[GANN, 62, 1-11; February, 1971] HISTOLOGY OF GASTRIC ULCER WITH REFERENCE TO CRITERIA OF ULCER CANCER*1. Toshio KUBO

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1 [GANN, 62, 1-11; February, 1971] UDC HISTOLOGY OF GASTRIC ULCER WITH REFERENCE TO CRITERIA OF ULCER CANCER*1 (Plates I-II) Toshio KUBO (Division of Pathology, Cancer Research Institute, Faculty of Medicine, Kyushu University*2) Synopsis Three hundred and seventy-three surgically resected ulcers of the stomach, comprising both open active and healed inactive ulcers, were histologically examined with close attention on the structural alteration in microscopical appearance in different states of ulcer. In open active ulcers, the histological pictures frequently observed were (1) thick necrotic layer and (2) absence of regenerates, fusion, and granulation tissue. In the healed ulcers, they were (1) presence of regenerates and fusion, and (2) involusion of fibrosis. The results were confirmed by histological examination of 27 ulcers, which had been proved as active or healed by retrospective study of a series of X-ray and gastrocamera films. It is likely that the histological appearance of gastric ulcer may differ according to pendulation from open ulcer to healed ones. The elements of "histological criteria of ulcer-cancer", such as the breach of musculares, fusion, fibrosis, and regenerates, are proved not to be stable and unchangeable findings. It is probable that they can be produced within a short period of time, and that they can disappear within a short time. Presence of these pictures in a gastric ulcer does not always indicate the long standing of the lesion, but merely shows the state of ulcer whether it is inclined toward healing or toward ulceration. These histological pictures, therefore, may not provide any reliable basis for histological criteria of ulcer-cancer. INTRODUCTION Frequency of the so-called "ulcer-cancer" of the stomach has been calculated on the basis of histological examination. Cases which conform histologically to "criteria of ulcer-cancer" are regarded as carcinoma originating from pre-existing gastric ulcer. Findings of ulcer, which are adopted as the criteria, are microscopical features such as complete breach of musculares, cancer cell-free fibrosis, fusion of both musculares, presence of tufty regenerates, and so on.1,2,6,10,11,16,20,21,24,26) On listing these findings as criteria, investigators agree that the spread of cancer should be limited to the margin of the ulcer. On the other hand, they disagree in putting stress on each of the above-mentioned findings. For instance, the presence of thick fibrosis is supposed to be the most reliable finding by some investigators, while others think that the fusion is pathognomonic of ulcer-cancer. It is obvious that the listing of these histological findings as criteria might be strongly influenced according to the investigators' subjective point of view. Some findings such as endoarteritic and neuri- *1 Presented at the 26th and 27th Annual Meetings of the Japanese Cancer Association in 1967 and (1)

2 T. KUBO nomatous changes at the ulcer base, which had been regarded as one of the elements of the criterion, have been excluded from the current usage of the criteria. Discrepancy among the pathologists in expressing the percentage of ulcer-cancer can be understood when these problems are taken into consideration. Theory of the so-called criteria of "ulcer-cancer" has been founded on the idea that antecedency of ulcer to cancer can be amply proved by histological examination. However, so far as the age of cancer and ulcer in individual cases has remained undetermined, it may incline toward a hasty dogmatism to draw any conclusion on the sequential relation between ulcer and cancer. Recent information about the growth-rate of gastric cancer indicates that cancer can remain confined to the mucosa for a considerable period of time, not infrequently exceeding one year or more. This gives a challenge to the reliability of the criteria, suggesting the possibility that, if peptic ulceration takes place within cancerous area, it may become chronic before cancer cells infiltrate the deeper tissue, as pointed out by several investigators.7,12,17,18,22,25) Crohn pointed out that the chronic ulcer might form in such a short period as 2 or 3 weeks,4) which is by no means long enough to support the antecedency of ulcer to cancer. To approach the problem of ulcer-cancer, it is necessary to elucidate the growth rate of gastric cancer and morphogenesis of peptic ulcer. The present communication deals with the morphogenesis of gastric ulcer, especially that of a complete breach of musculares, fibrosis, fusion, and special types of mucosal regenerates. MATERIALS AND METHODS A total of 373 stomachs with gastric ulcers resected surgically during the period of 1964 to 1967 were examined histologically. These materials were sent to our laboratory for histological examination from several public and private hospitals in and near Fukuoka City. The materials covered the cases with lesions in various phases from active large ulcers to healed small ones. Cases with pyloric and/or duodenal ulcers were excluded from the present series. The stomachs were opened in most cases along the average size, comprising both margins of ulcer, were cut out parallel to the lesser curva- thickness. They were stained with Hematoxylin-Eosin. Van Gieson stain and Masson's Trichrome stain were also employed when necessary. Classification of Peptic Ulcer The present author proposes the following classification of peptic ulcer for the histological analysis of morphogenesis of gastric ulcer. The principle of this classification is based on various phases or states of ulceration, which is clinically observed as a pendulating phenomenon of peptic ulcer. Therefore, it is formulated according to the extent of the mucosal covering (healed area) over the denuded area (open area). The destroyed area is shown by a complete absence of the mucosa, muscularis mucosae, and underlying tissues. It was not difficult to define the destroyed area in open active ulcer, but in healing or healed ulcers the previously affected areas were covered by regenerating mucosa, sometimes making the borderline indistinct between the affected and unaffected areas. In such ulcers, the gap between proximal and distal edges of muscularis 2 GANN

3 CRITERIA OF ULCER-CANCER Fig. 1. Diagram of the four types of ulcer m=mucosa, sm=submucosa, mp=muscularis propriae, s=serosa. Arrows indicate the possible route of transformation of histological appearance of gastric ulcer according to the pendulation between open ulcer and healed ulcer. mucosae at the ulcer-scar was regarded as the margin of the pre-existing ulcer. This classification consists of four types (Fig. 1). Type O is applied to ulcers with complete absence of mucosal covering, and there is no regenerative mucosa which consists of epithelium and lamina propria mucosae, although the extension of a single layered epithelium is frequently encountered at the margins of ulcer in this type. Type Oh refers to ulcers with partial mucosal covering at the margins, although the non-covered denuded area still exceeds the covered area. Type Ho refers to cases where the area of mucosal covering predominates over the denuded area. Type H is applied to cases in which the area of destruction is completely covered by regenerative mucosa. OBSERVATION 1) Grouping of 373 Ulcers In this series, 142 ulcers (38.1%) were of Type O, 86 (23.1%) were Type Oh, 41 (11.1%) were Type Ho, and the remaining 104 (27.3%) were Type H. 2) Frequency of Histological Pictures in Question (a) Complete Breach of Muscle Coat In 219 (58.9%) of 373 ulcers, a complete breach of musculares was present; 163 of these 219 ulcers were grouped into Types O and Oh, while remaining 56 were Types Ho and H. Out of 373 ulcers studied in this series, 228 cases were available for comparison between the period of complaint and histology. It was found that there was little correlation between the breach of muscular coat and the period of complaint. (b) Fusion of Muscularis Mucosae and Muscularis Propriae Fusion was present in 224 (65.4%) of 373 ulcers; in 49 of 224 ulcers it was observed solely at the proximal margin of the ulcer, it was seen only at the distal margin in 40, and it was found at both margins in the remaining 115 ulcers. Occurrence of fusion in each type of ulcer was as follows: Fusion was present in 61 (42.9%) of 142 ulcers of Type O; in 58 (67.4%) of 86 ulcers of Type Oh; in 34 (82.9%) of 41 ulcers of Type Ho; and in 91 (87.5%) of 104 ulcers of healed state (Type H). These findings indicate that fusion had a tendency to occur frequently in the healing and healed ulcers (Types Ho and H). (c) Fibrosis Occurrence of voluminous and well developed fibrosis at the ulcer base differed considerably in frequency according to the state of ulcer. In Type O ulcer, such fibrosis 62(1)

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6 T. KUBO was found in 89 (62.7%) out of 142, it was present in 54 (62.8%) of 86 ulcers of Type Oh, in 24 (38.4%) of 41 ulcers of Type Ho, and it was present only in 3 cases (2.9%) out of 104 healed ulcers of Type H. The above results may suggest the possibility that the reduction or involution of fibrous tissue might occur soon after the mucosa covers the denuded area. Histological appearance of ulcer base was not uniform; in acute exacerbating ulcer (Types O and Oh), the majority of ulcer base consisted of three zones, exudation layer, fibrinoid necrotic layer, and fibrous layer. Layer of granulation tissue was rarely present in these ulcers, and fibrous tissue at the ulcer base was often the subject of peptic action as shown in Photo 10. Other instances of acute open ulcer showed the ulcer base consisting of immature granulation tissue and of immature fibrosis. In either case, the thick layers of exudation and fibrinoid necrosis were recognized as the characteristics of acute exacerbating large ulcer. On the other hand, in healing or healed ulcers (Types Ho and H), the layers of granulation and fibrous tissues tend to disappear in the majority of cases. (d) Mucosal Regenerates Mucosal regenerates can be classifiable into the following five histological patterns; single-layered epithelial extension, tufty anlage of glands (Photo 5), immature glands with tufty foveolar portion (Photo 6), mucosa composed of simple glands (Photo 7), and normal-appearing mucosa (Photos 8 and 9). In 142 ulcers of Type O, the single-layered epithelial extension was found in 63 ulcers, and glandular anlage in the shape of tuft was present in 15 ulcers. Other pattern of regenerates was not encountered in this Type. The regenerates observed in this Type O ulcers were found situated over the muscularis mucosae at the margin and, therefore, they played no essential role on the covering of the denuded area. In Type Oh ulcers (86 cases), the single-layered epithelial extension was observed in 69, tufty anlage in 67, immature glands in 31, simple glands in 44, and normal-appearing mucosa in 14 ulcers. Of 41 ulcers of Type Ho, a single-layered epithelial extension was found in 30, tufty anlage in 36, immature glands in 31, simple glands in 26, and almost normal mucosa in 10 ulcers. Among the Type H ulcers (104 cases), a singlelayered epithelial extension was present only in 8 cases, tufty anlage in 24, immature glands in 41, simple glands in 55, and normal-appearing mucosa in 62 ulcers. The immature regenerates (single-layered epithelium and tufty anlages) were observed predominantly in the open active ulcers (Types O and Oh), while the matured regenerates (simple glands and normal appearing mucosa) occurred frequently in the healing and healed ulcers (Types Ho and H). Twenty-seven cases, in which the detailed clinical informations were available, were picked up from the above 373 cases, and a series of X-ray and gastrocamera films, which were taken from the beginning of the complaint till the time of surgery, were re-examined thoroughly. These ulcers could be divided into three groups according to the state of ulcer at the time of operation; cases operated when ulcer increased in size, cases operated when ulcer decreased in size, and cases which showed little fluctuation in size during the whole course. These 27 cases are summarized in Table I. Eight illustrative cases will be presented in a condensed manner. 6 GANN

7 CRITERIA OF ULCER-CANCER (a) Cases Operated When Ulcer Increased in Size Case 1 44-year-old male. The period of observation was 48 months. One month prior to the operation, ulcer increased in size. Resected specimen showed an open punched-out ulcer with breach of muscular coat. No regenerative mucosa was seen at the margin, and the distal margin of this ulcer was devoid of fusion. A thick layer of necrotic tissue was covering the fibrous tissue of the ulcer base. No granulation tissue intervened between the zones of necrosis and fibrosis (Photo 10). Case 2 73-year-old male. Period under observation was 4 months, during which large ulcer once shrunk and then re-enlarged. Resected specimen showed a punchedout ovoid ulcer, 4.5cm in maximum diameter, on the lesser curvature. Histologically it was a penetrating deep ulcer; muscular coat was completely destroyed and no regenerates were seen at the margin. Fusion was not demonstrated. A zone of thick necrotic tissue covered the floor of the ulcer. Formation of immature fibrosis was found at the ulcer base. Case 3 62-year-old male. Twenty-seven months' period of observation, during which ulcer once healed, reappeared, and rapidly increased in size before the operation. Histologically, it was a penetrating ulcer. Fusion was not found at either proximal or distal margin. Necrotic tissue at the floor was marked in degree and the underneath fibrosis was moderately developed, though it was still immature. There were 10 other cases in addition to the above 3 cases. (b) Cases Operated When Ulcer Decreased in Size or Disappeared Case year-old male. During 14 months, an ulcer-scar changed to an open ulcer, which again shrunk to a small ulcer within 22 days. Resected specimen showed the presence of a healing ulcer, which was histologically proved to be a penetrating one in healing phase (Photo 2). Regenerating mucosa was seen at both proximal and distal margins, assuming the form of tufty glandular anlage. Fusion was found in both margins. Fibrosis at the ulcer base was not voluminous. Case year-old female. An ulcer in open state, about 1.7cm in size on X-ray films, diminished in size after a lapse of 25 days. In the resected specimen, a healing ulcer (Type Ho) was found, which was histologically an ulcer involving the muscularis propriae. At both margins, mucosal regenerates in the form of tufty and simple glands were observed. Thin layer of necrotic tissue covered the denuded area. Fusion occurred underneath the distal margin. Fibrosis in the base was not voluminous. Case year-old female. An ulcer healed within 30 days, and the resected specimen showed an ulcer-scar in the form of stellate pattern. This was histologically a case of healed ulcer with incomplete disruption of muscular coat. The surface of the scar was covered with normal-appearing mucosa. Fusion was seen underneath both proximal and distal margins. Fibrosis in the scar was not voluminous. There were seven other cases in this group and they all showed in general the same histological features as above. (c) Cases Which Showed Little Changes During the Course Case year-old female. A constant ulcer-scar was observed during the period of 20 months. Resected specimen proved it to be an ulcer-scar. The surface of the scar was covered with normal appearing fundic mucosa (Photo 9). Fusion was present at both proximal and distal margins. Fibrosis was not found in the ulcer-scar. 62(1)

8 T. KUBO Case year-old male. A large ulcer at the gastric angle was constantly found during the period of 7 months, which showed little fluctuation in size. Resected specimen revealed an ulcer, 1.5cm in maximum diameter, on the lesser curvature. Histologically this was a case of typical chronic ulcer furnished with thick fibrous tissue at its base. Mucosal regenerates and fusion were observed at the margins. Two other cases were almost the same as Case 25 in clinical course and histological appearances. DISCUSSION The classification of gastric ulcer into four types was introduced by the present author. Its usefulness is enhanced by the fact that it can represent each phase of peptic ulceration. Each of these types has their own histological characteristics. In Type O ulcer, they were evidence of fibrosis which was undergoing necrosis at the floor of ulcer, presence of thick necrotic layer at the ulcer floor, and frequent absence of fusion and regenerates. The presence of overhanging mucosa at the margin was also one of the representative pictures in this type. On the other hand, the microscopical characteristics of Type H ulcer were presence of mucosal regenerates and fusion, and reduction or involution of fibrous tissue at the ulcer base. Inbetween the above two extremes lay Types Oh and Ho, showing intermediate or transitional histological appearances. From this evidence, it is correct to say that the histological appearance of peptic ulcer varies according to the state or phase of ulcer. When open ulcer heals, its histological feature transforms from that of Type O to that of Type H, and when healed ulcer changes to open active ulcer, its histological appearance transforms to that of open active ulcer. Gastroenterologists estimated the healing time of peptic ulcer to be from 4 to 6 weeks.3,5,14,19) This suggests that the histological features of Type O ulcer may be changed into that of Type H ulcer within a period of 4 to 6 weeks. On the other hand, when rapid exacerbation of Type H ulcer takes place, resulting in an open active ulcer, the microscopical appearance of healed ulcer may undergo a change into that of open ulcer within a short period of time. These cyclic changes, which were beautifully illustrated roentgenologically and endoscopically by Schindler and others,14,23) have been examined histologically as well by a few investigators.3,5,14,19) Animal experiments on artificially produced ulcer provides information on the healing process of ulcer.8,13,15,17,27) Taking these data into consideration, it is likely that occurrence of fusion and fibrosis, a breach of musculares, and presence of regenerates are the changes which depend largely on the state of peptic ulceration. They are by no means stable and unchangeable findings. Even a thick layer of fibrosis could be the subject of reduction after the epithelial covering takes place over the denuded area, as suggested by Cases 16, 18, and 19. Fusion seems to be often destroyed by the exacerbating action of peptic ulcer, but it could be re-built at the time of healing. We have an experience of observing the formation of fusion which occurred within 16 days after the production of thermal ulcer in a dog's stomach. Tufty regenerates were added by Oota to one of the pictures indicating the antecedency of ulcer to cancer.21) Concerning the histogenesis of regenerative mucosa, growth of regenerates from a single-layered epithelium to tufty anlage, and further to simple glands, and finally to normal-appearing mucosa, was clearly demonstrated in the 8 GANN

9 CRITERIA OF ULCER-CANCER present investigation. This is in accordance with the results obtained from animal experiments.8,17,27,28) Therefore, it seems that the presence of certain types of mucosal regenerate does not indicate the chronicity of ulcer but indicates the predominance of healing process over the destructive action. The present author thinks that they are the stigmata which show the time elapsed since the commencement of epithelial covering. Twenty-seven cases described above provide valuable information about the time required for the occurrence of histological pictures in question. When active open ulcer heals, fusion will occur and fibrosis will be reduced in size. When healing ulcer shows acute exacerbation, fibrosis will appear and destruction of fusion will result. The age of each of the pictures could thus be roughly estimated on the ground of informations from these 27 cases. (1) Complete Breach of Musculares: The absence of correlation between the breach of muscular coat and the period of complaints suggests that it occurs rapidly or slowly, and that its presence does not always mean a long standing of ulcer. (2) Fusion: It may occur within a period of 25 to 42 days as suggested by Cases 14, 15, 16, and 17. In a dog's stomach it occurred within 16 days. (3) Fibrosis: It may occur within a relatively short period of time ranging from 52 to 80 days as suggested by the fact that moderate fibrosis was found in cases of ulcer which enlarged rapidly from healed state within a short period (Cases 2, 3, 4, 6, 7). In steroid and other drug-induced ulcer in man and animals, moderate fibrosis was encountered in 15 to 16 days in animals, and in man with a short history of cortisone treatment.9,13,17) Kahn et al. administered large doses of cortisone intermittently to rats with thermally produced gastric ulcer, and found that the ulcer progressed into chronic type with considerable amount of fibrous tissue at their bases within 90 days.15) (4) Regenerates: Tufty regenerates can occur within 34 or 36 days as shown in Cases 14, 17, and 18. Experimentally they were observed in 57 days in mice,17) and in 16 days in a dog (Photo 14). Hirayama observed formation of tufty regenerates in human ulcer which healed within 20 days.14) Normal appearing mucosa can appear within 98 days, as indicated by Case 20. These findings agree in general with the results obtained from experimental studies conducted by Ferguson8) and by Williams.28) To summarize, the present author has become skeptical over the true efficacy of the histological criteria of ulcer-cancer of the stomach. Histological pictures accepted as the criteria are ever-changing or ever-changeable ones. Presence of tissue changes under discussion does not always indicate the antecedency of ulcer to cancer, but merely shows the state or phase of ulcer with regard to whether the ulcer in question is inclined toward healing or toward ulceration. If secondary ulceration takes place within cancerous area, it is quite probable that the sequential occurrence of the above-mentioned histological pictures may result within the short period of time given above. The author thanks Dr. Tsuneyoshi Yao, Second Department of Internal Medicine, Kyushu University, for reading the X-ray and gastrocamera films. He also thanks Prof. Tamaki Imai, Director of this Institute, for his kind guidance. (Received July 7, 1970) 62(1)

10 T. KUBO REFERENCES 1) Beasley, W. H., J. Clin. Pathol., 13, 315 (1960). 2) Cabot, H., Adie, G. C., Ann. Surg., 82, 86 (1925). 3) Cummings, G. M., Jr., et al., Gastroenterology, 7, 20 (1946). 4) Crohn, B. B., et al., Arch. Intern. Med., 35, 405 (1925). 5) Idem, ibid., 37, 217 (1926). 6) Dible, J. H., Brit. J. Surg., 12, 666 (1924). 7) Ewing, J., Ann. Surg., 67, 715 (1918). 8) Ferguson, A. N., Am. J. Anat., 42, 403 (1928). 9) Garb, A. E., et al., Arch. Intern. Med., 116, 899 (1965). 10) Gomori, G., Surg. Gynecol. Obstet., 57, 439 (1933). 11) Hauser, G., Peptishe Schodigungen des Magens. In Henke-Lubarsch "Handbuch der pathologische Anatomie," 4, Heft. 1 (1926). Springer, Berlin. 12) Hebbel, R., Bull. Univ. Minn. Hosp. Minn. Med. Found., 22, 59 (1950). 13) Hedinger, C., et al., Z. ges. exptl. Med., 136, 64 (1962). 14) Hirayama, J., Nippon Shokakibyo Gakkaishi, 58, 1193 (1961). 15) Kahn, S. D., et al., Exptl. Mol. Pathol., 2, 481 (1963). 16) Klein, S. H., Arch. Surg., 37, 155 (1938). 17) Kubo, T., Acta Pathol. Japon., 18, 227 (1968). 18) Mallory, T. B., Arch. Pathol., 30, 348 (1940). 19) Meireles, J. S., et al., Am. J. Digest. Dis., 7, 661 (1962). 20) Newcomb, W. D., Brit. J. Surg., 20, 279 (1932). 21) Oota, K., Nippon Byori Gakkai Kaishi, 53, 3 (1964). 22) Palmer, W. L., et al., Gastroenterology, 3, 257 (1944). 23) Schindler, R., "Gastroscopy," 2nd ed., (1950). Hafner Publishing Co., New York. 24) Stewart, M. J., cited from Beasley.1) 25) Stromeyer, F., Beitr. Pathol. Anat. Allg. Pathol., 54, 1 (1912). 26) Waugh, T. R., Ann. Int. Med., 37, 534 (1952). 27) Williams, A. W., Brit. J. Surg., 41, 319 (1953). 28) Idem, ibid., 48, 564 (1961). EXPLANATION OF PLATES I-II Photo 1. Type O ulcer, resected at the time of acute exacerbation (Case 7). Overhang of marginal mucosa, absence of fusion, and thick necrotic layer at ulcer floor are the characteristics Photo 2. Type Ho ulcer, resected at the time of rapid healing (Case 14). Presence of fusion Photo 3. Type Ho ulcer. Tufty anlages of glands are covering the floor of ulcer. Fibrosis Photo 4. Ulcer is completely covered by tufty regenerates (Type H ulcer). Fusion is present Photo 10. Ulcer floor observed in Case 1. There is a thick layer of fibrinoid necrosis affecting Photo 11. Ulcer floor in healing ulcer. A single-layered extension of epithelium is seen over Photo 12. Glands composed of parietal and chief cells found in healed ulcer in Photo 8. H-E. 10 GANN

11 CRITERIA OF ULCER-CANCER Photo 14. Tufty regenerates at the ulcer margin, observed 16 days after the production of thermal

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