE, Herlinger H, Gastroenterology 1993;105:1098–1103. cer. 2nd ed. Tokyo, Japan: Igaku-Shoin, Laufer I. Double contrast upper gastroin- 1982; 1–18. testinal examination: technique and inter- 29. Wotherspoon AC, Ortiz-Hidalgo C, Flaxon, pretation. Radiology 1988;168:593–602. Isaccson PG. Helicobacter pylori associated 43. Laufer I, Hamilton J, Mullens JE. Demon-

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stration of superficial gastric erosions by WE, Goldsmith MR. Improved radio- 73. Cherukuri R, Levine MS, Furth EE, Rubesin double contrast radiography. Gastroenter- graphic detection of multiple gastric ulcers. SE, Laufer I. Giant hyperplastic polyps in ology 1975;68:387–391. AJR Am J Roentgenol 1977;128:949–952. the stomach: radiographic findings in seven patients. AJR Am J Roentgenol 2000;175: 44. Op den Orth JO, Dekker W. Gastric 58. Braver JM, Paul RE, Philipps E, Bloom S. 1445–1448. erosions: radiological and endoscopic as- Roentgen diagnosis of linear ulcers. Radiol- pects. Radiol Clin (Belg) 1976;45:88–89. ogy 1979;132:29–32. 74. Hizawa K, Iida M, Matsumoto T, Aoyagi K, Yao T, Fujisima M. Natural history of fundic 45. Kikuchi Y, Levine MS, Laufer I, Herlinger 59. Nelson SW. The discovery of gastric ulcers gland polyps without familial adenomatous H. Value of flow technique for double-con- and the differential diagnosis between be- coli: follow-up observations in 31 patients. trast examination of the stomach. AJR nignancy and malignancy. Radiol Clin Radiology 1993;189:429–432. Am J Roentgenol 1986;147:1183–1184. North Am 1969;7:5–25. 75. Op den Orth JO, Dekker W. Gastric adeno- 46. Lanza FL, Nelson RS, Rack MF. A con- 60. Wolf BS. Observations on roentgen fea- mas. Radiology 1981;141:289–293. trolled endoscopic study comparing the tures of benign and malignant ulcers. Semin toxic effects of sulindac, naproxen, aspirin, Roentgenol 1971;6:140–150. 76. Daniel ES, Ludwig SL, Lewin KJ, Ruprecht and placebo on the gastric mucosa of RM, Rajacich GM, Schwabe AD. The healthy volunteers. J Clin Pharmacol 1984; 61. Ott DJ, Gelfand DW, Wu WC. Detection of Cronkhite-Canada syndrome: an analysis of 24:89–95. gastric ulcer: comparison of single and dou- clinical and pathologic features and therapy ble-contrast examination. AJR Am J Roent- in 55 patients. Medicine 1982;61:293–309. 47. Lanza FL. NSAIDS and the gastrointestinal genol 1982;139:93–97. tract. Abdom Imaging 1997;22:1–4. 77. Suster S. Gastrointestinal stromal tumors. 62. Barragry TP, Blatchford JW, Allen MO. Semin Diagn Pathol 1996;13:297–313. 48. Grace E. Approach to the patient with Giant gastric ulcers: a review of 49 cases. gross gastrointestinal bleeding. In: Yamada 78. Maderal F, Hunter F, Fuselier G, Gonzales- Ann Surg 1986;203:255–259. T, ed. Textbook of gastroenterology. Phila- Rogue P, Torres O. Gastric lipomas: an delphia, Pa: Lippincott Williams & Wilkins, 63. Kottler RE, Tuft RJ. Benign greater curva- update of clinical presentation, diagnosis 2003; 698–723. ture gastric ulcer: the “sump ulcer.” Br J and treatment. Am J Gastroenterol 1984; Radiol 1981;54:651–654. 79:964–967. 49. Levine MS, Verstandig A, Laufer I. Serpiginous gastric erosions caused by aspirin and other 64. Hocking BV, Alp MH, Grant AK. Gastric 79. Megibow AJ, Redmond PE, Bosniak MA, nonsteroidal anti-inflammatory drugs. AJR ulceration with hiatus hernia. Med J Aust Horowitz L. Diagnosis of gastrointestinal Am J Roentgenol 1986;146:31–34. 1976;2:207–208. lipomas by CT. AJR Am J Roentgenol 1979; 133:743–745. 50. Roberts DM. Chronic gastritis, alcohol and 65. Thompson G, Somers S, Stevenson GW. non-ulcer dyspepsia. Gut 1972;13:768– Benign gastric ulcer: a reliable radiologic 80. Imoto T, Nobe T, Koga M, Miyamoto Y, 774. diagnosis? AJR Am J Roentgenol 1983;141: Nakata H. Computed tomography of gastric lipomas. Gastrointest Radiol 1983;8:129– 51. Balthazar EJ, Megibow AJ, Hulnick DH. Cy- 331–333. 131. tomegalovirus esophagitis and gastritis in 66. Zboralske FF, Stargardter FL, Harel GS. AIDS. AJR Am J Roentgenol 1985;144: 81. Barbosa JJ, Dockerty MB, Waugh JM. Profile roentgenographic features of benign 1201–1204. Pancreatic heterotopia: a review of the lit- greater curvature ulcers. Radiology 1978; erature and report of 41 authenticated sur- 52. Laufer I, Trueman T. Multiple superficial 127:63–67. gical cases of which 25 were clinically signif- gastric erosions due to Crohn’s disease of 67. Levine MS, Kelly MR, Laufer I, Rubesin SE, icant. Surg Gynecol Obstet 1946;82:527– the stomach: radiologic and endoscopic di- Herlinger H. Gastrocolic fistulas: the in- 542. agnosis. Br J Radiol 1976;49:726–728. creasing role of aspirin. Radiology 1993; 82. Lai EC, Tompkins RK. Heterotopic 53. Ariyama J, Wehlin L, Lindstrom CG, 187:359–361. pancreas: review of a 26-year experience. Wenkert A, Roberts GM. Gastroduodenal 68. Eisenberg RL, Levine MS. Miscellaneous Am J Surg 1986;151:697–700. erosions in Crohn’s disease. Gastrointest abnormalities of the stomach. In: Gore RM, Radiol 1980;5:121–125. 83. Besemann EF, Auerbach SH, Wolfe WW. Levine MS, eds. Textbook of gastrointesti- The importance of roentgenologic diagnosis 54. Sloan JM. Acute haemorrahagic gastritis nal radiology. Philadelphia, Pa: Saunders, of aberrant pancreatic tissue in the gastro- and acute infective gastritis: gastritis 2000; 659–681. intestinal tract. Am J Roentgenol Radium caused by physical agents and corro- Ther Nucl Med 1969;107:71–76. sives—uraemic gastritis. In: Whitehead 69. Treichel J, Gerstenberg E, Palme G, R, ed. Gastrointestinal and oesophageal Klemm T. Diagnosis of partial gastric diver- 84. Rubesin SE, Levine MS, Glick SN. Gastric pathology. 2nd ed. Edinburgh, Scotland: ticula. Radiology 1976;119:13–18. involvement by omental cakes: radio- Churchill-Livingstone, 1995; 461–470. 70. Gordon R, Laufer I, Kressel HY. Gastric graphic findings. Gastrointest Radiol 1986; 11:223–228. 55. Rumerman J, Rubesin SE, Levine MS, Long polyps found on routine double-contrast ex- WB, Laufer I. Gastric ulceration caused by amination of the stomach. Radiology 1980; 85. Carucci LR, Levine MS, Rubesin SE, Laufer heater probe coagulation. Gastrointest Ra- 134:27–30. I. Tumorous gastric varices: radiographic diol 1988;13:200–202. findings in 10 patients. Radiology 1999;212: 71. Joffe N, Antonioli DA. Atypical appear- 861–865. 56. Levine MS, Creteur V, Kressel HY, Laufer ances of benign hyperplastic polyps. AJR I, Herlinger H. Benign gastric ulcers: diag- Am J Roentgenol 1978;131:147–152. 86. de Lange EE. Radiographic features of gas- nosis and follow-up with double-contrast tritis using the biphasic contrast technique. 72. Smith HJ, Lee EL. Large hyperplastic pol- radiography. Radiology 1987;164:9–13. Curr Probl Diagn Radiol 1987;16:273–308. yps of the stomach. Gastrointest Radiol 57. Bloom SM, Paul RE JR, Matsue H, Poplack 1983;8:19–23. 87. Gelfand DW, Ott DI, Chem MY. Radiologic

Radiology: Volume 246: Number 1—January 2008 47 REVIEW FOR RESIDENTS: Double-Contrast Upper Gastrointestinal Radiography Rubesin et al

evaluation of gastritis and duodenitis. AJR in 40 patients. Radiology 1999;213:347– graphic diagnosis and clinical signiﬁcance. Am J Roentgenol 1999;173:357–361. 351. Radiology 1979;132:593–598.

88. Sohn J, Levine MS, Furth EE, et al. Helico- 94. Reese DF, Hodgson JR, Dockerty MB. Gi- 99. Balthazar EJ, Goldfine S, Davidian NM. bacter pylori gastritis: radiographic find- ant hypertrophy of the gastric mucosa (Me- Carcinoma of the esophagogastric junction. ings. Radiology 1995;195:763–767. netrier’s disease): a correlation of the Am J Gastroenterol 1980;74:237–243. roentgenographic, pathologic, and clinical 100. Freeny PC, Marks WM. Adenocarcinoma 89. Levine MS, Rubesin SE. The Helicobacter findings. Am J Roentgenol Radium Ther of the gastroesophageal junction: barium pylori revolution: radiologic perspective. Nucl Med 1962;88:619–626. and CT examination. AJR Am J Roentgenol Radiology 1995;195:593–596. 1982;138:1077–1084. 95. Smart HL, Triger DR. Clinical features, 90. Ellison EH, Wilson SD. The Zollinger- pathophysiology, and relevance of portal 101. Levine MS, Laufer I, Thompson JJ. Carci- Ellison syndrome: re-appraisal and evalua- hypertensive gastropathy. Endoscopy noma of the gastric cardia in young people. tion of 260 registered cases. Ann Surg 1991;23:224–228. AJR Am J Roentgenol 1983;140:69–72. 1964;160:512–530. 102. Laveran-Stieber RL, Laufer I, Levine MS. 96. Chang D, Levine MS, Ginsberg GG, Rubesin Greater curvature antral flattening: a radio- 91. Olmsted WW, Cooper PH, Madewell JE. SE, Laufer I. Portal hypertensive gastropathy: logic sign of NSAID-related gastropathy. Involvement of the gastric antrum in Men- radiographic findings in eight patients. AJR Abdom Imaging 1994;19:295–297. etrier’s disease. AJR Am J Roentgenol Am J Roentgenol 2000;175:1609–1612. 1976;126:524–529. 103. Levine MS, Kong V, Rubesin SE, Laufer I, 97. Levine MS, Kieu K, Rubesin SE, Herlinger Herlinger H. Scirrhous carcinoma of the 92. Glick SN, Cavanaugh B, Teplick SK. The H, Laufer I. Isolated gastric varices: splenic stomach radiographic and endoscopic diag- hypertrophied antral-pyloric fold. AJR vein obstruction or portal hypertension? nosis. Radiology 1990;175:151–154. Am J Roentgenol 1985;145:547–549. Gastrointest Radiol 1990;15:188–192. 104. Balthazar EJ, Rosenberg H, Davidian MM. 93. Arora R, Levine MS, Harvey RT, Laufer I, 98. Muhletaler C. Gerlock J, Goncharenko V, Scirrhous carcinoma of the pyloric channel Rubesin SE. Hypertrophied antral-pyloric Avant GR, Flexner JM. Gastric varices sec- and distal gastric antrum. AJR Am J Roent- fold reassessment of radiographic findings ondary to splenic vein occlusion: radio- genol 1980;134:669–673.

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