260 3. C L I N I C A L C O U R S E O F E A R L Y G A S T R I C C A N C E R A N D ITS POSITION IN THE NATURAL HISTORY OF GASTRIC CANCER Haruya Okabe, M.D.

(Director: Prof. S. Katsuki) Second Department of Internal Medicine, Faculty of Medicine, Kyushu University, Fukuoka, Japan It is said t h a t a prognosis of the gastric cancer h a s been destined to be poor or fair, when a patient with gastric cancer visit a doctor because of some gastric distress, and this destined prognosis can not be changed largely even by a markedly advanced p r e s e n t surgical procedure. T h i s hypothesis is known as biological p r e d e t e r m i n i s m (Mac Donald: 1951). On the other hand, however, it is also advocated t h a t to detect the gastric cancers in the early stage is a way to suppress them. It is very i m p o r t a n t to know which opinion is true, and to make this problem clear, we have to know the n a t u r a l history of the gastric cancer, especially its growing p a t t e r n as well as growing rate, and the clinical f e a t u r e s w h e n they are still staying w i t h i n curable stage. To find a solution to these problems, t h e r e will be, generally, t h r e e methods as follows; 1) prospective study on the non-cancerous subjects i) follow-up study of the so-called precancerous lesions ii) repeated annual e x a m i n a t i o n s on a settled healthy group 2) retrospective study on the cases w i t h confirmed gastric cancers i) comparison between the periods of s y m p t o m s and the histological features of the gastric cancers ii) comparison between t h e previous objective records such as X-ray and g a s t r o c a m e r a films which have been collected retrospectively and the histological features. 3) follow-up study of the cases with the gastric c a n c e r i) comparison between findings at operation and the prognosis ii) f u r t h e r follow-up study on inoperable cases F o r these several years, we h a v e been investigating the n a t u r a l history of the gastric c a n c e r utilizing the all methods above described. In this papers, results obtained by the retrospective methods of 2)-i and 2)-ii will be mainly presented. Materials and analized items Materials were classified into 5 groups. 1. Croup A: 281 consecutive patients with advanced gastric cancer, who were found in out-patients of a cancer detection institite for 4 years. Duration of the s y m p t o m s was analized on the patients of this group. 2. Group B: 96 selected patients with advanced gastric cancer: all of t h e m were operated on and for the most of t h e m radical operations were p e r f o r m e d and the surgical specimen were all examined. T h e markedly advanced cases were excluded f r o m this group. Not a few cases of this group showed f e a t u r e s of the early cancers macroscopically. In this group, t h e r e are m a n y cases found in several other hospitals and not included in group-A. Durations of the symptoms, macroscopical f e a t u r e s such as the size, shape and microscopical f e a t u r e s were analized. 3. Group C: 49 cases with advanced cancer, endowed with previous objective m a t e r i a l s such as X-ray a n d / o r g a s t r o c a m e r a films t r a c i n g b a c k to the past r a n g i n g f r o m 7 m o n t h s to 59 months, 25.4 m o n t h s in average. 4. Group D: 60 patients with the so-called early cancer, whose carcinomatous invasions were proved to r e m a i n within t h e mucosal or at most within the submucosal layers. 5. Group E: 16 cases with the early cancer, endowed with previous objective m a t e r i a l s t r a c i n g back to the past r a n g i n g f r o m 7 to 52 months, 27.6 m o n t h s in average. All cases of this group are included in group D. Frequencies of the cases with various durations of symptoms in groups A, B and D. In the group A, which is consisted of markedly advanced cancers, the durations of s y m p t o m s

261 were quite s h o r t in many cases; i.e. 42% were within 3 months, 60% within 6 months, and 70% within one year. On the other hand, in group D, which is consisted of the early cancers, they were apt to be longer; i.e. only 25% were within 3 months, 37% within 6 months and 42% within one year. In group B, which is consisted of selected advanced cancers, the tendecy was almost similar with group D. This results suggest a paradoxical relation that the patients whose prognosis are expected to be bad show subjective s y m p t o m s of rather short duration and the patients expected to be good in prognosis show these of long duration. This results was compatible with the hypothesis of biological p r e d e t e r m i u i s m by Mac Donald and also the basis of this hypothesis. As far as this result concerned, the Mac Donald's hypothesis appears to be true. Comparison of the cancers between group D (early cancer g r o u p ) a n d group B (selected advanced cancer group) Size of the cancers: M a x i m u m diameters of the cancers along the mucosal surface were measured on the surgical specimen, and compared between group D and group B. As seen on Fig. 1, t h e r e is an evident tendency that the size of early cancer group is smaller than the advanced cancer group, although the durations of the subjective s y m p t o m s were almost similar as mentioned before. Fig. 1. Comparison of size of the gastric cancer in the early and advanced cancer groups er (group D) zancer (group B)

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Diameter (mm) Although the time of clinical onset, when the subjective s y m p t o m occured, does n e v e r means the exact time of the beginning of the cancer, an average of the growing rate s e e m s slower in the so-called early cancers than in the advanced cancers when compared t h e s e results. Durations of the subjective s y m p t o m s in each of macroscopically classified types in group D and B.: The early cancer group (group D) were classified into 6 types, namely, types I, IIa, I I a + I I c , IIc, I I c + I I I , and III. Type I is an eminently proteuded type, IIa is a slightly elevated type, I I a + I I c is a slightly elevated type with central depression, IIc is a slightly depressed type, I I c + I I I is IIc with central excavation or more depressed u l c e r scar, and III is an excavated

262 type. Group D is consisted of the early cancer type I: 5, IIa: 5, I I a + I I c : 8, IIc and I I c + I I I : 60 and III: 3. In all types, the cancerous invasion remained at most within submucosal layer. The advanced cancer group (group B) was classified also into 6 types, namely B o r r m a n n I, II, III, IV and other 2 types, which looked like the early cancer macroscopically. These 2 types were classified as IIc+III-likely, and III-likely. This group B is consisted of B (Borrmann) I: 4, B. II: 12, B. III: 31, I I c + I I I - l i k e l y : 18, III-likely: 21 and B. IV: 3. As seen on table 1, in both groups B and D, the protruded types have a tendency of short duration of the s y m p t o m s and the depressed as well as excavated types have, on the contrary, a tendency of long duration of the symptoms. Relation of the horizontal diameter to the vertical depth of carcinomatous invasion in each corresponging types. : Early cancer type I and IIa is roughly similar with B o r r m a n n I macroscopically, I I a + I I c is conceivable as small B. II. The following tendencies were noted; 1. I, IIa, and B. I type have a fairly imtimate relation between the horizontal and vertical invasion. The borderline between the early and advanced (B. I) cancer was 55 m m in diameter. 2. I I a + I I c and B. II also have a very d o s e relation between t h e m and t h e r e were no advanced cancer among the tumors in which the diameters were less than 30 m m and also no early cancers among the tumors in which the diameters were more than 30 m m (Fig. 2). Fig. 2. Correlation of size and vertieal invasion of the cancer .

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less t h a n 20 m m (Fig.3). 4. III type h a v e also no relation between t h e m and a t e n d e n c y to invade m a i n l y vertically w i t h o u t s p r e a d i n g horisontally. Retrospective a n a l y s i s of t h e g r o w i n g rates and g r o w i n g p a t t e r n s by m e a n s of comparison of t h e previous objective m a t e r i a l s s u c h as X-ray a n d / o r g a s t r o c a m e r a films. In g r o u p E (early c a n c e r group) and g r o u p C (advanced c a n c e r group), the objective m a t e r i a l s s u c h as X-ray a n d / o r g a s t r o c a m e r a films t a k e n at least m o r e t h a n 6 m o n t h s previousely f r o m the last e x a m i n a t i o n were available. T h e oldest m a t e r i a l were traced b a c k to 52 m o n t h s a m o n g the g r o u p E and 59 m o n t h s a m o n g the g r o u p C. T h e a v e r a g e of the r e t r o s p e c t i v e l y observable period were 27.6 m o n t h s in the early c a n c e r and 25.4 m o n t h s in the advanced cancer group. It is v e r y i m p o r t a n t and i n t e r e s t i n g t h a t the types of the cases were all depressed IIc or I I c $ I I I type in t h e early c a n c e r g r o u p and also d e p r e s s e d or e x c a v a t e d type in the advanced c a n c e r group, no p r o t r u d e d type w i t h o u t ulceration was included in both g r o u p s E and C. T h i s s u g g e s t s t h a t types w i t h o u t a n y ulceration are h a r d to p r e s e n t long h i s t o r y of s y m p t o m s . R e t r o s p e c t i v e d i a g n o s i s of the first objective m a t e r i a l s . : T h e r e were 4 c a s e s w h o s e first m a t e r i a l s were not a d e q u a t e to diagnose r e t r o s p e c t i v e l y b e c a u s e of not fine pictures. T h e r e w a s only one advanced cancer, of which the first X-ray films t a k e n as medical checkup 48 m o n t h s ago showed no a b n o r m a l i t y in spite of the fairly good pictures. In all of t h e r e m a i n i n g , t h e r e were noted s o m e a b n o r m a l i t y on the first films at the s a m e place w h e r e t h e c a n c e r found finally. I n t e r p r e t i n g the findings on the first films, t h e r e was not e v e n one lesion w h i c h could be diagnosed as u n q u e s t i o n a b l y b e n i g u f r o m the p r e s e n t view point. T h e m o s t of t h e m s h o u l d be diagnosed as m a l i g n a n c y or s u s p i c i o u s of m a l i g n a n c y at the very first time. F r o m t h i s r e s u l t s , it could be e m p h a s i z e d t h a t the early c a n c e r of t h i s d e p r e s s e d IIc type h a d existed as the c a n c e r at t h e first t i m e w h e n the p a t i e n t visited the doctor w i t h s o m e g a s t r i c s y m p t o m s . T h i s m a l i g n a n t type will s t a y as the superficial early c a n c e r for inconceivable long t i m e s u c h as 3 or 4 years. T h i s IIc type could be insisted on as a v e r y slow g r o w i n g cancer. On the o t h e r hand, about the advanced cancer g r o u p (all ulcerated), the t i m e w h e n t h e y had been s t a y i n g w i t h i n s u b m u c o s a l layer as the e a r l y c a n c e r could not be confirmed, so t h a t t h e reliable g r o w i n g r a t e s could not be known. T h e case whose first X-ray film did not s h o w a n y detectable a b n o r m a l i t y at the area where the advanced c a n c e r was found 48 m o n t h s later was an only case of medical check-up, w h e n he had not a n y s u b j e c t i v e complaint. T h e c a n c e r itself of t h i s case w a s ulcerated B o r r m a n n III type which h a d already invaded t h e s e r o s a with local m e t a s t a s i s , T h e r e f o r e t h i s case's g r o w i n g rate w a s s u p p o s e d to be p r e t t y f a s t compared with the IIc type, if clinically detectable c a n c e r had not existed c e r t a i n l y 4 y e a r s previousely. All of the r e m a i n i n g s h a d received e x a m i n a t i o n s with s o m e subjective c o m p l a i n t at t h e first time, w h e n t h e cancer appeared to e x i s t there already by r e t r o s p e c t i v e interpretation. Therefore, s y m p t o m s by which the p a t i e n t s visited t h e doctors were s u p p o s e d to be due to g a s t r i c c a n c e r itself at t h a t time, even if it was several y e a r s ago;

264 This result may suggest that ulcerated gastric carcinoma presents long history of symptoms. Growing pattern of the gastric cancer in group E and C, : Observing the development of the IIc type by the findings of gastrocamera films, it was noted that the malignant appearance of the depressed area became progressively exaggerated but did not enlarged their extent evidently. Also it was observed on the g a s t r o c a m e r a films retrospectively that the ulcer located in the cancerous lesion itself reduced the size very often and sometimes almost disappeared. Some of this disappeard ulcer was proved histologically that the surface of the ulcer was covered by regenerated non-malignant epithelium at the center of the malignant lesion. It is very important evidence to elucidate the ulcer-cancer relationship. On the other hand, in the advance cancers (group C), it was noted that the t u m o r grew up in almost similar figures on the X-ray films. A m o n g them, there were 2 cases whose X-ray films taken on several times extending over 4 years could be collected. About these 2 cases, the doubling time of the main tumors were obtained plotting the diameter of the t u m o r on the X-ray films to semilog graphs. The doubling times were 27 and 33 months respectively. No reports could be found, so far, describing the doubling time of the growing rate determined about the h u m a n gastric cancer. Prognosis of the patients in group E and C.: As the follow-up t e r m s were still short, the conclusion should not be given yet. The prognosis of the group E is, however, quite good and only 1 case had died with liver metastasis 2 years after the operation. Among the advanced cancer group (group C), cases with I I c § like features are all alive at the present time. Discussion F r o m the results of these above mentioned, it is possible, to a certain extent, to consider the natural history of the gastric cancer and a position w h e r e the so-called early cancers locate. A schema of the growing patterns of the h u m a n gastric cancer was deviced (Fig. 5). The marks on the schema, A - F , followed the example of Mac Donald's schema. The D line means the s t a r t i n g line of the regional metastasis, the E line is the s t a r t i n g line of the remote metastasis, and the F line means cancerous death. Therefore, this schema dose not mean the exact growing rate of the tumor itself, although the t u m o r will grow up as time goes by. It is now unquestionable that there are 2 extreme types among growing patterns of the gastric cancers. One is the case of the noncurable cancer which grows insidiousely without any s y m p t o m s until it markedly advanced with remote metastasis. Sometime the t u m o r itself in the stomach is small, but the remote metastasis is remarkable (CH). The growing rate of this type is not known yet. The other one is the curable so-called early cancer which spreads only superficially and stays within the mucosa or submucosal layer for a long time with various kind of indigestive s y m p t o m s (CG). The f o r m e r is extremely malignant and the latter is

Fig. 5. Natural History of Gastric Cancer (Okabe) cancer death

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265 opposite. All growing p a t t e r n s of t h e g a s t r i c c a n c e r will be included between the CH and CG. Accordingly, the n a t u r a l history of the g a s t r i c cancer will be different in each case. However, f r o m the results above described, it appears possible to classify to several group, in which the growing p a t t e r n s are supposed to be similar in the same group. W h e r e should locate the real early gastric cancer in these broad variety of n a t u r a l history ? Theoretically, the real early cancer should be in recent occurrence, although there is no way to detemine when it occured, and its cancerous invasion should be limited within the mucosal layer without any metastasis. They may correspond to the left vertical-striped region in the schema. However, this stage of the gastric cancer will not detectable clinically even if how advanced the diagnostic methods and also t h e r e will be no symptoms suggesting a lesion. Now, where in this figure does the so-called early cancer locate ? Among the so-called early cancers. IIc type or I I c + I I I are most frequently being detected presently. As this IIc type was proved to stay within the submucosal layer for m a n y years, this type should locate in r i g h t vertical striped region and this type could be t h o u g h t as a kind of riped full-blown cancer which have originally extremely slow-growing character. T h i s type is not a real early cancer in the initial stage which can proceed to t h e classical advanced cancer. This typed c a n c e r should be regarded as a special type which is not included in B o r r m a n n ' s classification. T h e frequency of this type will be limited within 10% a m o n g the all cancers. Therefore, even if all of this type were detected clinically, the real suppression of the gastric cancer could not be gained. Type III seems to have tendency to p e n e t r a t e perpendicularly, but its growing rate seems not always so fast, as usually they show fairly long clinical history. To detect this type, as early as possible a strict differential diagnosis between m a l i g n a n t and benign ulcer is the most important. T h e m a l i g n a n t change of the originally benign ulcer seems to be quite r a r e f r o m the results obtained by the retrospective method. Although types I, IIa and I I a + I I c have possibility to be connected to the classical advanced cancer, it is still not clear how long they stay as early cancer within at most, submucosal layer without any r e m o t e metastasis. T h i s point m u s t be solved clearly in f u r t h e r study, although t h e i r t e r m s staying as an early cancer are supposed to be fairly short. T h e i r location in the n a t u r a l history will be between both vertical striped areas. As the f u r t h e r study to solve this problem, the prospective study would be only and a useful method. 0 n l y by this method, clinically detectable early stage of all kinds of gastric cancer will be captured and t h e i r growing p a t t e r n s and r a t e s will be settled.

4. S E C R E T I O N

OF GASTRIC

JUICE

IN EARLY

GASTRIC

CANCER

Kazuo Yunoki*

Department of Pathological Physiology, Institute for Cancer Research, and the 2nd Department of Internal Medicine, Faculty of Medicine, Kagoshima University (Director: Prof. Hachiro Sato) T h e successful t r e a t m e n t of gastric cancer depends upon its early diagnosis. T h e diagnostic i n f o r m a t i o n s of early gastric cancer are successively clarifing in recent year. T h e r e m a r k a b l e increase of detection ratio of early g a s t r i c cancer is m u c h indebted to the m a r k e d i m p r o v e m e n t of detection technics and the populalisation of gastric mass screening. T h e commonly available methods of diagnosis, such as r o e n t g e n o g r a p h y and endoscopy, depend upon the gross appearance of the gastric lesion. T h e s e methods, therefore, occasionally fail the early stage of gastric c a r c i n o m a to find out and in m a n y caseses the benign or m a l i g n a n t n a t u r e of the lesion can be * Professor, D e p a r t m e n t of Pathological Physiology, I n s t i t u t e for Cancer Research. Docent, the 2nd D e p a r t m e n t of I n t e r n a l Medicine. I acknowledge w i t h deep gratitude the kind cooperation of the m e m b e r s of the division of gastroenterology, the 2nd D e p a r t m e n t of Internal Medicine.