GastroenterologiaJaponica Copyright 9 1976 by The Japanese Societyof Gastroenterolog~

Vol. 11, No. 4 Printed in Japan

--Original Article--

GASTRIC CARCINOMA COMBINED WITH DISTANT GASTRIC ULCER Hiroshi Y A M A G I W A , M.D., Akinori I S H I H A R A , M.D., M i n o r u H A M A Z A K I , M.D., T s u t o m u S E K O G U C H I , M.D., and O s a m u M A T S U Z A K I , M.D.

Department of Clinical Pathology, Faculty of Medicine, Mie University, Tsu, Japan Summary The cases of the gastric carcinoma combined with distant benign gastric ulcer were 90 of 1257, 7.1%, and the carcinomas were frequently found in the lesser curvature of the antrum and the combined gastric ulcers frequently in the lesser curvature and posterior wall of the corpus. Average age in the combined cases was 58.8 which was older about 7 years than that in the cases of the gastric ulcer. The cases, in which the ulceration in the gastric ulcer was same or deeper than that in the gastric carcinoma, occupied about 70% of these combined cases. It should be considered that the malignant transformation does not always occur in the preceding ulcerative lesion. However, the intestinal metaplasia was usually severe, and so the welldifferentiated carcinomas were twice frequent to the low-differentiated ones. The repeated regeneration of the epithelial cells associated with the erosive or ulcerative change may be of some relation to the carcinogenesis, because the intestinal metaplasia appears usually associated with the repeated defect and repair of the propria mucosae. Key Words:

gastric carcinoma, gastric ulcer, ulcer carcinoma, malignant transformation of gastric ulcer.

Although the possibility and frequency for the malignant transformation u p o n the margin of the benign gastric ulcer have been studied since Hauser's report, in 19261), the answer to these problems has not given yet untill now. However, the majority of investigators have reported for the frequency of the ulcer carc i n o m a about 1 to 10% in these 5 years, in Japan. I n the present paper, the cases of the gastric carcinoma combined with distant benign gastric ulcer were collected and studied by statistic and pathologic methods to elucidate the relationship of the carcinoma and ulcer. Materials and Methods T h e investigated stomachs were 1257, 2367 and 853 cases with gastric carcinoma, gastric ulcer and duodenal ulcer, respectively. T h e c o m b i n e d cases of gastric carcinoma and

distant gastric ulcer were studied on the age distribution, microscopic appearance, site, depth of the ulceration, n u m b e r of the gastric ulcer, grade of the intestinal metaplasia and acidity of the gastric juice. Macroscopically, the advanced carcinomas and early ones were classified according to B o r r m a n n ' s classification 2) and criteria of J a p a n Gastroenterological Endoscopy Society, respectively. Histological examination was performed by the staining methods of Hematoxylin-Eosin, Azan-Mallory, Van-Gieson, Silver, PAS and Alcian-blue. T h e intestinal metaplasia was divided into four grades, i.e. no, mild, moderate and m a r k e d according to the distribution in the stomach. T h e depth of the ulcer was also classified according to the intramucosal, submucosal, muscular and subserosal defects, like as ul.I, II, I I I and IV, respectively. T h e carcinomas were classified into two types,

314

Vol. 11, No. 4

H. Y A M A G I W A E T A L .

i.e. l o w - d i f f e r e n t i a t e d type showing a d e n o carcinoma tubulare, adenocarcinorna tubulare m u c o c e l l u l a r e or signet ring cell c a r c i n o m a , a n d w e l l - d i f f e r e n t i a t e d one showing a d e n o c a r c i n o m a p a p i l l a r e or p a p i l l o t u b u l a r e . Results

1) T h e cases of the gastric c a r c i n o m a c o m b i n e d w i t h d i s t a n t gastric ulcer were found in 90 o f 1257, 7.1~o a n d those with d u o d e n a l ulcer in 22 o f 1757, 1.7~ . T h e analysis of the cases o f gastric c a r c i n o m a c o m b i n e d with d i s t a n t gastric ulcer were shown in the T a b l e 1 ( T a b l e 1). 2) Age d i s t r i b u t i o n a n d microscopic a p p e a r a n c e in the cases o f the gastric c a r c i n o m a

T a b l e 1. Analysis of the cases of the gastric carcinoma

combined with distant benign gastric ulcer Gastric ulcer+Gastric carcinoma 72 Duodenal ulcer+Gastric ulcer+Gastric carcinoma 7 Duodenal ulcer+Adenoma+Gastric ulcer+Gastric carcinoma 1 Adenoma+Gastric ulcer+Gastric carcinoma 3 Regenerative hyperplastic polyp+Gastric ulcer+ Gastric carcinoma 4 Aberrant pancreas+Gastric carcinoma+Gastric ulcer 3 Total cases 90

c o m b i n e d w i t h d i s t a n t gastric ulcer: A v e r a g e age was 58.8 a n d m a l e to female r a t i o 8 to 1 in the c o m b i n e d cases. M a c r o s c o p i c a l l y , Borrmann Ill, IIc+III, Borrmann II and I I c type c a r c i n o m a s o c c u p i e d the m a j o r i t y in these c o m b i n e d cases ( T a b l e 2). M i c r o scopically, the r a t i o of well-differentiated c a r c i n o m a to l o w - d i f f e r e n t i a t e d one was a b o u t 2 to 1. T h e a v e r a g e age was 32.9, 47.8, 52.1, 50.4 a n d 61.3 in the cases of d u o d e n a l ulcer, g a s t r o d u o d e n a l ulcer, gastric ulcer, lowdifferentiated c a r c i n o m a a n d well-different i a t e d c a r c i n o m a , respectively. 3) Sites o f the gastric c a r c i n o m a a n d gastric ulcer in the c o m b i n e d cases: T h e gastric c a r c i n o m a s were frequently f o u n d in the lesser c u r v a t u r e of the a n t r u m a n d the c o m b i n e d gastric ulcers f r e q u e n t l y in the lesser c u r v a t u r e a n d posterior wall o f the corpus ( T a b l e 3, 4, P h o t o . 1). 4) D e p t h of the m c e r a t i o n in the gastric c a r c i n o m a a n d gastric ulcer in the c o m b i n e d cases: T h e d e p t h of the u l c e r a t i o n in the gastric c a r c i n o m a was d i v i d e d a c c o r d i n g to the classification of the benign ulcer. I n the carcinomas, the ulcerations of u l . I V were frequent in the lesions of B o r r m a n n t y p e I I , a n d those of u l . I I a n d I I I in the B o r r m a n n

Table 2. Age distribution and microscopic appearance in the cases of gastric carcinama combined with distant gastric ulcer

Macro. of carcinoma Borrmann II III IV IIc IIc + I I I IIa + IIc IIa IIa + I I I Total cases (female)

Age 20-29 30-39 40-49

50-59

1

6

15(1)

1

1

2

5(1)

2

3 1 2

7(2) 3 2

4(1)

60-69

70-79

4(1)

5(1)

10

5(1)

unover 80 known 1 1

1

1 1 1

3

9

27(2)

32(4)

13(2) 24 1 3

4(2)

1 1

Micro. of carcinoma lowwelldiff. diff.

15(4)

1

2

1(1) 15(2) 6(1)

10(1) 4 5 1

7(2)

61 (3)

29(7)

December 1976

Combination of Gastric Carcinoma and Ulcer

T a b l e 3.

--~.... ---~_

Sites of gastric carcinoma and gastric ulcer in the combined cases

Macro. of gastric carcinoma

Advanced carcinoma Borrmann type

Sits

I

lower

315

a.w. 1/3 1.c. p.w. g.c.

I[

III

8(2) 2 4(1)

9 7 5(1)

a.w. Sites of carcinoma middle 1/3 1.c. p.w. (lesions) g.c.

IV

6 6 1 3(1)

Early carcinoma lIc§ IIa+ IIa-+IIc

III

1 2(1)

3 5(1)

1

1

3 1

1(1) 2(1) 2 2(1)

IIc

IIa

2 1 1

2 2

III

Total (female) 6 29(4) 12 11(2) 7(1) 12(1) 4 5(2)

a.w.

upper 1/3 1.c. p.w.

1 1

1

1

g.c.

1

a.w.

lower

1/3 1.c.

1

1

4(1)

3

1

9(1) 1

p.w.

g.c. g.c. a.w.

middle 1/3 1.e. Sites of ulcer (lesions)

3(1) 9(1)

p.W. g.c.

kissing a.w.

4 19 7 1

2 8(2) 6(2) 1

4

1

6(1) 4

3 2

2

2

2

7

1

upper 1/3 I.e.

4

1

1

p.w.

9(1) 46(5) 21(2) 2 1 6(1) 2

1(1) 1

g.c,

kissing 1

Number of gastric ulcer (cases)

2 3 4

1(1)

1(1) 14(2) I (1)

31(2) 7

1

6(1) 3

11(3) 3(1) 2

3 1

3 2

I

70(8) 17(2) 2 1

t y p e I I I a n d I I c + I I I . T h e d e p t h of the c o m b i n e d gastric ulcer was f r e q u e n t i n u l . I I I a n d g r a d u a l l y d e c r e a s e d i n u l . I I to u l . I V .

u s u a l l y m o d e r a t e to m a r k e d i n these c o m b i n e d

The

the w e l l - d i f f e r e n t i a t e d ones ( T a b l e

cases, i n w h i c h the u l c e r a t i o n s i n the

gastric ulcers were s a m e to or d e e p e r t h a n those i n the c o m b i n e d gastric c a r c i n o m a s , o c c u p i e d a b o u t 7 0 % i n the c o m b i n e d cases ( T a b l e 5). 5) G r a d e of the i n t e s t i n a l m e t a p l a s i a i n the cases of the gastric c a r c i n o m a c o m b i n e d w i t h d i s t a n t gastric u l c e r : A l t h o u g h the g r a d e s of the i n t e s t i n a l m e t a p l a s i a were

cases, t h e y were u s u a l l y m i l d i n the lowd i f f e r e n t i a t e d type c a r c i n o m a s a n d severe i n 6).

6) A c i d i t y i n the cases of the gastric c a r c i n o m a c o m b i n e d w i t h d i s t a n t gastric u l c e r : T h e cases s h o w i n g n o r m a l or h y p e r a c i d i t y o f gastric j u i c e were r e l a t i v e l y f r e q u e n t i n the l o w - d i f f e r e n t i a t e d c a r c i n o m a s a n d those s h o w i n g a n a c i d i t y or h y p o a c i d i t y i n the welld i f f e r e n t i a t e d ones b e c a u s e o f the m i l d intes-

316

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H. Y A M A G I W A E T A L .

Table

Sites of gastric carcinoma a n d distant gastric ulcer in the combined cases

4.

Sites of carcinoma (case n u m b e r of carcinoma) lower

1/3

a.w. (6) 1.c. (29 )

1 1

g,c. (11) middle 1/3

1.c. p.w.

g.c.

(7) 12) (4) (5)

3

6

p.w. (12) a.w.

Sites cf gastric ulcer middle 1/3 a . p . w . a . w . 1.c. p.w. g.c.

lower 1/3 a.w. 1.c. p.w.

a.w.

upper 1/3 1.c. p.w. a.p.w.

2

4

3

17

1

2

1

1

1

3 8

3 1

2

1

1 3

3 8 1 1

4 4 1 4

1

2

1

1

1 1

2

1 1

a.W.

upper

1/3

1.c. p.e. g.c.

(3) (1)

Total

1

1

1 1

9

1

7

1 9

46

21

2

1

6

2

1

106 a.w.: anterior wall, 1.c.: lesser curvature, p.w.: posterior wall, g.c.: greater curvature, a.p.w.: kissing ulcer in anterior and posterior wall.

P h o t o . 1. B o r r m a n n I l I type carcinoma a n d ulcer scar. C: carcinoma, U : ulcer. T a b l e 5.

ulcer scar a n d

Ilc

Relation of depth of ulcerations in gastric carcinoma a n d gastric ulcer in the combined cases

D e p t h of ulceration in carcinoma (case n u m b e r of carcinoma) U1. II U1. III U1. I V No ulceration Total

P h o t o . 2. Linear carcinoma.

(26) (25) (20) (19)

D e p t h of benign gastric ulcer U1. II U1. III U1. IV

Total ( n u m b e r of lesion of ulcer)

8 11 7 10

17 12 8 10

7 8 10 6

32 31 25 26

36

47

31

114

type early

December 1976

Combination of Gastric Carcinoma and Ulcer

Table

6.

317

Grade of intestinal metaplasia in the cases of gastric carcinoma combined with distant gastric ulcer

Macro. of carcinoma

Grade of intestinal metaplasia slight mild moderate

no

Borrmann II IlI IV IIc IIc + l I I IIa + IIc IIa IIa + I I I Total cases

2(1)

6(1)

1(1)

3(1) 4(1)

3(1) 4

severe

Total (female)

10(2) 27

14(3) 39(2)

1

1

(female)

3(2)

Table

2

Total

- i3(3)

8(1~

9(1) 17(4)

3

4

5

5

1

1

64(4)

90(10)

Gastric carcinomas combined other gastric diseases

7.

30 39 Adenoma+ Carcinoma Aberrant pancreas + Carcinoma Regenerative hyperplastic polyp + Carcinoma Leiomyoma + Carcinoma Eosinophilic granuloma+ Glomus tumor+Carcinoma Duodenal ulcer + Carcinoma

1

5 12(2)

40 49

50-59

1

3

60 69 12(1)

1

70-79

un80 89 known

4

Total (female)

1

2 8(4)

5(1)

2 ( 1)

3 3(1) I(1)

2

18(6) 3(2)

1

1 1

1

1

3 ( 1)

6(1)

3

7(2)

17(5)

22(2)

21(I)

2 11(2)

14(2) 2

Stromeyer 19~,

the latter in the m a j o r i t y of each series.

Stout 16) stated in the old literatures on the

7) T h e cases of the gastric c a r c i n o m a comb i n e d with distant a d e n o m a t o u s polyp, re-

ulcer c a r c i n o m a that the ulceration occurs i n

generative hyperplastic polyp, non-epithelial

ical investigations like as roentgenologic a n d

tumor, a b e r r a n t pancreas tissue etc. d e m o n s t r a t e d in the table ( T a b l e 7).

endoscopic methods for the gastric diseases have been explored to discover very small carcinomas, especially i n Japan8, 9~. T h e n c e ,

Discussion

I t has been one of the most i m p o r t a n t problems whether the m a l i g n a n t transformation of the b e n i g n gastric ulcer occurs or not ~19~. It has been the reason that there has been no definite histological feature on the secondary m a l i g n a n t t r a n s f o r m a t i o n from the b e n i g n gastric ulcer. However, M a l l o r y 17~,

the carcinomatous tissue.

M a r s h a l 15)

61(11)

tinal metaplasia in the former a n d severe i n

were

Grimes ~4~,

1

and

Recently, the clin-

it has been cleared that the c a r c i n o m a t o u s lesions show a t e n d e n c y to ulcerate more easily t h a n the n o r m a l tissue a n d the defect a n d r e g e n e r a t i o n in the t u m o r tissue are repeated not infrequently4-7,1~ For example, the resected gastric carcinomas have u l c e r a t i o n at rate of 80% or over in the a d v a n c e d cases, a n d the d e p t h of the ulceration

318

H. Y A M A G I W A E T A L .

shows a tendency to progress parallel with the size of the tumor 1~176 Murakami n a m e d "malignant cycle" on the phenomenon of these repeated defect and regeneration of the tumor tissue in the gastric carcinoma 8~. Although a number of studies on the secondary malignant transformation of the benign gastric ulcer by the histopathologic methods for the resected stomachs have been reported, any accurate data have not been known untill now because of the difficulty to prove the kinetic malignant transformation from the benign ulcer on the each cases. I f the carcinomas localized upon the margin of the chronic gastric ulcers with the depth of ul.IV might be the secondary malignant transformation from the benign ulcer l~, the frequency of the ulcer carcinoma occupy about 1 to 80% and 0.15 to 3.75% of gastric carcinomas and gastric ulcers, respectively 413~. The other hand, the detailed pathological study on the combination of gastric carcinoma and gastric ulcer has not been reported in the literatures 21~. However, the study on the combined cases m a y contribute toward the investigation of the malignant transformation of the benign gastric ulcer for the reasons as follows. As the cases, in which the ulceration in the benign gastric ulcer was same to or deeper than that in the carcinoma, were about 70%, and the average age was older about 7 years than that of benign gastric ulcer, in the cases of the gastric carcinoma combined with gastric ulcer, it should be considered that the malignant transformation does not always occur in the preceding ulcerative lesion. It has been cleared on the histopathogenesis of the gastric carcinoma that the well-differentiated carcinoma has intimate relationship to the intestinal metaplasia and the low-differentiated one occurs usually from the nonmetaplastic mucosae2~ The well-differentiated carcinomas occur frequently in the

Vol. 11, No. 4

pyloric gland area or lower area of the lesser curvature and posterior wall, and the other hand, the low-differentiated ones in the fundic gland area or middle area of the lesser curvature and posterior wall. Accordingly, the lesions of well-differentiated carcinoma were usually found in the anal site than those of gastric ulcer, and the lesions of low-differentiated carcinoma not infrequently in the oral site or pararell to those of the combined gastric ulcer. The macroscopic appearances of the gastric carcinoma showed frequently Borrmann I I I and concaved type of early gastric carcinoma, i.e. I I c + I I I or IIc. The 61% of the combined gastric ulcer were on the healing stage or scar, and the combined ulcers were found frequently in the lesser curvature and posterior wall of the middle third. Namely, in these combined cases of gastric carcinoma and gastric ulcer, two or more ulcerative lesions were found by the X ray examination, and the anal lesions were usually malignant in our cases (82%). About 30% of the resected cases of benign gastric ulcer were multiple, however, 7.1% of the cases of gastric carcinoma combined benign gastric ulcer. Although the incidence of the combination of these two lesions is low, it should be considered that the multiple ulcerative lesions do not always mean benign. While, the combined cases of gastric carcinoma and duodenal ulcer were found at rate of about 1.7% in the cases with gastric carcinoma. In these combined cases, the carcinomas were usually low-differentiated type, and the intestinal metaplasia was also usually mild. The mucosal damage like as the intestinal metaplasia was usually rather slight or mild in the cases of the duodenal ulcer than that found in those of the gastric ulcer. As the intestinal metaplasia was usually severe in the combined cases o1" the gastric carcinoma and gastric ulcer, the well-differentiated carcinomas were twice frequent to the

Combinationof GastricCarcinomaand Ulcer

December 1976

low-differentiated ones, a n d the ratio of the former to the latter was higher t h a n that of 3 to 2 in the total gastric carcinomas. T h e repeated r e g e n e r a t i o n of the epithelial cells m a y be of some relation to the carcinogenesis, because the intestinal m e t a p l a s i a appears usually associated with the repeated defect a n d repair of the propria mucosae 22). Probably, the repeated mucosal d a m a g e m a y cause the r e d u c t i o n of control activity to develop the n o r m a l epithelial differentiation. T h e acidity in the c o m b i n e d cases h a d i n t i m a t e relationship with the grades of the intestinal metaplasia like as low a n d high i n the severe a n d slight cases, respectively. N a m e l y , the cases with the low-differentiated c a r c i n o m a showed n o r m a l or high acidity more frequently t h a n those with the well-differentiated one, a n d these findings were a l r e a d y Stromeyer 19), Palmer ]8), e t c . .

reported

by

Acknowledgment A p a r t of this study was presented at the 34 A n n u a l M e e t i n g of the J a p a n e s e C a n c e r Association in Osaka, 1975. A p a r t of this study was supported by a G r a n t - i n - A i d for C a n c e r Research from the M i n i s t r y of E d u c a t i o n , Science a n d Culture, Japan.

References 1) Hauser, G.: Handb. spez. path. Anat. Histol. Henke-Lubarsch, IV/l, Julius Springer, Berlin, 497-518, 1926. 2) Borrmann, R.: Henke-Lubarsch, Handb. spez. path. Anat. Histol. IV, Berlin, 1926. 3) Kuru, M.: On the cancers developed upon ulcerative lesions of the stomach. Gann, 44: 47-54, 1953. 4) Oota, K." On the nature of the ulcerative changes in early carcinoma of the stomach. Gann Monogr., 3: 141-151, 1968. 5) Sugano, H. and Nakamura, K.: Frequency of the

319

ulcer cancer in early gastric cancer, 3: 133-137, 1968. 6) Imai, T.: Analysis of the ulcer cancer. Igaku no Ayumi, 62: 471-474, 1967. 7) Nagayo, T. and Yokoyama, H.: Ulcer cancer of the stomach. Igaku no Ayumi, 96: 20-21, 1976. 8) Murakami, T.: New concept of the ulcer cancer. Juntendo Igaku, 13: 157-161, 1967. 9) Okabe, H.: Analysis of the gastric carcinoma found in the follow-up observation of gastric ulcer, 3: 705-710, 1968. 10) Nakamura, K.: Causality of ulcer an cancer of the stomach. Stomach and Intestine, 6: 145-150, 1971. 11) Majima, S.: Clinical and experimental study on the malignant transformation of the gastric ulcer. Stomach and Intestine, 3: 685-690, 1968. 12) Enjoji, M.: Histopathologic study on the early gastric carcinoms, 7: 96-99, 1961. 13) Newcomb, W.D.: The relationship between peptic ulcer and gastric ulcer. Brit. J. Med., 20: 279-284, 1932. 14) Grimes, O.F. and Bell, H.G.: Clinical and pathologic studies of benign and malignant gastric ulcer. Surg. Gynec. Obstet., 90:359 364, 1956. 15) Marshal, S.F.: The relation of gastric ulcer to carcinoma of the stomach. Ann. Surg., 137: 891895, 1953. 16) Stout, A.P.: The relation of gastric ulcer to gastric carcinoma. Cancer, 3" 515 520, 1950. 17) Mallory, T.B.: Carc inoma in situ of the stomach and its bearing on the histogenesis of malignant ulcers. Arch. Path., 30: 348-352, 1940. 18) Palmer, W.L. and Humphrey, E.M.: Gastric carcinoma; observation on peptic ulceration and healing. Gastroent., 3: 257-261. 19) Stromeyer, F.: Die Pathogenese des Ulcus ventriculi, zugleich en Beitr. zur Frage nach den Beziehungen zwischen Ulcus und Carcinoma. Zieglers Beitr., 54: 1-9, 1912. 20) Yamagiwa, H.: Pathological study on the histogenesis and development of the gastric carcinoma. Japan J. Cancer Clin., 15: 970-979, 1969. 21) Yamagiwa, H.: Gastric carcinoma combined with gastric ulcer, .lapan J. Cancer Clin., 22: 592-597, 1976. 22) Yamagiwa, H.: Gastric carcinoma. The" relationship to the aging. Igaku no Ayumi, 96" 347-354, 1976.

Received August 2, 1976 Accepted September 20, 1976 ~4.ddress requests for reprints to : Dr. Hiroshi Yamagiwa, M.D., Dept. of Clinical Pathology, Faculty of Medicine, Mie University, Tsu, 514 Japan.