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A Possible Dual Control Mechanism in the Origin of Peptic Ulcer
Vo l. 57, No.3 Printed i n U.S.A .
G A STROE NTJ::R OL O G Y
Co py right© 1969 by The Willia m s & Wilkins Co.
A POSSIBLE DUAL CON~OL MECHANISM IN THE ORIGIN OF PEPTIC ULCER A study on ulcer location as affected by mucosa and musculature MINORU 01, M.D., YOJI ITO, M.D., FUMIYA KUMAGAI, M.D., KAN YOSHIDA, M.D., YosHIKI TANAKA, M.D. , KEIICHI YosHIKAWA, M .D . , 0TOMI MIHo, M .D. , AND MASAMURA KIJIMA, M.D.
Department of Surgery, Jikei University School of Medicine, Tokyo, Japan
In study I, 855 peptic ulcers were found in a group of 640 gastric specimens obtained surgically. The locations of these ulcers were observed in their relation to mucosae. It was found that nearly all ulcers were located adjacent to a mucosal boundary and, moreover, the ulcers were located on the side of the boundary opposite the fundic gland area. In study II, 269 ulcers were found in another group of 211 gastric specimens similarly obtained surgically. The locations of these ulcers were observed in their relation to musculature. It was found that nearly all ulcers were located within identifiable special muscular areas. In study III, by means of transparent cellophane overlays, the locations of the 269 ulcers of study II were observed in their relation to both musculature and mucosae. It was found that the locations of nearly all ulcers were seemingly affected or controlled by both mucosal boundaries and muscle bundles. This dual effect or influence of both the mucosae and musculature has been designated "dual control mechanism." Finally, by means of the concept of dual control mechanism an attempt speculatively has been made to explain the significance of the local pathogenic factor of peptic ulceration, a possible reason for the chronicity and single development of peptic ulcers, and the reason why gastric ulcers frequently appear at the gastric angulus of the lesser curvature of the stomach.
This paper presents what is considered to be a new hypothesis for the understanding of the local mechanism of peptic ulceration. Where peptic ulcers occur is felt to be of great significance when considering the cause of peptic ulcer. Previously, Oi and co-workers conducted histological studies concerning the locations Received July 11, 1968. Accepted March 17, 1969. A preliminary report of this work was p esented at the Third World Congress of Gastroenterology, Tokyo, Japan, held in September 1966. Address requests for reprints to: Dr. Minoru Oi, Director, Tokyo Welfare Pension Hospitai, 23 Tsukudo-cho, Shinjuku-Ku, Tokyo 162, Japan.
of peptic ulcers in relation to gastrointestinal mucosae. These studies indicated that generally ulcers were located near the boundary between types of mucosa. H In the present study, utilizing a greater number of gastric specimens, the locations of ulcers were again determined in relation to mucosae. In addition, using another group of gastric specimens, locations of ulcers were determined in relation to musculature! Results indicate that peptic ulcers tend to occur near the boundary between different mucosae, as well as at the points of intense kinetic strain, under the assumption that kinetic strain is intensified where certain special 280
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POSSIBLE DUAL CONTROL MECHANISM
muscle bundles are located. These facts suggest that peptic ulceration is controlled by some type of dual mechanism between the two principal structures, mucosa and musculature.
Materials and Methods Ulcer Location in Relation to Mucosae (Study[) Of 786 gastric specimens subjected to examination, 640 specimens contained ulcers and 146 specimens did not contain ulcers or other gross lesions, although they usually exhibited gastritis. An ulcer was defined as a chronic nonspecific mucosal defect which had penetrated the muscularis mucosae. All gastric specimens were obtained surgically. Of the 640 specimens containing ulcers, 366 ulcers were found in the stomach only, 236 ulcers were found in the duodenum only, 249 ulcers were found as cases of combined gastric (132 ulcers) and duodenal (117 ulcers) ulcers, and four ulcers were found in a case of combined esophageal (one ulcer), gastric (one ulcer), and duodenal (two ulcers) ulcers. A total of 855 ulcers were found. By site, there were 499 gastric ulcers, 355 duodenal ulcers, and one esophageal ulcer. Oi et al. 1 - 3 previously pointed out that ulcers were found usually at or near a mucosal boundary. In confirming this relation between ulcer location and mucosal boundaries, four mucosal boundaries were considered: the esophagocardiac, cardiofundic, fundopyloric (F-P), and pyloroduodenal (P-D) (fig. 1). As the first two are so close to each other, for practical purposes they were considered by the single name, the esophagogastric boundary. Procedures were similar to those previously ESOPHAGO · CARDIAC MUCOSAL BOUNDARY CARD\0 -FUNDIC MUCOSAL BOUNDARY FUNDIC GLAND AREA FUNDO -PYLORIC MUCO SAL BOUNDA RY
PYLORO DUODENAL MUCOSAL BOUNDARY
FIG . 1. Diagram showing terminology used for the various mucosae and mucosal boundaries observed in the present study.
281
reported.' ·" Gastric specimens were opened along the greater curvature, fastened to pasteboards with mucosal face upwards, and fixed with 10% formalin solution. After fixation, various strips were cut off in full thickness along the gastric axis in each specimen, and the strips were then cut into blocks for histological determination of mucosal boundaries. A life-size map or chart of each specimen was prepared, with the locations of ulcer(s), mucosal boundaries, and the pyloric ring (ridge of the pyloric sphincter) indicated. Standards were observed in designating a location of an ulcer. When there was a degree of width to the mucosal boundary as documented previously, 5 the boundary was determined as passing through the center of the width. When determining the distance of an ulcer from the mucosal boundary, the shortest distance between the edge of the uJcer and the nearby mucosal boundary was measured by inspecting the sections microscopically. For the purpose of this study, when an ulcer was within 2.0 em of mucosal boundary the ulcer was considered as "adjacent" ("proximal" in references 1 to 3) to the mucosal boundary, and when over 2.0 em from a mucosal boundary the ulcer was considered as "distant" ("distal" in references 1 to 3) from the mucosal boundary. Finally, distances were measured from the pyloric ring to ulcers and mucosal boundaries.
Ulcer Location in Relation to Musculature (Study II) Of 327 gastric specimens subjected to examination, 211 specimens contained ulcers and 116 specimens did not contain ulcers or other gross lesions, although they usually exhibited gastritis. These specimens were independent of those used in study I. All were obtained surgically, except eight which were from autopsy. Of the 211 specimens with ulcers, 128 ulcers were found in the stomach only, 86 ulcers were found in the duodenum only, and 55 ulcers were found as cases of combined gastric (30 ulcers) and duodenal (25 ulcers) ulcers. A total of 269 ulcers were found. By site, there were 158 gastric ulcers and 111 duodenal ulcers. Specimens were treated similarly to those used in study I up to the point of fixation; the mucosal layer was then separated from the muscle coat in each specimen by dissection through the submucosa, exposing the inner surface of the musculature . The gastric muscle coat consists of three layers of muscle bundles: the inner oblique, middle circular, and outer
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FIG. 2. Top left, the inner aspect of the muscle coat of the stomach opened along the greater curvature. Top right, schematic illustration of the oblique and circular muscle bundles of the gastric specimen shown at the top left. Bottom, the anterior and posterior medial oblique muscle bundles and the border circular muscle bundle especially freed for the purpose of demonstration.
longitudinal. Mter separating the mucosa from the muscle coat, the inner oblique and middle circular layers of the muscle coat are observable; the oblique muscle bundles, derived
from the circular bundles of the esophagus, extend downward in both anterior and posterior gastric walls, spreading out toward the greater curvature to disappear in gradual fu-
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POSSIBLE DUAL CONTROL MECHANISM
sion with the circular bundles of the body. In observing the oblique and circular bundles, four bundles were considered to be of special interest (fig. 2). For convenience they were named. The oblique muscle bundle which runs down the anterior wall nearest the lesser curvature was named the "anterior medial oblique" or AMO muscle bundle. The oblique muscle bundle which runs down the posterior wall nearest the lesser curvature was named the "posterior medial oblique" or PMO muscle bundle. The AMO and PMO muscle bundles lie symmetrically and fuse with a circular muscle bundle which can be considered as the boundary of the body and antrum of the musculature. This muscle bundle was given the name "border circular" or BC muscle bundle. Finally, since the thick circular muscle bundles at the pylorus form the pyloric sphincter, the bundle of the ridge of the sphincter was named the "pyloric circular" or PC muscle bundle. On the inner surface of the muscle coat an ulcer appears as a crater surrounded by cicatrization. In identifying the location of ulcers in relation to the musculature, the AMO, PMO, BC, and PC muscle bundles were used as "landmarks" ; and ulcers were macroscopically located in relation to them. A life-size transparent cellophane overlay was made for each musculature specimen, with locations of ulcer(s) and the muscle bundles as landmarks indicated. Distances from PC muscle bundles to BC muscle bundles were measured.
cers in the stomach only, 111 of the 132 gastric ulcers found in combination with duodenal ulcers, 234 of the 236 ulcers in the duodenum only, all of the 117 duodenal ulcers found in combination with gastric ulcers, and all of the four ulcers in the case of combined esophageal, gastric, and duodenal ulcers were adjacent to mucosal boundaries. By site, the one esophageal ulcer was adjacent to the esophagogastric mucosal boundary, 475 (95.2So) of the 499 gastric ulcers were adjacent to the F-P mucosal boundary, and 353 (99.4 %) of the 355 duodenal ulcers were adjacent to the P-D mucosal boundary. Thus, of the total 855 ulcers, 829 (97.0 %) were adjacent to mucosal boundaries (fig. 3). The average distance of these ulcers from their adjacent boundaries was 0.38 em. Furthermore, all ulcers adjacent to mucosal boundaries were located on the side of the boundary opposite the fundic gland area. Such ulcers were either free of, but still adjac~nt to, or in direct contact with the boundary itself; this was consistently noted, regardless of how high or low the muco5al boundaries were located (fig. 4). The varieties of gastric specimens with o
Ad j~c e n t Ulce r s
e
Di s tan t Ul ce rs
Ulcer Location in Relation to both Mucosae and Musculature (Study II[) This study was done using the 327 gastric specimens of study II. By the methods of study I, locations of ulcers were determined on mucosal layer specimens previously separated from the muscle coats. Thus, similar to study I, a life-size chart was developed for each specimen to show the relation of ulcer location to mucosae. Over these charts the transparent cellophane overlays of study II were superimposed. In a single visualization, then, the locations of ulcers were determined in relation to both mucosal boundaries and muscle bundles.
Results
Ulcer Location in Relation to Mucosae (Study l) Ulcers adjacent to mucosal boundaries. Three hundred sixty-three of the 366 ul-
t otal
829
( 97% )
855
26
(3% )
FIG. 3. Location of ulcers in relation to mucosae. Nearly all ulcers were adjacent to mucosal boundaries and on the side of the boundary opposite the fundi c gland area .
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FIG. 4. Locations of ulcers and mucosal boundaries are variable from specimen to specimen, but the relationships between ulcers and mucosal boundaries are consistent.
ulcers adjacent to mucosal boundaries are shown in the left half of figure 5. Ulcers distant from mucosal boundaries. Only 26 ulcers of the total 855, or 3.0%, were distant from mucosal boundaries. Of these, 21 appeared in the pyloric gland area distant from the F-P mucosal boundary, two appeared in the duodenal gland area distant from the P-D mucosal boundary, and three appeared in the fundic gland area distant from the F-P mucosal boundary. Concerning these ulcers which were distant from the mucosal boundaries and seemingly exceptions to the great majority, the following facts were noted: ulcers in the pyloric gland area and those in the duodenal gland area were all in combination with other duodenal ulcers adjacent to the P-D mucosal boundary; and one ulcer in the fundic gland area was in combination with another ulcer in the pyloric gland area adjacent to the F-P mucosal boundary. This relationship is shown in the right half of figure 5. Of the three ulcers in the fundic gland area distant from the F-P mucosal boundary, serial sections revealed that two had narrow mucosal portions of ectopic pyloric glands surrounding them. These two ulcers, then, actually occurred on pyloric gland islets in the fundic gland area. In the third case, the sections failed to show such ectopic pyloric glands in the environment of the ulcer; although in this case the ulcer was in combination with another
gastric (linear type) ulcer. The cases of these three ulcers in the fundic gland area are diagrammed in figure 6. Distances of ulcers and mucosal boundaries from the pyloric ring. Distances of gastric ulcers from the pyloric ring varied among individuals. Distances between F-P mucosal boundaries and pyloric rings were also variable, ranging on the lesser curvature, for example, from 0.2 to 17.0 em in specimens with ulcers and from 2.0 to 13.2 em in those without ulcers. In the case of duodenal ulcers, both the ulcers and the P-D mucosal boundaries were usually located just next to or on the pyloric ring (fig. 7).
Ulcer Location in Relation to Musculature (Study Il) Ulcers found in the stomach only. The 128 ulcers found in the stomach only consisted of 111 single ulcers, five cases of double ulcers, one case of triple ulcers, and one case of quadruple ulcers. In detail, locations of these ulcers were as follows: Of the 111 single ulcers, 2 were on the AMO muscle bundle; 16 were on the PMO muscle bundle; 46 were on the BC muscle bundle; six were on both the PMO and BC muscle bundles; 38 were inside the area formed by the AMO, PMO, and BC muscle bundles; and the three remaining ulcers were distal to the BC
September 1969
POSSIBLE DUAL CONTROL MECHANISM
muscle bundle or lateral to the AMO muscle bundle. Of the five double ulcers, four were cases of "kissing ulcers," and of these, one pair was at the junctions of the BC muscle bundle and the AMO and PMO muscle bundles, and the three other pairs were on the BC muscle bundle between these junctions. Concerning the fifth case of double ulcers, one ulcer was on the PMO muscle bundle and the other
Gastric Specimens with Ulcers
Adj ace nt to Mu cosa l Boundaries
Distant from Mucosal Boundaries
Ar ra ngement of Ulc ers
Ul ce r
St omac h
was lateral to it. With respect to the cases of triple and quadruple ulcers, all ulcers were on the BC muscle bundle lying between the AMO and PMO muscle bundles. It should be noted that, of the 128 ulcers found in the stomach only, 124, or 96.9%, were either on the AMO, PMO, or BC muscle bundles themselves, or were
Gas tri c Spe c imen s with Ul ce r s All Site of
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Arrangement of Ulcers
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ulcer adjacent to mucos al boundary
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Numerals mean the number of specimens. FIG. 5. Gastric specimens tabulated by the relationship between ulcers and the mucosal boundaries. All of the distant ulcers are in combination with adjacent ulcers.
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Cf@{) PYLORIC
GLANDS
CJ ULCER
FIG. 6. Cases of the three ulcers occurring in the fundic gland area distant from the fundopyloric mucosal boundary. In two cases (left and middle), tissues of ectopic glands were found surrounding the ulcer, and in the third case, (right) , no such tissue was found near the ulcer. In the third case, however, there was another gastric ulcer occurring in the pyloric gland area near the F-P mucosal boundary.
16 14 12
:
10
8
- MUCOSAL BOUNDARY ESOPHAGEAL ULCER • GASTRIC ULCER a DUODENAL ULCER
*
FIG. 7. Left, location of the F-P and P-D mucosal boundaries in 100 gastric specimens without ulcers selected at random. Middle, location of the F-P and P-D mucosal boundaries in 100 gastric specimens with gastric ulcers and 100 specimens with duodenal ulcers. Specimens were selected at random . Right, location of all of the 855 esophageal, gastric, and duodenal ulcers. It seems that location of gastric ulcers may be affected by the variableness in location of F-P mucosal boundaries which appears to be congenital, and that location of duodenal ulcers may be affected by the invariableness in location of P-D mucosal boundaries which appears also to be congenital.
inside the area (left diagram of Ulcers found The 86 ulcers
formed by these bundles fig. 8 and fig. 9). in the duodenum only. found in the duodenum
only consisted of 58 single ulcers, 11 double ulcers, and two triple ulcers. All ulcers were in the immediate vicinity of the PC muscle bundle, regardless of
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POSSIBLE DUAL CONTROL MECHANISM
whether they were on the anterior or posterior wall (middle diagram of fig. 8 and fig. 9). Combined gastric and duodenal ulcers. Gastric ulcers. The 30 gastric ulcers consisted of 16 single ulcers, four double ulcers, and two triple ulcers, and were generally found to be located similar to uncombined gastric ulcers. Of the 30 gastric ulcers, 24, or 80%, were found either on the AMO, PMO, or BC muscle bundles, or inside the area formed by these bundles; the other six (20 ~( ) were distal to the BC muscle bundle. Duodenal ulcers. The 25 duodenal ulcers consisted of 19 single ulcers and three double ulcers. All were found in the immediate vicinity of the PC muscle bundle (right diagram of fig. 8 and fig. 9). Muscular areas of special significance, zone G and zone D. When tabulating all of the 158 gastric ulcers by site, 148, or 93.7 ~( , were either on the AMO, PMO, or BC muscle bundles themselves, or were inside the particular area formed by these bundles. This area of special significance was named zone G. Of the total 111 duodenal ulcers, all appeared in the immediate vicinity of the PC muscle bundle; and this area of special significance
287
was named zone D. Over-all, 259 of 269 ulcers, or 96.3%, were found in the special areas (fig. 10) . Only 10 ulcers, or 3. 75(;, were not found in the areas of zone G and zone D. These 10 were gastric ulcers; of them, six occurred in combination with duodenal ulcers appearing in zone D, and one occurred in combination with another gastric ulcer appearing in zone G (fig. 10). Distance of the BC muscle bundle from the pyloric ring. ill the specimens examined, the distances between BC muscle bundles and pyloric rings varied, ranging on the lesser curvature, for example, from 0.2 to 9.4 em in specimens with gastric ulcers, and from 4.3 to 9.2 em in those without ulcers.
Ulcer Location in Relation to both Mucosae and Musculature (Study II[) Ulcer location in relation to mucosal boundaries and special muscular areas. Of the 158 gastric ulcers, 145, or 91.8%, were located adjacent to and on the nonfundic side of the F-P mucosal boundary and simultaneously in zone G. Of the 13 ulcers not so located, seven were either distant from the F-P mucosal boundary but within zone G, or were adjacent to
FIG. 8. A circle shows shape as well as location of an ulcer found on the musculature. Left, 64 ulcers, single or multiple, of the stomach only which were found in 60 specimens selected at random. Middle, 56 ulcers, single or multiple, of the duodenum only which were found in 50 gastric specimens selected at ran· dom. Right, all of the combined gastric (30) and duodenal (25) ulcers. Numbers of specimens or ulcers had to be reduced to keep illustration of ulcer shape clear.
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OJ ET AL .
loric glands, similar to such ulcers diagramed in study I. Only six ulcers were neither adjacent to the F-P mucosal boundary nor in zone G. All 111 duodenal ulcers were found in the duodenal gland area adjacent to the P-D mucosal boundary and in zone D. Thus, over-all, 256 of 269 ulcers, or 95.2%, were located adjacent to a mucosal boundary, and more specifically on the side of the boundary opposite the fundic gland area, as well as in one of the special muscular areas, zone G or zoneD (fig. 11). Relationship between F-P mucosal boundary and BC muscle bundle. Distances from the pyloric ring to both the F-P mucosal boundary and the BC muscle bundle varied as observed in studies I and II. Similarly, the distances between F-P mucosal boundaries and BC muscle bundles varied. An examination of the relationship between the F-P mucosal boundary and the BC muscle bundle revealed two major types of relationships: in one situation, the F-P mucosal boundary and the BC muscle bundle did not cross each other and in the other situation, they did cross each other. Further exam}nation disclosed that these situa. tions had subtypes; six such subtypes ~ul ce r s
in Special Area
• Ulcers outsid Special Area
3
148 7 FIG . 9. Samples of various musculature specimens with ulcers. The white lines indicate AMO, PMO, BC , and PC muscle bundles and the white circles indicate ulcer craters.
Ill total
the F-P mucosal boundary but not in zone G. Among these seven were two special ulcers which at first appeared in the fundic gland area outside zone G, but on histological examination were found to have developed on islets of ectopic py-
259 ( 96.3 °6)
269
10 ( 3. 7 % )
FIG. 10. Location of ulcers in relation to the musculature. Nearly all ulcers were found in special muscular areas.
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Gastric Specimens with Ulcers
Gastric Specimens with Ulcers
Distant from Mucosal
Adjacent to Mucosal Boundaries
Boundaries and /or Outside
and in Special Muscular Areas
Special Muscular
Site of Ulcer
Areas
Arrangement of U leers
Arrangement of Ulcers
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289
POSSIBLE DUAL CONTROL MECHANISM
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ulcer distant from mucosal boundary and on special muscular area ulcer distant from mucosal boundary and outside special muscular area
Numerals mean the number of specimens. FIG. 11. Gastric specimens tabulated by the relation of ulcers to both the mucosal boundaries and the special muscular areas.
were identified among the specimens examined (table 1). Gastric specimens were tabulated by the relationship between the F-P mucosal
boundary and the BC muscle bundle. Of the specimens without ulcers, 48So were of the "no crossing" type; and of the specimens with duodenal ulcers only, 64.8S(
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OJ ET AL . TABLE
Vol. 57, No. 3
1. Relationship between fundopy loric mucosal boundary and border circular m uscle bundle No. of Gastric Specime ns
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with Duodenal Ulcers
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with Gastric Ulcers
without Ulcers
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Relation between pyloroduodenal mucosal boundary and pyloric circular muscle bundle \ n. uf Gas tric Spec imens
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111
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with Gastri c
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l:lcer
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with GastnrluOOenal L'\cers
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with DuOOenal nct:r
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(2.6)
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13
ll
3
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(15.5)
(15.1)
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62
55
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(75. 3)
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28
7
6
(8. 3)
(8.2)
(14. 3)
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84
73
14
39
2
9
September 1969
POSSIBLE DUAL CONTROL MECHANISM
were of the no crossing type. Of gastric specimens with gastric ulcers, however, all but one were of the crossing type; and the ulcer of the one specimen which was of the no crossing type was one of the special ulcers previously mentioned, i.e., a gastric ulcer occurring on an islet of ectopic puloric glands in the fundic gland area. Relationship between P-D mucosal boundary and PC muscle bundle. The P-D mucosal boundary and the PC muscle bundle were not so variable in location as were the F-P mucosal boundary and BC muscle bundle described above. ill most instances, the P-D mucosal boundary and the PC muscle bundle were approximately rectilinear and parallel to each other when observed in specimens opened flat. Four types of relationships, however, were observed: the P-D mucosal boundary was situated either (1) proximal to, (2) on, (3) distal to, or (4) across the PC muscle bundle. A tabulation of gastric specimens by these relationships was made, but no particular trends were found (table 2). Discussion
Relationship between Ulcer Location and Mucosae Study I revealed that nearly all ulcers of the stomach were adjacent to the F-P mucosal boundary, and furthermore, were located on the side of the boundary opposite the fundic gland area, i.e., in the pyloric gland area. Study I also revealed that nearly all ulcers of the duodenum were adjacent to the P-D mucosal boundary, occurring in the duodenal gland area, and that the one esophageal ulcer was also adjacent to the esophogogastric mucosal boundary, occurring in the esophageal mucosa. The common feature of these findings was that most ulcers occur adjacent to the boundary between different mucosae, and on the side of the boundary opposite the fundic gland area or acidsecreting area. Concerning the percentage of the entire stomach taken up by the area in which most ulcers tend to occur, that area 2 em adjacent to the F-P mu-
291
cosal boundary, a separate study was made utilizing five whole stomach specimens from autopsy, and it was found on the average to be about 5%. If the mucosal folds especially prominent in the fundic gland area are considered, this percentage is even lower. Of the small number of ulcers which seemingly were exceptions to this common pattern, most occurred in combination with other gastric or duodenal ulcers which did conform. ill this regard, two single ulcers which occurred within the fundic gland area are of special significance. While at first they appeared to be "nonconformers" to the common pattern, upon histological examination they were found to have occurred on islets of ectopic pyloric glands; thus they also conformed to the common pattern. ill fact, such ulcers give strength to the common pattern, and it appears that the location of peptic ulcers is really controlled by the arrangement of mucosae. Study I showed that the vast majority of ulcers occur in a nonfundic gland mucosal area at a point nearest the acidsecreting area. Therefore, it is felt that ulcers may occur in a nonfundic gland area where acid gastric juice exerts its strongest action, and that, if so, such consideration tends to confirm the belief that peptic ulcers are caused by gastric juice. Examination of specimens, with or without ulcers, showed that from specimen to specimen the distance between the F-P mucosal boundary and the pyloric ring varies. Conversely, the distance between the P-D mucosal boundary and the pyloric ring was found to be generally invariable. Since most ulcers occur adjacent to these mucosal boundaries, gastric ulcers may be said to be variably located within the stomach with respect to the pyloric ring, and duodenal ulcers may be said to be invariably located within the duodenum with respect to the pyloric ring.
Relationship between Ulcer Location and Muscle Bundles Study II revealed that nearly all ulcers of the stomach were located in the
292
OJ ET AL .
area formed by the AMO, PMO, and BC muscle bundles, namely, zone G, and that all ulcers of the duodenum were located in the immediate vicinity of the PC muscle bundle, namely, zone D. These facts indicate that the occurrence of peptic ulcers may be influenced by the motility of the muscle of the stomach. Zone G is a part of the musculature which lacks oblique muscle bundles and which exists only at the narrow lesser curvature of the corpus of the stomach. The average size of zone G in relation to the size of entire stomach was about 11 % when studied in five whole stomach specimens from autopsy. Zone D is a part of the musculature where the bulk of the pyloric sphincter is abruptly lost distally and where connection between pyloric sphincter and a layer of the duodenal circular muscle bundles is interrupted by an interposition of connective tissue." Upon morphological observation, zone G and zone D have the common feature of being bordered with a thick portion of muscle coat. Therefore, with varying thicknesses in the muscle coat it is likely that there is an intensification of local kinetic strain in these areas. In an electromyographic examination of the stomach, action potential begins at the midportion of the stomach body and proceeds distally.' During this process, intensity of the action potential is seen to increase rather sharply at the BC muscle bundle and to continue to increase gradually, until it reaches the pylorus where the active gastric pattern of the action potential ceases suddenly and is no longer conducted to the duodenum.' Therefore physiological studies of gastric musculature, such as electromyographic examinations, generally seem to support the forementioned morphological interpretations. Zone G and zone D, in relation to the rest of the musculature, might be identified as areas of severe kinetic strain, in which case it may be said as a speculative possibility that peptic ulcers occur where kinetic strain due to gastric motility is great. Indeed, zone G and zone D may be called the "upper strain zone" and the "lower strain zone" respectively.
Vol. 57, No. 3
Dual Control Mechanism From results of studies I and II, it was found that ulcer location is believed influenced or controlled by both mucosae and musculature. Although it is uncertain whether these influences or controls are dependent of each other, valuable information with respect to this question is provided by study III, where transparent charts of the musculature were superimposed over those of the mucosae to provide specimen inspection in a single visualization. In study III, it was found that the locations of 95.2% of the ulcers examined conformed to or were affected by both mucosal and muscular controls. Especially significant in this regard are cases of gastric ulcers in which nearly all gastric ulcers occurred only in situations where the F-P mucosal boundary and the BC muscle bundle crossed. In these situations, both mucosal and muscular controls are coexistent at the ulcer site. Conversely, in those situations where the F-P mucosal boundary did not cross the BC muscle bundle, which was roughly half the time, there was only one gastric ulcer case, and this was an explainable, exceptional case. It is believed to be likely, then, that for the development of peptic ulceration, both mucosal and muscular controls must coexist at the site of the ulcer, and this principle has been named the "dual control mechanism." The occurrence of an ulcer means, therefore, that an anatomic relationship of the dual control mechanism probably exists, and that such an anatomic relationship or existence is permanent, unless artificially altered or removed. This may explain why peptic ulcers tend to become chronic, recurrent, or clinically intractable. It should also be noted that the focus where the dual control mechanism is effective is usually very small or narrow in comparison with the entire stomach or duodenum. This may explain why peptic ulcers are more likely to occur singly rather than multiply. In this respect, the gastric ulcer has been known to occur along the lesser curvature at the level of the gastric angulus, and this is probably
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POSSIBLE DUAL CONTROL MECHANISM
because the effective focus of the dual control mechanism for gastric ulcers is usually formed at or near the angulus which is part of the lesser curvature. Since this focus for gastric ulcers lies at varying distances from the pyloric ring, and for duodenal ulcers lies at a constant distance from the pyloric ring, this may explain the reason for the scattering of gastric ulcers in the stomach and the localizing of duodenal ulcers in the duodenum. It can be said that according to this principle, the development of a gastric ulcer is not always anatomically possible, regardless of whether or not systemic factors favorable for causing peptic ulcers are present, whereas the development of a duodenal ulcer is always anatomically possible. With this explanation, the meaning of such phrases as "ulcer diathesis" or "ulcer disposition" is perhaps somewhat clarified. Although the location, and indeed the existence, of an ulcer is believed affected by this dual control mechanism, this does not of course preclude the possibility that other factors contribute their influences
293
to the cause of peptic ulceration. It is believed that the results of these studies will add to the understanding and therapeusis of peptic ulcer in the future. REFERENCES 1. Oi, M., K. Oshida, and S. Sugimura. 1959. The location of gastric ulcers. Gastroenterology 36: 45-56. 2. Oi, M., and K. Oshida. 1959. The association of esophageal, gastric, and duodenal ulcers: case report. Gastroenterology 36: 57-59. 3. Oi, M., and Y. Sakurai. 1959. The location of duodenal ulcers. Gastroenterology 36: 60-64. 4. Oi, M., Y. Tanaka, K. Yoshida, and K. Yoshikawa. 1966. Dual control of peptic ulcers by both the gastric mucosa and musculature. Rev. Surg. 23: 373-374. 5. Oi, M., M. Kamiya, Y. Sakurai, and F. Kumagai. 1964. Reexamination of the histological determination of the border between fundic gland and pyloric gland areas in the human stomach. Jikei Med. J. 11: 52-65. 6. Oi, M., Y. Tanaka, K. Yoshida, K. Yanagisawa, Y. Sato, T . Yamanaka, K. Yoshikawa, and T. Koga. 1966. Pyloric function [in Japanese) Geka 28: 1326-1332. 7. Tanaka, Y., and K. Yanagisawa. 1963. The electromyography of the stomach and its clinical application. J. J. M . E. 1: 309-317.
G A STROE NTJ::R OL O G Y
Co py right© 1969 by The Willia m s & Wilkins Co.
A POSSIBLE DUAL CON~OL MECHANISM IN THE ORIGIN OF PEPTIC ULCER A study on ulcer location as affected by mucosa and musculature MINORU 01, M.D., YOJI ITO, M.D., FUMIYA KUMAGAI, M.D., KAN YOSHIDA, M.D., YosHIKI TANAKA, M.D. , KEIICHI YosHIKAWA, M .D . , 0TOMI MIHo, M .D. , AND MASAMURA KIJIMA, M.D.
Department of Surgery, Jikei University School of Medicine, Tokyo, Japan
In study I, 855 peptic ulcers were found in a group of 640 gastric specimens obtained surgically. The locations of these ulcers were observed in their relation to mucosae. It was found that nearly all ulcers were located adjacent to a mucosal boundary and, moreover, the ulcers were located on the side of the boundary opposite the fundic gland area. In study II, 269 ulcers were found in another group of 211 gastric specimens similarly obtained surgically. The locations of these ulcers were observed in their relation to musculature. It was found that nearly all ulcers were located within identifiable special muscular areas. In study III, by means of transparent cellophane overlays, the locations of the 269 ulcers of study II were observed in their relation to both musculature and mucosae. It was found that the locations of nearly all ulcers were seemingly affected or controlled by both mucosal boundaries and muscle bundles. This dual effect or influence of both the mucosae and musculature has been designated "dual control mechanism." Finally, by means of the concept of dual control mechanism an attempt speculatively has been made to explain the significance of the local pathogenic factor of peptic ulceration, a possible reason for the chronicity and single development of peptic ulcers, and the reason why gastric ulcers frequently appear at the gastric angulus of the lesser curvature of the stomach.
This paper presents what is considered to be a new hypothesis for the understanding of the local mechanism of peptic ulceration. Where peptic ulcers occur is felt to be of great significance when considering the cause of peptic ulcer. Previously, Oi and co-workers conducted histological studies concerning the locations Received July 11, 1968. Accepted March 17, 1969. A preliminary report of this work was p esented at the Third World Congress of Gastroenterology, Tokyo, Japan, held in September 1966. Address requests for reprints to: Dr. Minoru Oi, Director, Tokyo Welfare Pension Hospitai, 23 Tsukudo-cho, Shinjuku-Ku, Tokyo 162, Japan.
of peptic ulcers in relation to gastrointestinal mucosae. These studies indicated that generally ulcers were located near the boundary between types of mucosa. H In the present study, utilizing a greater number of gastric specimens, the locations of ulcers were again determined in relation to mucosae. In addition, using another group of gastric specimens, locations of ulcers were determined in relation to musculature! Results indicate that peptic ulcers tend to occur near the boundary between different mucosae, as well as at the points of intense kinetic strain, under the assumption that kinetic strain is intensified where certain special 280
September
1969
POSSIBLE DUAL CONTROL MECHANISM
muscle bundles are located. These facts suggest that peptic ulceration is controlled by some type of dual mechanism between the two principal structures, mucosa and musculature.
Materials and Methods Ulcer Location in Relation to Mucosae (Study[) Of 786 gastric specimens subjected to examination, 640 specimens contained ulcers and 146 specimens did not contain ulcers or other gross lesions, although they usually exhibited gastritis. An ulcer was defined as a chronic nonspecific mucosal defect which had penetrated the muscularis mucosae. All gastric specimens were obtained surgically. Of the 640 specimens containing ulcers, 366 ulcers were found in the stomach only, 236 ulcers were found in the duodenum only, 249 ulcers were found as cases of combined gastric (132 ulcers) and duodenal (117 ulcers) ulcers, and four ulcers were found in a case of combined esophageal (one ulcer), gastric (one ulcer), and duodenal (two ulcers) ulcers. A total of 855 ulcers were found. By site, there were 499 gastric ulcers, 355 duodenal ulcers, and one esophageal ulcer. Oi et al. 1 - 3 previously pointed out that ulcers were found usually at or near a mucosal boundary. In confirming this relation between ulcer location and mucosal boundaries, four mucosal boundaries were considered: the esophagocardiac, cardiofundic, fundopyloric (F-P), and pyloroduodenal (P-D) (fig. 1). As the first two are so close to each other, for practical purposes they were considered by the single name, the esophagogastric boundary. Procedures were similar to those previously ESOPHAGO · CARDIAC MUCOSAL BOUNDARY CARD\0 -FUNDIC MUCOSAL BOUNDARY FUNDIC GLAND AREA FUNDO -PYLORIC MUCO SAL BOUNDA RY
PYLORO DUODENAL MUCOSAL BOUNDARY
FIG . 1. Diagram showing terminology used for the various mucosae and mucosal boundaries observed in the present study.
281
reported.' ·" Gastric specimens were opened along the greater curvature, fastened to pasteboards with mucosal face upwards, and fixed with 10% formalin solution. After fixation, various strips were cut off in full thickness along the gastric axis in each specimen, and the strips were then cut into blocks for histological determination of mucosal boundaries. A life-size map or chart of each specimen was prepared, with the locations of ulcer(s), mucosal boundaries, and the pyloric ring (ridge of the pyloric sphincter) indicated. Standards were observed in designating a location of an ulcer. When there was a degree of width to the mucosal boundary as documented previously, 5 the boundary was determined as passing through the center of the width. When determining the distance of an ulcer from the mucosal boundary, the shortest distance between the edge of the uJcer and the nearby mucosal boundary was measured by inspecting the sections microscopically. For the purpose of this study, when an ulcer was within 2.0 em of mucosal boundary the ulcer was considered as "adjacent" ("proximal" in references 1 to 3) to the mucosal boundary, and when over 2.0 em from a mucosal boundary the ulcer was considered as "distant" ("distal" in references 1 to 3) from the mucosal boundary. Finally, distances were measured from the pyloric ring to ulcers and mucosal boundaries.
Ulcer Location in Relation to Musculature (Study II) Of 327 gastric specimens subjected to examination, 211 specimens contained ulcers and 116 specimens did not contain ulcers or other gross lesions, although they usually exhibited gastritis. These specimens were independent of those used in study I. All were obtained surgically, except eight which were from autopsy. Of the 211 specimens with ulcers, 128 ulcers were found in the stomach only, 86 ulcers were found in the duodenum only, and 55 ulcers were found as cases of combined gastric (30 ulcers) and duodenal (25 ulcers) ulcers. A total of 269 ulcers were found. By site, there were 158 gastric ulcers and 111 duodenal ulcers. Specimens were treated similarly to those used in study I up to the point of fixation; the mucosal layer was then separated from the muscle coat in each specimen by dissection through the submucosa, exposing the inner surface of the musculature . The gastric muscle coat consists of three layers of muscle bundles: the inner oblique, middle circular, and outer
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FIG. 2. Top left, the inner aspect of the muscle coat of the stomach opened along the greater curvature. Top right, schematic illustration of the oblique and circular muscle bundles of the gastric specimen shown at the top left. Bottom, the anterior and posterior medial oblique muscle bundles and the border circular muscle bundle especially freed for the purpose of demonstration.
longitudinal. Mter separating the mucosa from the muscle coat, the inner oblique and middle circular layers of the muscle coat are observable; the oblique muscle bundles, derived
from the circular bundles of the esophagus, extend downward in both anterior and posterior gastric walls, spreading out toward the greater curvature to disappear in gradual fu-
September 1969
283
POSSIBLE DUAL CONTROL MECHANISM
sion with the circular bundles of the body. In observing the oblique and circular bundles, four bundles were considered to be of special interest (fig. 2). For convenience they were named. The oblique muscle bundle which runs down the anterior wall nearest the lesser curvature was named the "anterior medial oblique" or AMO muscle bundle. The oblique muscle bundle which runs down the posterior wall nearest the lesser curvature was named the "posterior medial oblique" or PMO muscle bundle. The AMO and PMO muscle bundles lie symmetrically and fuse with a circular muscle bundle which can be considered as the boundary of the body and antrum of the musculature. This muscle bundle was given the name "border circular" or BC muscle bundle. Finally, since the thick circular muscle bundles at the pylorus form the pyloric sphincter, the bundle of the ridge of the sphincter was named the "pyloric circular" or PC muscle bundle. On the inner surface of the muscle coat an ulcer appears as a crater surrounded by cicatrization. In identifying the location of ulcers in relation to the musculature, the AMO, PMO, BC, and PC muscle bundles were used as "landmarks" ; and ulcers were macroscopically located in relation to them. A life-size transparent cellophane overlay was made for each musculature specimen, with locations of ulcer(s) and the muscle bundles as landmarks indicated. Distances from PC muscle bundles to BC muscle bundles were measured.
cers in the stomach only, 111 of the 132 gastric ulcers found in combination with duodenal ulcers, 234 of the 236 ulcers in the duodenum only, all of the 117 duodenal ulcers found in combination with gastric ulcers, and all of the four ulcers in the case of combined esophageal, gastric, and duodenal ulcers were adjacent to mucosal boundaries. By site, the one esophageal ulcer was adjacent to the esophagogastric mucosal boundary, 475 (95.2So) of the 499 gastric ulcers were adjacent to the F-P mucosal boundary, and 353 (99.4 %) of the 355 duodenal ulcers were adjacent to the P-D mucosal boundary. Thus, of the total 855 ulcers, 829 (97.0 %) were adjacent to mucosal boundaries (fig. 3). The average distance of these ulcers from their adjacent boundaries was 0.38 em. Furthermore, all ulcers adjacent to mucosal boundaries were located on the side of the boundary opposite the fundic gland area. Such ulcers were either free of, but still adjac~nt to, or in direct contact with the boundary itself; this was consistently noted, regardless of how high or low the muco5al boundaries were located (fig. 4). The varieties of gastric specimens with o
Ad j~c e n t Ulce r s
e
Di s tan t Ul ce rs
Ulcer Location in Relation to both Mucosae and Musculature (Study II[) This study was done using the 327 gastric specimens of study II. By the methods of study I, locations of ulcers were determined on mucosal layer specimens previously separated from the muscle coats. Thus, similar to study I, a life-size chart was developed for each specimen to show the relation of ulcer location to mucosae. Over these charts the transparent cellophane overlays of study II were superimposed. In a single visualization, then, the locations of ulcers were determined in relation to both mucosal boundaries and muscle bundles.
Results
Ulcer Location in Relation to Mucosae (Study l) Ulcers adjacent to mucosal boundaries. Three hundred sixty-three of the 366 ul-
t otal
829
( 97% )
855
26
(3% )
FIG. 3. Location of ulcers in relation to mucosae. Nearly all ulcers were adjacent to mucosal boundaries and on the side of the boundary opposite the fundi c gland area .
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FIG. 4. Locations of ulcers and mucosal boundaries are variable from specimen to specimen, but the relationships between ulcers and mucosal boundaries are consistent.
ulcers adjacent to mucosal boundaries are shown in the left half of figure 5. Ulcers distant from mucosal boundaries. Only 26 ulcers of the total 855, or 3.0%, were distant from mucosal boundaries. Of these, 21 appeared in the pyloric gland area distant from the F-P mucosal boundary, two appeared in the duodenal gland area distant from the P-D mucosal boundary, and three appeared in the fundic gland area distant from the F-P mucosal boundary. Concerning these ulcers which were distant from the mucosal boundaries and seemingly exceptions to the great majority, the following facts were noted: ulcers in the pyloric gland area and those in the duodenal gland area were all in combination with other duodenal ulcers adjacent to the P-D mucosal boundary; and one ulcer in the fundic gland area was in combination with another ulcer in the pyloric gland area adjacent to the F-P mucosal boundary. This relationship is shown in the right half of figure 5. Of the three ulcers in the fundic gland area distant from the F-P mucosal boundary, serial sections revealed that two had narrow mucosal portions of ectopic pyloric glands surrounding them. These two ulcers, then, actually occurred on pyloric gland islets in the fundic gland area. In the third case, the sections failed to show such ectopic pyloric glands in the environment of the ulcer; although in this case the ulcer was in combination with another
gastric (linear type) ulcer. The cases of these three ulcers in the fundic gland area are diagrammed in figure 6. Distances of ulcers and mucosal boundaries from the pyloric ring. Distances of gastric ulcers from the pyloric ring varied among individuals. Distances between F-P mucosal boundaries and pyloric rings were also variable, ranging on the lesser curvature, for example, from 0.2 to 17.0 em in specimens with ulcers and from 2.0 to 13.2 em in those without ulcers. In the case of duodenal ulcers, both the ulcers and the P-D mucosal boundaries were usually located just next to or on the pyloric ring (fig. 7).
Ulcer Location in Relation to Musculature (Study Il) Ulcers found in the stomach only. The 128 ulcers found in the stomach only consisted of 111 single ulcers, five cases of double ulcers, one case of triple ulcers, and one case of quadruple ulcers. In detail, locations of these ulcers were as follows: Of the 111 single ulcers, 2 were on the AMO muscle bundle; 16 were on the PMO muscle bundle; 46 were on the BC muscle bundle; six were on both the PMO and BC muscle bundles; 38 were inside the area formed by the AMO, PMO, and BC muscle bundles; and the three remaining ulcers were distal to the BC
September 1969
POSSIBLE DUAL CONTROL MECHANISM
muscle bundle or lateral to the AMO muscle bundle. Of the five double ulcers, four were cases of "kissing ulcers," and of these, one pair was at the junctions of the BC muscle bundle and the AMO and PMO muscle bundles, and the three other pairs were on the BC muscle bundle between these junctions. Concerning the fifth case of double ulcers, one ulcer was on the PMO muscle bundle and the other
Gastric Specimens with Ulcers
Adj ace nt to Mu cosa l Boundaries
Distant from Mucosal Boundaries
Ar ra ngement of Ulc ers
Ul ce r
St omac h
was lateral to it. With respect to the cases of triple and quadruple ulcers, all ulcers were on the BC muscle bundle lying between the AMO and PMO muscle bundles. It should be noted that, of the 128 ulcers found in the stomach only, 124, or 96.9%, were either on the AMO, PMO, or BC muscle bundles themselves, or were
Gas tri c Spe c imen s with Ul ce r s All Site of
Onl y
285
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Arrangement of Ulcers
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-
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25
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ulcer adjacent to mucos al boundary
e
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Numerals mean the number of specimens. FIG. 5. Gastric specimens tabulated by the relationship between ulcers and the mucosal boundaries. All of the distant ulcers are in combination with adjacent ulcers.
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OJ ET AL.
Cf@{) PYLORIC
GLANDS
CJ ULCER
FIG. 6. Cases of the three ulcers occurring in the fundic gland area distant from the fundopyloric mucosal boundary. In two cases (left and middle), tissues of ectopic glands were found surrounding the ulcer, and in the third case, (right) , no such tissue was found near the ulcer. In the third case, however, there was another gastric ulcer occurring in the pyloric gland area near the F-P mucosal boundary.
16 14 12
:
10
8
- MUCOSAL BOUNDARY ESOPHAGEAL ULCER • GASTRIC ULCER a DUODENAL ULCER
*
FIG. 7. Left, location of the F-P and P-D mucosal boundaries in 100 gastric specimens without ulcers selected at random. Middle, location of the F-P and P-D mucosal boundaries in 100 gastric specimens with gastric ulcers and 100 specimens with duodenal ulcers. Specimens were selected at random . Right, location of all of the 855 esophageal, gastric, and duodenal ulcers. It seems that location of gastric ulcers may be affected by the variableness in location of F-P mucosal boundaries which appears to be congenital, and that location of duodenal ulcers may be affected by the invariableness in location of P-D mucosal boundaries which appears also to be congenital.
inside the area (left diagram of Ulcers found The 86 ulcers
formed by these bundles fig. 8 and fig. 9). in the duodenum only. found in the duodenum
only consisted of 58 single ulcers, 11 double ulcers, and two triple ulcers. All ulcers were in the immediate vicinity of the PC muscle bundle, regardless of
September 1969
POSSIBLE DUAL CONTROL MECHANISM
whether they were on the anterior or posterior wall (middle diagram of fig. 8 and fig. 9). Combined gastric and duodenal ulcers. Gastric ulcers. The 30 gastric ulcers consisted of 16 single ulcers, four double ulcers, and two triple ulcers, and were generally found to be located similar to uncombined gastric ulcers. Of the 30 gastric ulcers, 24, or 80%, were found either on the AMO, PMO, or BC muscle bundles, or inside the area formed by these bundles; the other six (20 ~( ) were distal to the BC muscle bundle. Duodenal ulcers. The 25 duodenal ulcers consisted of 19 single ulcers and three double ulcers. All were found in the immediate vicinity of the PC muscle bundle (right diagram of fig. 8 and fig. 9). Muscular areas of special significance, zone G and zone D. When tabulating all of the 158 gastric ulcers by site, 148, or 93.7 ~( , were either on the AMO, PMO, or BC muscle bundles themselves, or were inside the particular area formed by these bundles. This area of special significance was named zone G. Of the total 111 duodenal ulcers, all appeared in the immediate vicinity of the PC muscle bundle; and this area of special significance
287
was named zone D. Over-all, 259 of 269 ulcers, or 96.3%, were found in the special areas (fig. 10) . Only 10 ulcers, or 3. 75(;, were not found in the areas of zone G and zone D. These 10 were gastric ulcers; of them, six occurred in combination with duodenal ulcers appearing in zone D, and one occurred in combination with another gastric ulcer appearing in zone G (fig. 10). Distance of the BC muscle bundle from the pyloric ring. ill the specimens examined, the distances between BC muscle bundles and pyloric rings varied, ranging on the lesser curvature, for example, from 0.2 to 9.4 em in specimens with gastric ulcers, and from 4.3 to 9.2 em in those without ulcers.
Ulcer Location in Relation to both Mucosae and Musculature (Study II[) Ulcer location in relation to mucosal boundaries and special muscular areas. Of the 158 gastric ulcers, 145, or 91.8%, were located adjacent to and on the nonfundic side of the F-P mucosal boundary and simultaneously in zone G. Of the 13 ulcers not so located, seven were either distant from the F-P mucosal boundary but within zone G, or were adjacent to
FIG. 8. A circle shows shape as well as location of an ulcer found on the musculature. Left, 64 ulcers, single or multiple, of the stomach only which were found in 60 specimens selected at random. Middle, 56 ulcers, single or multiple, of the duodenum only which were found in 50 gastric specimens selected at ran· dom. Right, all of the combined gastric (30) and duodenal (25) ulcers. Numbers of specimens or ulcers had to be reduced to keep illustration of ulcer shape clear.
288
Vol. 57, No . 3
OJ ET AL .
loric glands, similar to such ulcers diagramed in study I. Only six ulcers were neither adjacent to the F-P mucosal boundary nor in zone G. All 111 duodenal ulcers were found in the duodenal gland area adjacent to the P-D mucosal boundary and in zone D. Thus, over-all, 256 of 269 ulcers, or 95.2%, were located adjacent to a mucosal boundary, and more specifically on the side of the boundary opposite the fundic gland area, as well as in one of the special muscular areas, zone G or zoneD (fig. 11). Relationship between F-P mucosal boundary and BC muscle bundle. Distances from the pyloric ring to both the F-P mucosal boundary and the BC muscle bundle varied as observed in studies I and II. Similarly, the distances between F-P mucosal boundaries and BC muscle bundles varied. An examination of the relationship between the F-P mucosal boundary and the BC muscle bundle revealed two major types of relationships: in one situation, the F-P mucosal boundary and the BC muscle bundle did not cross each other and in the other situation, they did cross each other. Further exam}nation disclosed that these situa. tions had subtypes; six such subtypes ~ul ce r s
in Special Area
• Ulcers outsid Special Area
3
148 7 FIG . 9. Samples of various musculature specimens with ulcers. The white lines indicate AMO, PMO, BC , and PC muscle bundles and the white circles indicate ulcer craters.
Ill total
the F-P mucosal boundary but not in zone G. Among these seven were two special ulcers which at first appeared in the fundic gland area outside zone G, but on histological examination were found to have developed on islets of ectopic py-
259 ( 96.3 °6)
269
10 ( 3. 7 % )
FIG. 10. Location of ulcers in relation to the musculature. Nearly all ulcers were found in special muscular areas.
September 1969
Gastric Specimens with Ulcers
Gastric Specimens with Ulcers
Distant from Mucosal
Adjacent to Mucosal Boundaries
Boundaries and /or Outside
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Site of Ulcer
Areas
Arrangement of U leers
Arrangement of Ulcers
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289
POSSIBLE DUAL CONTROL MECHANISM
3
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e
ulcer distant from mucosal boundary and on special muscular area ulcer distant from mucosal boundary and outside special muscular area
Numerals mean the number of specimens. FIG. 11. Gastric specimens tabulated by the relation of ulcers to both the mucosal boundaries and the special muscular areas.
were identified among the specimens examined (table 1). Gastric specimens were tabulated by the relationship between the F-P mucosal
boundary and the BC muscle bundle. Of the specimens without ulcers, 48So were of the "no crossing" type; and of the specimens with duodenal ulcers only, 64.8S(
290
OJ ET AL . TABLE
Vol. 57, No. 3
1. Relationship between fundopy loric mucosal boundary and border circular m uscle bundle No. of Gastric Specime ns
~ ~
II
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,
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(27)
TABLE 2.
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:!:)
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(45.1-i)
'il (47)
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(34 .7)
I ( 1)
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with both Gastric and Duode nal Ulcers
.,l l l· l
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with Gastric Ulcers
without Ulcers
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Relation between pyloroduodenal mucosal boundary and pyloric circular muscle bundle \ n. uf Gas tric Spec imens
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111
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with Gastri c
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l:lcer
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with DuOOenal nct:r
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ll
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(15.5)
(15.1)
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62
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7
6
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84
73
14
39
2
9
September 1969
POSSIBLE DUAL CONTROL MECHANISM
were of the no crossing type. Of gastric specimens with gastric ulcers, however, all but one were of the crossing type; and the ulcer of the one specimen which was of the no crossing type was one of the special ulcers previously mentioned, i.e., a gastric ulcer occurring on an islet of ectopic puloric glands in the fundic gland area. Relationship between P-D mucosal boundary and PC muscle bundle. The P-D mucosal boundary and the PC muscle bundle were not so variable in location as were the F-P mucosal boundary and BC muscle bundle described above. ill most instances, the P-D mucosal boundary and the PC muscle bundle were approximately rectilinear and parallel to each other when observed in specimens opened flat. Four types of relationships, however, were observed: the P-D mucosal boundary was situated either (1) proximal to, (2) on, (3) distal to, or (4) across the PC muscle bundle. A tabulation of gastric specimens by these relationships was made, but no particular trends were found (table 2). Discussion
Relationship between Ulcer Location and Mucosae Study I revealed that nearly all ulcers of the stomach were adjacent to the F-P mucosal boundary, and furthermore, were located on the side of the boundary opposite the fundic gland area, i.e., in the pyloric gland area. Study I also revealed that nearly all ulcers of the duodenum were adjacent to the P-D mucosal boundary, occurring in the duodenal gland area, and that the one esophageal ulcer was also adjacent to the esophogogastric mucosal boundary, occurring in the esophageal mucosa. The common feature of these findings was that most ulcers occur adjacent to the boundary between different mucosae, and on the side of the boundary opposite the fundic gland area or acidsecreting area. Concerning the percentage of the entire stomach taken up by the area in which most ulcers tend to occur, that area 2 em adjacent to the F-P mu-
291
cosal boundary, a separate study was made utilizing five whole stomach specimens from autopsy, and it was found on the average to be about 5%. If the mucosal folds especially prominent in the fundic gland area are considered, this percentage is even lower. Of the small number of ulcers which seemingly were exceptions to this common pattern, most occurred in combination with other gastric or duodenal ulcers which did conform. ill this regard, two single ulcers which occurred within the fundic gland area are of special significance. While at first they appeared to be "nonconformers" to the common pattern, upon histological examination they were found to have occurred on islets of ectopic pyloric glands; thus they also conformed to the common pattern. ill fact, such ulcers give strength to the common pattern, and it appears that the location of peptic ulcers is really controlled by the arrangement of mucosae. Study I showed that the vast majority of ulcers occur in a nonfundic gland mucosal area at a point nearest the acidsecreting area. Therefore, it is felt that ulcers may occur in a nonfundic gland area where acid gastric juice exerts its strongest action, and that, if so, such consideration tends to confirm the belief that peptic ulcers are caused by gastric juice. Examination of specimens, with or without ulcers, showed that from specimen to specimen the distance between the F-P mucosal boundary and the pyloric ring varies. Conversely, the distance between the P-D mucosal boundary and the pyloric ring was found to be generally invariable. Since most ulcers occur adjacent to these mucosal boundaries, gastric ulcers may be said to be variably located within the stomach with respect to the pyloric ring, and duodenal ulcers may be said to be invariably located within the duodenum with respect to the pyloric ring.
Relationship between Ulcer Location and Muscle Bundles Study II revealed that nearly all ulcers of the stomach were located in the
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area formed by the AMO, PMO, and BC muscle bundles, namely, zone G, and that all ulcers of the duodenum were located in the immediate vicinity of the PC muscle bundle, namely, zone D. These facts indicate that the occurrence of peptic ulcers may be influenced by the motility of the muscle of the stomach. Zone G is a part of the musculature which lacks oblique muscle bundles and which exists only at the narrow lesser curvature of the corpus of the stomach. The average size of zone G in relation to the size of entire stomach was about 11 % when studied in five whole stomach specimens from autopsy. Zone D is a part of the musculature where the bulk of the pyloric sphincter is abruptly lost distally and where connection between pyloric sphincter and a layer of the duodenal circular muscle bundles is interrupted by an interposition of connective tissue." Upon morphological observation, zone G and zone D have the common feature of being bordered with a thick portion of muscle coat. Therefore, with varying thicknesses in the muscle coat it is likely that there is an intensification of local kinetic strain in these areas. In an electromyographic examination of the stomach, action potential begins at the midportion of the stomach body and proceeds distally.' During this process, intensity of the action potential is seen to increase rather sharply at the BC muscle bundle and to continue to increase gradually, until it reaches the pylorus where the active gastric pattern of the action potential ceases suddenly and is no longer conducted to the duodenum.' Therefore physiological studies of gastric musculature, such as electromyographic examinations, generally seem to support the forementioned morphological interpretations. Zone G and zone D, in relation to the rest of the musculature, might be identified as areas of severe kinetic strain, in which case it may be said as a speculative possibility that peptic ulcers occur where kinetic strain due to gastric motility is great. Indeed, zone G and zone D may be called the "upper strain zone" and the "lower strain zone" respectively.
Vol. 57, No. 3
Dual Control Mechanism From results of studies I and II, it was found that ulcer location is believed influenced or controlled by both mucosae and musculature. Although it is uncertain whether these influences or controls are dependent of each other, valuable information with respect to this question is provided by study III, where transparent charts of the musculature were superimposed over those of the mucosae to provide specimen inspection in a single visualization. In study III, it was found that the locations of 95.2% of the ulcers examined conformed to or were affected by both mucosal and muscular controls. Especially significant in this regard are cases of gastric ulcers in which nearly all gastric ulcers occurred only in situations where the F-P mucosal boundary and the BC muscle bundle crossed. In these situations, both mucosal and muscular controls are coexistent at the ulcer site. Conversely, in those situations where the F-P mucosal boundary did not cross the BC muscle bundle, which was roughly half the time, there was only one gastric ulcer case, and this was an explainable, exceptional case. It is believed to be likely, then, that for the development of peptic ulceration, both mucosal and muscular controls must coexist at the site of the ulcer, and this principle has been named the "dual control mechanism." The occurrence of an ulcer means, therefore, that an anatomic relationship of the dual control mechanism probably exists, and that such an anatomic relationship or existence is permanent, unless artificially altered or removed. This may explain why peptic ulcers tend to become chronic, recurrent, or clinically intractable. It should also be noted that the focus where the dual control mechanism is effective is usually very small or narrow in comparison with the entire stomach or duodenum. This may explain why peptic ulcers are more likely to occur singly rather than multiply. In this respect, the gastric ulcer has been known to occur along the lesser curvature at the level of the gastric angulus, and this is probably
September 1969
POSSIBLE DUAL CONTROL MECHANISM
because the effective focus of the dual control mechanism for gastric ulcers is usually formed at or near the angulus which is part of the lesser curvature. Since this focus for gastric ulcers lies at varying distances from the pyloric ring, and for duodenal ulcers lies at a constant distance from the pyloric ring, this may explain the reason for the scattering of gastric ulcers in the stomach and the localizing of duodenal ulcers in the duodenum. It can be said that according to this principle, the development of a gastric ulcer is not always anatomically possible, regardless of whether or not systemic factors favorable for causing peptic ulcers are present, whereas the development of a duodenal ulcer is always anatomically possible. With this explanation, the meaning of such phrases as "ulcer diathesis" or "ulcer disposition" is perhaps somewhat clarified. Although the location, and indeed the existence, of an ulcer is believed affected by this dual control mechanism, this does not of course preclude the possibility that other factors contribute their influences
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to the cause of peptic ulceration. It is believed that the results of these studies will add to the understanding and therapeusis of peptic ulcer in the future. REFERENCES 1. Oi, M., K. Oshida, and S. Sugimura. 1959. The location of gastric ulcers. Gastroenterology 36: 45-56. 2. Oi, M., and K. Oshida. 1959. The association of esophageal, gastric, and duodenal ulcers: case report. Gastroenterology 36: 57-59. 3. Oi, M., and Y. Sakurai. 1959. The location of duodenal ulcers. Gastroenterology 36: 60-64. 4. Oi, M., Y. Tanaka, K. Yoshida, and K. Yoshikawa. 1966. Dual control of peptic ulcers by both the gastric mucosa and musculature. Rev. Surg. 23: 373-374. 5. Oi, M., M. Kamiya, Y. Sakurai, and F. Kumagai. 1964. Reexamination of the histological determination of the border between fundic gland and pyloric gland areas in the human stomach. Jikei Med. J. 11: 52-65. 6. Oi, M., Y. Tanaka, K. Yoshida, K. Yanagisawa, Y. Sato, T . Yamanaka, K. Yoshikawa, and T. Koga. 1966. Pyloric function [in Japanese) Geka 28: 1326-1332. 7. Tanaka, Y., and K. Yanagisawa. 1963. The electromyography of the stomach and its clinical application. J. J. M . E. 1: 309-317.