Observations on the Healing of Ulcerations in Early Gastric Cancer

GASTROENTEROLOGY Official Publication of the American Gastroenterological Association ~ COPYRIGHT 1971 THE WILLIAMS

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May 1971

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OBSERVATIONS ON THE HEALING OF ULCERATIONS IN EARLY GASTRIC CANCER The life cycle of the malignant ulcer TAKAO SAKITA, M.D., YANAO OGURO, M.D., SACHIO TAKASU, M.D., H:!SAYUKI FUKUTOMI, M.D., TAKESHI MIWA, M.D., AND MASAYOSHI YOSHIMORI, M.D.

II Department of InterTUlI Medicine, Japan NatioTUlI Cancer Center Hospital, Tsukiji 51-1, Chuo-ku, Tokyo, Japan

Significant healing was observed in 51 (70.8%) of 72 malignant gastric ulcers found in a group of 122 cases of early gastric cancer. An unusually well documented case of complete healing of a malignant gastric ulcer has been described in detail. A plea for careful endoscopic follow-up of gastric ulcer healing has been made. A life cycle of ulceration, healing, and recurrent ulceration for malignant ulcers has been proposed. Traditional teaching l - 3 has been that benign ulcers of the stomach can be expected to heal within a reasonably short period of time, but that malignant ulcers rarely show significant healing. A few reports of apparent healing of malignant ulcers have appeared in the English literature.'-6 Bachrach 7 reviewed all the published reports of apparent complete healing of malignant ulcers up to 1962 and surReceived May 13, 1970. Accepted November 23, 1970. Presented in part at the First International Symposium in Detection of Cancer, Spa, Belgium, September 26 to 28, 1968. Address requests for reprints to: Professor Takao Sakita, II Department of Internal Medicine, Japan National Cancer Center Hospital, Tsukiji 5-1-1, Chuo-ku, Tokyo, Japan. The assistance of Dr. R. Sano for the histopathological study is acknowledged. Adapted for publication in English by John F. Morrissey... M.D.~ Madison, Wisconsin.

veyed a large group of radiologists in an effort to find additional cases. He found that the evidence for complete healing for most of the reported cases was not convincing. In his opinion, his study reconfirmed the value of the therapeutic trial in the management of gastric ulcer. This traditional concept has been challenged recently by several Japanese studies 8- 12 which have documented healing of malignant ulcers by the newly developed technique of gastrocamera photography. 13 This study describes the frequency of ulceration and the extent of ulcer healing in a group of 122 cases of early gastric cancer seen at the Japanese National Cancer Center Hospital. An unusually well documented example of complete healing of a malignant ulcer is presented in detail. Methods Cases of early gastric cancer showing open ulceration or ulcer scarring were included in 835

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examination or when surgery was refused by the patient. All patients were operated on at the National Cancer Center Hospital. Very detailed histopathological studies were carried out on each gastrectomy specimen. All cases of advanced cancer were excluded from the study by this examination, and the cases of early gastric cancer were divided into two groups based on the presence or absence of submucosal invasion. The healing of the malignant ulcerations was described using the same five-stage system which is routinely used to describe healing of benign ulcerations. The system is based on the degree of mucosal regeneration observed at endoscopy. The stages are: active stage 1, active stage 2, healing stage 1, healing stage 2, and scarring stage. The change in size of ulcerations was estimated using the results of both X-ray and endoscopic examinations. The 80 0 angle of view of the gastrocamera lens usually permits visualization of the ulceration in the same field with a fixed landmark, such as the angulus or the pylorus, to aid in determining its size. Careful comparison of comparable photographs of the lesion taken at successive gastrocamera examinations was of great assistance in determining the extent of healing. In the tabulations, the term remarkable, when used describing the healing of an ulcer, meant that the healing process had advanced more than two stages or more than a 50% reduction in size. Appreciable referred to a lesser extent of healing of from 25 to 50%. The endoscopic diagnosis of ulcer scar was based on the finding of an area of converging gastric folds or the presence of a sharp deformity of the angulus or pylorus. Malignancy in a scar was suspected when there was a deType I Pro truded type pressed area in the center, bleeding at the II a Elevated margin of a depressed area, or a cutting off of the folds before they reached the center of the scar area. Thickening, thinning, or irregularity Type II Superficial type II b Flat of the fold tips was particularly helpful in differentiating benign from malignant scars. II c Depre ss ed~ All patients with open ulceration were treated with conventional ulcer therapy . ProType 111 [ >\Cavated type pantheline bromide (15 mg), aluminum hyFIG . 1. The Japanese system for the macroscopic droxide (0.3 g), calcium carbonate (0.3 g), and classification of early gastric cancer. Type I lesions magnesium carbonate (0.3 g) were given 2 hr are polypoid in appearance. Type II lesions, although after each meal three times daily.

the study when the endoscopic and pathological documentation of the lesion was adequate to localize it accurately within the stomach. Early gastric cancer was defined as cancer limited to the mucosa and submucosa. The classification of early gastric cancer adopted by the Japanese Endoscopic Society (fig. 1) was used.'" 15 In addition to the types illustrated, there are some combined types. For example, a shallow depression (ilc) with a central excavation (ill) is classified as type ilc + m. The first Roman numeral indicates the predominant feature of the lesion. A large ulcer with a small depressed area at the margin would be referred to as ill + ilc. All patients were examined by barium meal X-ray examination. Gastric analysis for hydrochloric acid was performed using the KatschKalk caffeine stimulation technique in all patients. When achlorhydria was found by this technique, a second study with either 1 mg per kg of betazole or 4 j.Lg per kg of pentagastrin was performed. Endoscopic biopsy and cytology under direct vision were performed in many of the patients at the time of the first examination and in nearly all patients prior to surgery. Cases were observed from 2 to 71 weeks with an average of 5 weeks. A minimum of two and an average of three gastrocamera examinations were performed on each patient. There was a minimum 3- to 4-week waiting period for operation for all patients, even when a definite diagnosis of cancer was made at the first examination, because of the limited facilities at the hospital. Longer delays in some patients occurred when there was uncertainty as to the exact diagnosis based on the results of the first

they may be large, are very superficial and consist of three subtypes: IIa are elevated, lIb are flat, and lIe are depressed. The extent of elevation or depression is usually less than the thickness of the mucosal layer. Type III lesions are malignant ulcers, often with a benign appearance.

Results One hundred twenty-two cases of early gastric cancer were included in this study. Seventy-one patients were seen first in the

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HEALING IN EARLY GASTRIC CANCER Healin!! tendency of ulcer in early ~astric cancer

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122 FIG. 2. The relationship between the healing tendency of ulcerations in early gastric cancer and the depth of the cancerous invasion. Solid circles indicate tumors with submucosal invasion; open circles indicate tumors with only mucosal involvement.

outpatient department. Ninety per cent of these patients had gastrointestinal complaints. Fifty-one patients were detected by mass survey examinations, 10% of whom had gastrointestinal complaints. A diagnosis of early gastric cancer was definitely made or suspected at the first gastrocamera examination performed on all of these patients. Seventy-two cases showed open ulceration on the first examination. Fifty-two of these lesions were classified lIc + III, 18 as III + lIe, and two as m. The latter lesions were indistinguishable endoscopically from benign ulcers. Fifty cases showed malignant-appearing ulcer scars and were classified lIc. Seventy-five patients underwent endoscopic biopsy and 20 underwent direct lavage cytology at the time of the first examination. There were no cases of achlorhydria following betazole or gastrin stimulation in this series. Figure 2 shows the results of follow-up examinations performed on these patients. Significant healing was observed in 51, or 70.8%, of the 72 patients with open ulcerations. No change occurred in the remaining ulcer cases and in the 50 cases of scar. Slightly more extensive healing was seen in those patients with malignancy limited to the mucosa. At the time of surgery, submucosal invasion was found in 48 of the 122 cases. Figure 3 shows the time required for the observed healing to take

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FIG. 3. The t ime required for healing to occur in early gastric cancer. Solid circles indicate tumors with submucosal invasion; open circles indicate tu mors with only mucosal involvement.

place. The rate of healing is very similar to that seen with benign ulcers. 16 Most of the cases in the appreciable healing category were observed for only a short time. Seventy-five of the 122 patients were biopsied at the time of the first examination. All of these biopsies were positive for cancer. Forty-four of these biopsies were obtained from the group of 51 patients who later showed either remarkable or appreciable ulcer healing. Twelve of the 20 cytological examinations performed in the latter two groups of patients at the first examination were also positive for malignant cells. Repeat cytological examinations in the remaining 8 patients were positive for malignant cells prior to operation. Thus, malignancy was documented before healing occurred in the great majority of ulcerations in this series which showed significant healing.

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FIG . 4a . First examination. The heavy oblique lined area indicated by the arrow is the ulcer crater. The dotted lines enclose the depressed area.

FIG. 5a. Four weeks. The ulcer crater was much smaller.

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FIG. 6a. Eight weeks. The ulcer crater was healed, leaving a minimal mucosal depression with slight congestion of the surrounding mucosa.

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FIG. 7a . Forty-three weeks. The depressed area was more prominent, with more irregularity of its mucosal surface.

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FIG. Sa . Sixty-three weeks. The depressed area was larger (indicated by the dotted line) and its surface was covered with a thin layer of mucus. The upper arrow points to a reddened nodular area. The fold tips were thinned, a sign of malignancy.

FIG. 9a. Seventy-one weeks. A large ulcer crater recurred at the same site as the original ulcer. The area of mucosal depression persisted.

FIG. 4.

0 weeks

FIG. 5.

4 weeks

FIG. 6.

8 weeks

FIG. 7.

43 weeks

FIG. 8.

63 weeks

FIG. 9.

71 weeks

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HEALING IN EARL Y GASTRIC CANCER

Case Report A 50-year-old woman entered with a chief complaint of abdominal pain of a few weeks' duration. Gastrocamera examination revealed (figs. 4 and 4a) a round ulceration of the anterior wall of the body of her stomach. The ulcer had a smooth, white, mucus-covered base. Although a diagnosis of benign ulcer was made at this time, in retrospect, a slight depression of the margin of ulcer and some interruption of folds can be seen, features which suggest malignancy. Mter 4 weeks of medical therapy, the ulcer was much smaller (figs. 5 and 00). It had assumed a horseshoe shape with a small peninsula-like mucosal intrusion. Mter 8 weeks the ulcer (figs. 6 and 6a) had completely healed, leaving a slightly depressed scar with folds radiating toward it. There was slight mucosal congestion around the depressed area. This appearance was quite benign . The next examination (figs. 7 and 7a) was made at 43 weeks. The scarred area showed some irregular nodularity with erythema and hemorrhage in the depressed

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portion. The endoscopic diagnosis of early gastric cancer was made at that time. That diagnosis was confirmed by a direct vision endoscopic biopsy. Surgery was advised. The patient refused operation and conservation therapy was continued. Twenty weeks later, 63 weeks after her initial examination, she was again examined with the gastrocamera (figs. 8 and 8a) At this time the depressed area was larger and covered with a thin coat of mucus. There were small erythematous nodules in the center of the area. The radiating folds showed thinning of their central ends. The final examination (figs. 9 and 9a) was made at 71 weeks. An ulceration was found with irregular depression of the surrounding mucosa. Endoscopically this was a classic example of early gastric cancer (type III + lIc). X-ray examinations were made at the time of each of the gastrocamera examinations. These studies confirmed the observation that the ulceration had healed and had recurred. Gastric analysis revealed a normal acid output.

FIG . 10. Photograph of the resected specimen showing an irregular ulcer crater on the lesser curvature sur· rounded by a slight mucosal depression with an uneven floor. The thinning of the fold tips can be clearly seen.

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FIG. 11. a, low power photograph of the microscopic specimen (X 3) . The area from A ~ B is invaded with cancerous cells. b, an enlarged view of the area indicated by C in a (X 30). Cancer was limited to the mucosa. e, high power photograph (X 150). The tumor was classified as adenocarcinoma tubulare.

May 1971 Benign-Ulcer. 'VV'\./'\I\fV'V

HEALING IN EARL Y GASTRIC CANCER Mllcosal Carcinoma.

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cR_~ FIG. 12. Life cycle of malignant ulcer. The black area indicates cancerous invasion. The malignant ulcer described in the Case Report traced a part of this cycle from A ~ B ~ C ~ D ~ A.

Gastrectomy was performed a few days after the last gastrocamera examination. The gross specimen is shown in figure 10. Photomicrographs of the specimen (fig. 11, a, b, and c) show an adenocarcinoma tubulare limited to the mucosa surrounding a large ulcer crater which extends into the muscularis. Discussion More than half of the early gastric cancers described in this study showed open ulceration. Seventy per cent of these ulcerations demonstrated significant healing during a short period of medical therapy. The complete healing of a malignant ulcer has been well documented. The remaining patients had malignant lesions with endoscopic features consistent with ulcer scarring. A peptic etiology for the ulceration seen in this series is suggested by the demonstration of acid secretion by all patients. In order to explain the findings of this study, a life cycle for a malignant ulcer has been proposed (fig. 12). Presumably, a malignant ulcer may begin as an ulceration in an area of mucosal cancer or as malignant degeneration of the margin of a benign ulcer. The data from this study would be consistent with either hypothesis, but would favor the first. A type III early gastric cancer (malignant ulcer) is shown

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in diagram A (fig. 12). Healing takes place when benign tissue grows in from the margins (diagram B, fig. 12), giving the lesion a relatively benign appearance (fig. 6). Murakami et al. 17 have confirmed the noncancerous nature of the regenerated center of a malignant ulcer crater. Next, malignant invasion of the scar occurs (diagram C, fig. 12; see figs. 7 and 8). Finally, in diagram D (fig. 12), a fresh ulceration again occurs (see fig. 9), completing the life cycle of the malignant ulcer. The growth of malignant tumors in the stomach is sufficiently slow that, theoretically, this cycle could repeat itself several times. Fifty of the cases of early gastric cancer described in this series showed scars on all examinations. The appearance of these lesions suggested that active ulceration had been present in the past. It is quite possible, if the period of observation had been longer, that many of these lesions would have developed open ulcers again and passed through the life cycle of the malignant ulcer which has been proposed. Many auth ors 4, 6, 18, 19 since Stromeyer20 advanced the theory in 1912 have discussed the possibility of peptic ulceration within a malignant lesion. Theoretically, in early gastric cancer, if ulceration were extensive enough, the malignancy could be cured. However, the occurrence of such an event would be very difficult to prove. Cases have been reported 21 • 22 where metastatic adenocarcinoma has been found in the liver of patients with histologically benign gastric ulcers. The demonstration of frequent significant healing and occasional complete healing of malignant gastric ulcers forces the revision of some traditional concepts of gastric ulcer management. The finding of 50% or greater healing of a gastric ulcer after 3 to 4 weeks of medical therapy permits the continuation of medical therapy, but should not result in a relaxation of the intensity of follow-up observations. The frequency with which asymptomatic recurrences of benign ulcerations occur and the real, although small, possibility of finding a malignancy similar to the case described

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here should make a late follow-up 6 to 12 months after the completion of ulcer healing a routine procedure for all patients with gastric ulcer. The subtleness of the changes of early gastric cancer, well demonstrated in the case described here, gives support to the recommendation of endoscopic rather than X-ray follow-up of gastric ulcer patients. The use of direct vision target biopsy and direct vision lavage or brush cytology significantly increases the value of endoscopy in managing gastric ulcer patients. With proper follow-up examinations, almost all cases of malignancy can be detected within a few months.1O As long as the cancer remains in the early stage, as it did in the cases described here, the prognosis remains excellent, with a 5year survival of approximately 90%.23

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REFERENCES 1. Taylor H: Practical evaluation of gastroscopy. Lancet 1:131-135, 1941 2. Gutmann RA: Ulceres benins, ulceres transformes et cancers ulceriformes. Gastroenterologia (Basel) 64:259-263, 1939 3. Jordan SM: Gastric ulcer and cancer. Gastroenterology 34:254-268, 1958 4. Mallory TB: Carcinoma in situ of the stomach and its bearing on the histogenesis of malignant ulcer. Arch Path (Chicago) 30:348-362, 1940 5. Eusterman GB: Carcinomatous gastric ulcer; misleading results of medical therapy. JAMA 118:1-5, 1942 6. Palmer WL, Humphreys EM: Gastric carcinoma: observation of peptic ulceration and healing. Gastroenterology 3:257-274, 1944 7. Bachrach WH: Observations upon the complete roentgenographic healing of neoplastic ulcerations of the stomach. Surg Gynec Obstet 114:69-82, 1962 8. Katsuki S, Okabe H, Otabe S, et al: Follow-up studies of malignant ulcers. Gastroent Endosc 7: 94-96, 1965 9. Imai T, Kubo T: Relationships between gastric

16. 17.

18.

19.

20.

21.

22. 23.

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ulcer and gastric cancer. Stomach and Intestine 3:677-679, 1968 Omori K, Miwa T, Kumagai H: Follow-up studies on healing ulcer in the early carcinoma of the stomach. Stomach and Intestine 3: 1643-1650, 1968 Sakita T, Oguro Y, Takasu S, et al: Endoscopic follow-up study of the gastric cancer in its early stage. Proceedings of the First International Symposium on Detection of Cancer, Spa, Belgium, 1968, p 442-449 Okabe H: Recent advances in gastroenterology, The Proceedings of the 3rd World Congress of Gastroenterology, vo!' 1, 1967, P 595-598 Tasaka S, Sakita T: Progress of gastrocamera examination, Proceedings of the Congress of the International Society of Endoscopy. Edited by Y Yoshitoshi. Tokyo, 1966, p 70-77 Kuru M, Sakita T, Ichikawa H, et al: Atlas of early carcinoma of the stomach. Tokyo, Nakayama-Shoten, 1967 Tasaka S: Statistical study of early gastric cancer collected throughout Japan. Gastroent Endosc 4: 4-14, 1962 Doll R: Medical treatment of gastric ulcer. Scot Med J 9:183-196, 1964 Murakami T, Yasui A, Takekawa H, et al: Noncancerous regenerated area at the center of ulcercancer. Trans Soc Path Jap 55:229-230, 1966 Gruber GB: Beitrag zur frage nach den beziehungen zwischen krebs und peptischem geschwur im oberen digestionstrakt. Z Krebsforsch 13:105138, 1913 Borrman R: Geschwulste des magens und duodenums, Henke-Lubarsch's Hanbuch der Speziellen Pathologischen Anatomie und Histologie, 8121016, 1926 Strom eyer F: Die pathogenese des ulcus ventriculi zugleich ein beitrag zur frage nach den beziehungen zwischen ulcus und carcinom. Beitr Path Anat 54:1-67, 1912 Willensky AO, Thalheimer W: The etiological relationship of benign ulcer to carcinoma of the stomach. Ann Surg 67:215-225, 1918 Ewing J: The beginnings of gastric cancer. Arner J Surg 31:204-206, 1936 Hayashida T, Kidokoro T: End results of early gastric cancer collected from 22 institutions. Stomach and Intestine 4:1077-1085, 1969