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Intramural Injection of Ethanol Under Direct Vision for the Treatment of Protuberant Lesions of the Stomach
GASTROENTEROLOGY 69:123-129, 1975 Copyright© 1975 by The Williams & Wilkins Co.
Vol. 69. No. I Printed in U.S .A.
INTRAMURAL INJECTION OF ETHANOL UNDER DIRECT VISION FOR THE TREATMENT OF PROTUBERANT LESIONS OF THE STOMACH TORU OTANI, M.D., PH.D., TAKESHI TATSUKA, M.D., KIYOHIKO KANAMARU, M.D., AND SHIGERU OKUDA, M.D., PH .D.
Department of Gastroenterologv . Cent er for Adult Diseases. Osaka. Japan
The experimental production of gastric ulcers in dogs by submucosal injection of ulcerogenic agents is described. The most satisfactory agent tested was 95% ethanol, because it produced immediate changes in the mucosa which delineated the size of the ulcer. The depth of ulceration could be controlled and the ulcer healed readily. Using this technique of ulcer formation, treatment of protuberant gastric lesions was attempted. Eradication of the pedunculated and narrow-based polyps in stomach was almost totally successful by injection into the base. Wide-based lesions, including atypical hyperplasia and the elevated type of early gastric cancer, were also completely eradicated in 96% of the treated cases. There have been no complications. An initial assessment of the practicality of this method in poor risk patients is presented. general condition was too poor to allow laparotomy and partial gastrectomy.
Since the use of the electrodiathermy snare with fiberoptic endoscopes, polypectomy in the stomach 1• 2 and colon 3 is performed more frequently by endoscopists, particularly for the treatment of pedunculated polyps. However, sessile polyps and wide-based polypoid growths pose certain difficulties and satisfactory results have not been reported . The local injection of antitumor agents or other ulcerogenic agents has been reported for the removal of gastric polypoid lesions, 4 • 5 although neither this method nor fulguration permits micros.copic examination of the lesion. This paper describes how the local injection of ethanol may effectively remove gastric polyps and wide-based polypoid growths. This method has also been used to eradicate elevated types of early gastric cancer in a small number of patients whose
Methods
Received March 19, 1974. Accepted September 11, 1974. Address requests for reprints to : Dr. Toru Otani , Department of Gastroenterology, The Cente r for Adult Diseases , 3-3, Nakamichi 1-chome, Higashinari-ku , Osaka 537, .Japan .
123
For experiment of artificial ulcer formation in the stomach, healthy mongrel dogs were anesthetized by Ketamine (Sankyo Co. Ltd., Tokyo), c30 mg per kg of body weight, by intramuscular injection. The stomach was washed out with tepid tap water prior to the insertion of the gastrofiberscope (Olympus GF-B 2 , Tokyo). The ulcers were produced by injection of the l<>llowing ulcerogenic agents: bleomycin (Nihonkagaku Co. Ltd., Tokyo) , mitomycin Sankyo Co. Ltd., Tokyo) , OK -432 (Chugai Pharmaceutical Co. Ltd. , Tokyo) , acetic acid (Wako Pure Chemical Industries Ltd ., Osaka), and 95 % ethanol. The agents were injected intramurally into the animal's stomach in various doses and concentrations. Ulcer formation was recorded by a gastrocamera examination before killing the animals for the pathological studies . In several animals, the experimental ulcer was followed endoscopically until it had healed. The animals were then killed and the ulcer site was examined histologically. About 50 patients with protuberant gastric lesions were treated by gastroscopic injection with 95% ethanol. These patients had previ-
124
OTANI ETAL.
ously been gastroscoped and a histological diagnosis was made by biopsy of the lesion. The amount of the injection varied according to the size and type of the lesion. In several patients, the gastroscopic injection had to be repeated to achieve complete necrosis. Eradication of the lesion was confirmed by gastroscopy a few days after the final injection.
Results The optimal doses and concentrations of the ulcerogenic agents required to form ul.cers at the submucosal level (Ul. II on Murakami's scale 6 ) are listed in table 1. To produce experimental ulcers, 0.2 ml each of bleomycin, mitomycin, and OK-432 was injected into the gastric mucosa of 3 dogs , along the lesser curvature: i.e., four injections of four decreasing concentrations (see table 1 for concentrations). To mark the injection point, each solution was colored by a few drops of India ink. The dogs were killed 3 days later and ulcers were found in all dogs in which the full concentration was used and in about one-half the dogs in which one-half the concentration was used, but the size of the experimental ulcer was not necessarily constant even when injections of similar concentrations of the same agent were compared. After injection of the two most diluted concentrations, ulcers rarely appear. Accurate measurement of the actual injected dose is difficult because leakage from the injection site may occur: therefore, it is difficult to predict the size of the ulcer. There was an added difficulty in controlling the size of the experimental ulcer after injection of the antitumor drugs, because no immediate change in the inTABLE
1. Artificial ulcer formation by ulcerogenic
agents Agent
Concentration
DifDose Ul. fusion
Immediate change
ml
Bleomycin M Mitomycin
15 mg/ml
0.2
II
+
-
2 mg/ml
0.2
II
+
-
5 KE/ml 15%
0.2 0.5
II II
+ ++
+
95%
0.5
II
-
++
c OK-432 Acetic acid EtOH
-
Vol . 69, No. I
jected mucosa was apparent. Both acetic acid and ethanol showed immediate change in the injected mucosa; ethanol showed not only more definite white discoloration than acetic acid, but the injection site was accompanied by marginal hyperemic change. This enabled us to predict the size of the ulcerated area after ethanol injection. To measure diffusion, methylene blue dye was dissolved along with 15% acetic acid and 95% ethanol solution. Three days after the injection, dogs were killed and infiltration of the dye from the margins of the experimental ulcer was examined macroscopically and histologically. Acetic acid infiltrated widely into the surrounding tissues, and although the ulcer formed extended only to the submucosa, methylene blue dye had diffused to the serosa. On the other hand, in~iltration of the dye into the surrounding tissue was almost negligible after ethanol injection. Superficial injections, which were intramucosal, made using a needle with a 2-mm tip, produced white bullae; deeper injections, to the submucosal level, resulted in white discoloration, followed by marginal hyperemic reactions within a few minutes of ethanol injection. Ethanol 95% produced the most effective results. Pure ethanol 99.5% caused catarrhal change with marked edema of submucosal layer in the surrounding area. Neither 60% nor 70% ethanol showed as clear a mucosal change as did the higher concentration. The histologically examined ulcers are shown in figure 1 according to the depth and amount of the injections. The ulcers were located in the lower portion of the stomach body in all cases. After injection of 0.5 ml, almost all ulcers extended to the submucosal level (Ul. II in the depth of ulcer by Murakami's scale 6 ), but when the needle was inserted in a direction perpendicular to the stomach wall with the stomach fully inflated, deeper ulcers were formed in 3 cases. A 1-ml injection usually produced ulcers to the level of the muscularis propria (Ul. III). Histological features of these ulcers are shown in figure 2. All ulcers of Ul. II produced by the injection of 0.5 ml of ethanol in the 3 dogs, showed considerable diminution in size in 2 weeks without
July 1975
125
REMOVAL OF GASTRIC POLYPS BY ETHANOL
any special treatment, and complete healing in 3 to 4 weeks. Microscopic studies of the healed mucosa revealed the smooth and regular configuration of a healed gastric ulcer. Because there was an immediate change in the mucosa, which made control of the depth and size of the ulcers relatively simple, and because these ulcers healed readily, we found that the production of experimental ulcers was best achieved by ethanol injection. By using this technique of ulcer formation with 95% ethanol injection, eradication of protuberant gastric lesions was then attempted clinically. The treated 54 cases are listed in table 2 according to size and type. The protuberant lesions were classified in 3 groups, as follows: pedunculated, narrow-based sessile, and wide-based sessile (fig. 3). The wide-based group includes not only hemispherical polyps, but also atypical hyperplasia and the elevated type of early gastric cancer. Not all treatments were successful. We failed to remove two of the pedunculated polyps. Since these were some of our earliest cases, this failure could possibly be attributed to inexperience. In later cases, we were totally successful in removing pedunculated and narrow-based types of lesions. The wide-based sessile group, including atypical hyperplasia and Ul
II
0
0
m
000
000 0 000 00
0 0
N
00
0
0.5
1.0
O : Lesser O : Greater
curvature
0.25
mJ!
curvature
FIG. 1. Relationship between depth of artificial ulcer and injected doses of ethanol in the dog's stomach. 0, e , the ulcers made on the lesser curvature side and greater curvature side, respectively.
FIG. 2. Cut surface of artificial ulcers produced by intramural injection of95% ethanol. The smaller ulcer (left) was produced by intramural injection of 0.5 ml of ethanol, and the larger one (right) was produced by that of 1.0 ml.
TABLE
2. Protuberant lesion of the stomach treated by ethanol injection Size
Type -1.0 1.1 - 2.0 2.1 - 3.0
Widebased Narrowbased Pedunculated Total
7
11 (1)"
5
3.1-
Total
2
25 (1)
8 3 (2) 14
18 (2) 25 (1)
8 21 (2)
4
9
2
54 (3)
"Numbers in parentheses are unsuccessful cases.
Ila type of early gastric cancer, were successfully eradicated in 96% of the cases. Histological diagnosis of the 54 lesions was made by biopsies performed before the ethanol injection (table 3). The classification of N agayo et al. 7 for histological diagnosis of stomach biopsies was used, and is as follows: group I, normal tissue and benign lesions without atypism; group II, benign lesions with slight atypism; group III, borderline between benign and malignant lesions; group IV, cancer is strongly suspected; group V, cancer. Of 54 cases, 35 were hyperplastic or adenomatous polyps (group I), 17 showed atypical hyperplasia (group Ill), and 2 were cases of early gastric cancer, type Ila (group V). In cases which showed lesions of groups III and V, complete eradication was confirmed by biopsy from the margin of the resulting ulcer. The 17 cases of atypical hyperplasia were all successfully removed.
126
OTANI ETAL.
Wide- based sessile FIG .
N arrow - based sessile
P eduncul ated
3. Injection sites for the three categories of
polyp. TABLE
3. Histology of the protruberant lesio n
Grade of atypism
Widebased
Group V: Ila early 2 (1) " gastric cancer Group Ill: atypical 17 (2) hyperplasia Group 1: hyperplastic polyp Total a
25 (3)
Narrowbased
Pedunculated
Total
2 17 8
21
35
8
21
54
Numbers in parentheses are operated cases.
Details of the 2 cases of early gastric cancer will be discussed later in the paper. Table 4 shows the number of treatments needed for complete removal. As might be expected, wide- based sessile growths required a greater number of injections and t he treatment occasionally had to be repeated, but this depended very much on the experience of the endoscopist. Three treatments were required to remove the two largest wide-based growths which were more than 3 em in diameter. With both pedunculated and wide-based lesions, removal during the first treatment is, of course, desirable. This can be achieved by adjusting the injection dose and by properly selecting the injection sites. Intramural injection of ethanol usually causes marginal elevation, a few days later, around t he resultant ulcer, which often makes it difficult to discern the border of the original lesion. Table 5 shows the healing time of the resultant ulcers in 43 cases. Complete healing with scar formation was seen within 6 weeks in every case, including large widebased atypical hyperplasia of more than 3 em in diameter (figs. 4-6).
widely accepted, although the evidence is debatable. 8 • 9 On the other hand, t he risk of cancer in gastric polyps seems to be extremely small, 10 - 13 so that it is questionable whether an asymptomatic polyp of the stomach should be excised. McNeer, 14 however, has maintained that the safest procedure to follow in the management of polyps in low risk patien ts is removal. With the availabi lity of electrodiathermy snares for use with fiberoptic endoscopes, excision biopsy is the treatment of choice for narrow-based sessile and pedunculated polyps, because the lesion can be recovered for histological examination in good condition . Polyp removal by intramural injection of ethanol is appropriate for the management of early gastric cancer in poor ri sk patients who have other diseases and for elderly patients with a short life expectancy. Experiments with intramural injections to remove gastric polypoid lesions have been reported using antitumor agents' or acetic acid. 5 Antitumor agents, however, seem to cause not only slower repair of the resultant ulcer, but also diffiTABLE 4.
Numb er of treatments for eradication Size Total
Treatment' -1.0
1
w N
p 2
w p
3
5 5 1
-
1
-
4
w
-
3
-
4
-
1
8
1 1
N
p
1.1 - 2.0 2.1 - 3.0 3. 1-
-
N
1
-
-
5
4
1
9
2
7
-
1
2
-
3
1
-
3 1 3
1
9 5
3
1
-
-
4
w
1 1
N
p Tota l
Discussion The concept that adenomatous polyps of the colon are precancerous growt h s is
Vol . 69, No.1
16
1
-
2
1
24
9
2
51
a W, wide-based sessile growth (24 cases); N , narrow-based sessile polyp (8 cases); P, pedun cu lated polyp (19 cases) .
July 1975
REMOVAL OF GASTRIC POLYPS HY ETHANOL
TABLE
5. Healin{< time of resultant ulcer Size
Term
Toto) - 1.0
1.1 - 2.0 2.1-3.0
3.1-
wks
2-3
w N p
2 -
-
-
I
3
-
6 (14 %)
-
16 (:l7 %)
-
13 (:lO%)
3-4
w
2
N p
4 1
3
-
I
-
4
I
4-5
w N p
1 4
-
2
2
-
-
2
2
5-6
w N p Total
-
-
14
19
2
1 4
-
1
9
127
sile polyp it is better to produce necrosis of the whole lesion at the first treatment, giving several injections from the surface. Otherwise, it becomes difficult to discern the actual border of the lesion from the marginal elevation of the artificial ulcer. Using Okuda's criteria. endoscopic dia~ nosis of the depth of involvement of the cancerous lesion in early gastric cancer is reasonably reliable. Therefore, in cases of small early ~astr i c cancer, whose depth of involvement is rest ricted within the submucosa, it is reasonable to eradicate the cancer tissue by producing an artificial ulcer of the degree Ul. II. if the patient is a bad risk for surgery. Complete eradication should be confirmed by post-treatment biopsy and follow-up. One cancer case was a 65-year-old male with a small gastric cancer type IIa (0.5 em
8 (19 %)
1
43
"W, wide-based sessile growth (15 cases); N, narrow-based sessile polyp (8 cases); P, pedunculated polyp ( 18 cases).
culty in controllin~ its size because of the absence of immediate change in the injected mucosa. Accurate measurement of the injected doses is difficult because of the possibility of leaka~e of the injected material. Acetic acid showed some immediate change in the intramural injection , but it was not as clearly defined as that produced by ethanol. It was also inferior in localization, as indicated by tests of the extent of diffusion with methylene blue. Ethanol injection seems to produce a sharp delineation between the necrotized area and the surrounding tissue by a hyperemic reaction. Injection sites for the three categories of polyp are indicated in figure 3. Although a pedunculated polyp may be eradicated by injection at the middle of the stalk, the base of the stalk still resembles a small sessile polyp. Therefore, the best method is to inject a root of the stalk. A successful injection can be recognized by the discoloration of the tip of polyp which becomes dark red when necrosis by ethanol involves the main vessels of the stalk. For a wide-based ses-
F1c:. 4. A case of pedunculated pol yp. A. gas trocamera findings beli>re treatment; B. sequential ulcers I week after injection; C. complete scarring several weeks lat er.
128
OTANI ETAL.
Vol . 69, No.1
diameter) situated close to the cardiac orifice . Total gastrectomy was contraindicated because of poor respiratory function due to emphysema. The biopsy examination from the margin of the resultant ulcer was negative on the 3rd day after the first treatment by ethanol injection, but evidence of malignancy was demonstrated again in the follow-up examination by biopsy 1 month later. This may have been due to a reduction in the ethanol dose which was made in an attempt to avoid the production of stenosis of the gastroesophageal junction which might result if a large ulceration was formed. Another ethanol injection was given and a biopsy was taken after complete repair of the second artificial ulcer 3 months later was negative. The
FIG. 6. A case of atypical hyperplasia. A, gastrocamera findings before treatment; B, sequential ulcers I week after injection; C, complete scarring several weeks later.
FIG . 5. A case of narrow-based sessile polyp . A, gastrocamera findings before treatment; B, sequential ulcers I week after injection ; C, complete scarring several weeks late r .
condition of the patient's stomach is now satisfactory and he does not have dysphagia. The other cancer case was a 74-year-old female with IIa type early gastric cancer of approximately 2.0 em in diameter on the lesser curvature of the middle portion of the stomach. She underwent operation 3 days after the first ethanol injection. To our disappointment, postoperative histological examination of the resected stomach still revealed some residual cancer tissue on the anal side of the artificial ulcer. This is the only unsuccessful case in the wide-based sessile growths shown in table 2; complete eradication might have been achieved by another ethanol injection. With additional trials of preoperative
July 1975
REMOVAL OF GASTRIC POLYPS BY ETHANOL
treatment by ethanol injection, followed by postoperative histological examination, it is expected that a more precise evaluation of this technique will be achieved. REFERENCES 1. Akasaka Y, Kawai K, Nakajima M, et al: Endo· scopic polypectomy with diathermy snare EPD . Gastroenterol Enclose 15: 389-393, 1973 2. Classen M, Demling L: Operative Gastroskopie, fiberendoskopische Polypenabtragung in Magen. Deutsche Med W, 96:1466-1467, 1971. 3. Wolff WI, Shinya H: Colonofiberscopic management of colonic polyps. Dis Colon Rectum 16:87-93, 1973 4. Ujiie T, Ikeda S, et al: Studies on intramural stomach injection under direct gastrofiberscope observation. Proceedings of the 2nd World Congress of Gastrointestinal Endoscopy in Rome and Copenhagen. Piccin Medical Books, 1970, p 197202 5. Ak asa ka Y, K awa i K, Toriie S, et al : Endoscopi· cal local injection method (ELl) for cancer and polypous lesion . J Kyoto Prefect Univers Med 8 1:365-381 , 1972 6. Murakami T , Matsui T , Koide H, et al: Operative indication of gastric ulcer: from the point of view of pathology. (in Japanese). Saishin lgaku 14:1013-1017. 1959 7. Nagayo T, Mochizuki T, Sano R, et al: A draft for histological grouping of biopsied materials of the
8.
9.
10.
11. 12. 13. 14.
15.
16.
129
stomach for diagnosis of gastric carcinoma. J ap J Cancer Clinics 15:937-952, 1969 Rinder JA, Kirsner JB, Moeller HC, et al: Polyps of the colon and rectum. Their incidence and relationship to carcinoma. Am J Med 16:555-564, 1954 Spratt JS Jr, Ackerman LV , Moter CA: Relationship of polyps of the colon to colonic cancer. Ann Surg 148:682-698, 1958 Monaco AP, Roth SI: Adenomatous polyps of the stomach. A clinical and pathological study of 153 cases. Cancer 15: 456-467, 1962 Marshak RH , Feldman F: Gastric polyps. Am J Dig Dis 10:909-935, 1965 Yarnis H , Marshak RH: Gastric polyps. JAMA 148:1088-1094, 1952 Carey JB , Hay LJ: Gastric polyps . Gastroenterology 14:280-286, 1950 McNeer G: The diagnosis and treatment of early and established cancer of the stomach. Fourth National Cancer Conference Proceedings. Phila· delphia, JB Lippincott Co, 1960, p 413 Okuda S : Differential dia!(nosis of early J.(astric carcinoma from advanced carcinoma. Gann Monograph on Cancer Research 11: Early gastric cancer. University of Tokyo Press, 1971, p 283301 Murakami T : Pathomorphological dia!(nosis. Def· inition and gross classification of early gastric cancer. Gann Mono!(raph on Cancer Resea rch 11: Early ga;tric ca ncer. University of Tokyo Press, 1971, p 53-55
Vol. 69. No. I Printed in U.S .A.
INTRAMURAL INJECTION OF ETHANOL UNDER DIRECT VISION FOR THE TREATMENT OF PROTUBERANT LESIONS OF THE STOMACH TORU OTANI, M.D., PH.D., TAKESHI TATSUKA, M.D., KIYOHIKO KANAMARU, M.D., AND SHIGERU OKUDA, M.D., PH .D.
Department of Gastroenterologv . Cent er for Adult Diseases. Osaka. Japan
The experimental production of gastric ulcers in dogs by submucosal injection of ulcerogenic agents is described. The most satisfactory agent tested was 95% ethanol, because it produced immediate changes in the mucosa which delineated the size of the ulcer. The depth of ulceration could be controlled and the ulcer healed readily. Using this technique of ulcer formation, treatment of protuberant gastric lesions was attempted. Eradication of the pedunculated and narrow-based polyps in stomach was almost totally successful by injection into the base. Wide-based lesions, including atypical hyperplasia and the elevated type of early gastric cancer, were also completely eradicated in 96% of the treated cases. There have been no complications. An initial assessment of the practicality of this method in poor risk patients is presented. general condition was too poor to allow laparotomy and partial gastrectomy.
Since the use of the electrodiathermy snare with fiberoptic endoscopes, polypectomy in the stomach 1• 2 and colon 3 is performed more frequently by endoscopists, particularly for the treatment of pedunculated polyps. However, sessile polyps and wide-based polypoid growths pose certain difficulties and satisfactory results have not been reported . The local injection of antitumor agents or other ulcerogenic agents has been reported for the removal of gastric polypoid lesions, 4 • 5 although neither this method nor fulguration permits micros.copic examination of the lesion. This paper describes how the local injection of ethanol may effectively remove gastric polyps and wide-based polypoid growths. This method has also been used to eradicate elevated types of early gastric cancer in a small number of patients whose
Methods
Received March 19, 1974. Accepted September 11, 1974. Address requests for reprints to : Dr. Toru Otani , Department of Gastroenterology, The Cente r for Adult Diseases , 3-3, Nakamichi 1-chome, Higashinari-ku , Osaka 537, .Japan .
123
For experiment of artificial ulcer formation in the stomach, healthy mongrel dogs were anesthetized by Ketamine (Sankyo Co. Ltd., Tokyo), c30 mg per kg of body weight, by intramuscular injection. The stomach was washed out with tepid tap water prior to the insertion of the gastrofiberscope (Olympus GF-B 2 , Tokyo). The ulcers were produced by injection of the l<>llowing ulcerogenic agents: bleomycin (Nihonkagaku Co. Ltd., Tokyo) , mitomycin Sankyo Co. Ltd., Tokyo) , OK -432 (Chugai Pharmaceutical Co. Ltd. , Tokyo) , acetic acid (Wako Pure Chemical Industries Ltd ., Osaka), and 95 % ethanol. The agents were injected intramurally into the animal's stomach in various doses and concentrations. Ulcer formation was recorded by a gastrocamera examination before killing the animals for the pathological studies . In several animals, the experimental ulcer was followed endoscopically until it had healed. The animals were then killed and the ulcer site was examined histologically. About 50 patients with protuberant gastric lesions were treated by gastroscopic injection with 95% ethanol. These patients had previ-
124
OTANI ETAL.
ously been gastroscoped and a histological diagnosis was made by biopsy of the lesion. The amount of the injection varied according to the size and type of the lesion. In several patients, the gastroscopic injection had to be repeated to achieve complete necrosis. Eradication of the lesion was confirmed by gastroscopy a few days after the final injection.
Results The optimal doses and concentrations of the ulcerogenic agents required to form ul.cers at the submucosal level (Ul. II on Murakami's scale 6 ) are listed in table 1. To produce experimental ulcers, 0.2 ml each of bleomycin, mitomycin, and OK-432 was injected into the gastric mucosa of 3 dogs , along the lesser curvature: i.e., four injections of four decreasing concentrations (see table 1 for concentrations). To mark the injection point, each solution was colored by a few drops of India ink. The dogs were killed 3 days later and ulcers were found in all dogs in which the full concentration was used and in about one-half the dogs in which one-half the concentration was used, but the size of the experimental ulcer was not necessarily constant even when injections of similar concentrations of the same agent were compared. After injection of the two most diluted concentrations, ulcers rarely appear. Accurate measurement of the actual injected dose is difficult because leakage from the injection site may occur: therefore, it is difficult to predict the size of the ulcer. There was an added difficulty in controlling the size of the experimental ulcer after injection of the antitumor drugs, because no immediate change in the inTABLE
1. Artificial ulcer formation by ulcerogenic
agents Agent
Concentration
DifDose Ul. fusion
Immediate change
ml
Bleomycin M Mitomycin
15 mg/ml
0.2
II
+
-
2 mg/ml
0.2
II
+
-
5 KE/ml 15%
0.2 0.5
II II
+ ++
+
95%
0.5
II
-
++
c OK-432 Acetic acid EtOH
-
Vol . 69, No. I
jected mucosa was apparent. Both acetic acid and ethanol showed immediate change in the injected mucosa; ethanol showed not only more definite white discoloration than acetic acid, but the injection site was accompanied by marginal hyperemic change. This enabled us to predict the size of the ulcerated area after ethanol injection. To measure diffusion, methylene blue dye was dissolved along with 15% acetic acid and 95% ethanol solution. Three days after the injection, dogs were killed and infiltration of the dye from the margins of the experimental ulcer was examined macroscopically and histologically. Acetic acid infiltrated widely into the surrounding tissues, and although the ulcer formed extended only to the submucosa, methylene blue dye had diffused to the serosa. On the other hand, in~iltration of the dye into the surrounding tissue was almost negligible after ethanol injection. Superficial injections, which were intramucosal, made using a needle with a 2-mm tip, produced white bullae; deeper injections, to the submucosal level, resulted in white discoloration, followed by marginal hyperemic reactions within a few minutes of ethanol injection. Ethanol 95% produced the most effective results. Pure ethanol 99.5% caused catarrhal change with marked edema of submucosal layer in the surrounding area. Neither 60% nor 70% ethanol showed as clear a mucosal change as did the higher concentration. The histologically examined ulcers are shown in figure 1 according to the depth and amount of the injections. The ulcers were located in the lower portion of the stomach body in all cases. After injection of 0.5 ml, almost all ulcers extended to the submucosal level (Ul. II in the depth of ulcer by Murakami's scale 6 ), but when the needle was inserted in a direction perpendicular to the stomach wall with the stomach fully inflated, deeper ulcers were formed in 3 cases. A 1-ml injection usually produced ulcers to the level of the muscularis propria (Ul. III). Histological features of these ulcers are shown in figure 2. All ulcers of Ul. II produced by the injection of 0.5 ml of ethanol in the 3 dogs, showed considerable diminution in size in 2 weeks without
July 1975
125
REMOVAL OF GASTRIC POLYPS BY ETHANOL
any special treatment, and complete healing in 3 to 4 weeks. Microscopic studies of the healed mucosa revealed the smooth and regular configuration of a healed gastric ulcer. Because there was an immediate change in the mucosa, which made control of the depth and size of the ulcers relatively simple, and because these ulcers healed readily, we found that the production of experimental ulcers was best achieved by ethanol injection. By using this technique of ulcer formation with 95% ethanol injection, eradication of protuberant gastric lesions was then attempted clinically. The treated 54 cases are listed in table 2 according to size and type. The protuberant lesions were classified in 3 groups, as follows: pedunculated, narrow-based sessile, and wide-based sessile (fig. 3). The wide-based group includes not only hemispherical polyps, but also atypical hyperplasia and the elevated type of early gastric cancer. Not all treatments were successful. We failed to remove two of the pedunculated polyps. Since these were some of our earliest cases, this failure could possibly be attributed to inexperience. In later cases, we were totally successful in removing pedunculated and narrow-based types of lesions. The wide-based sessile group, including atypical hyperplasia and Ul
II
0
0
m
000
000 0 000 00
0 0
N
00
0
0.5
1.0
O : Lesser O : Greater
curvature
0.25
mJ!
curvature
FIG. 1. Relationship between depth of artificial ulcer and injected doses of ethanol in the dog's stomach. 0, e , the ulcers made on the lesser curvature side and greater curvature side, respectively.
FIG. 2. Cut surface of artificial ulcers produced by intramural injection of95% ethanol. The smaller ulcer (left) was produced by intramural injection of 0.5 ml of ethanol, and the larger one (right) was produced by that of 1.0 ml.
TABLE
2. Protuberant lesion of the stomach treated by ethanol injection Size
Type -1.0 1.1 - 2.0 2.1 - 3.0
Widebased Narrowbased Pedunculated Total
7
11 (1)"
5
3.1-
Total
2
25 (1)
8 3 (2) 14
18 (2) 25 (1)
8 21 (2)
4
9
2
54 (3)
"Numbers in parentheses are unsuccessful cases.
Ila type of early gastric cancer, were successfully eradicated in 96% of the cases. Histological diagnosis of the 54 lesions was made by biopsies performed before the ethanol injection (table 3). The classification of N agayo et al. 7 for histological diagnosis of stomach biopsies was used, and is as follows: group I, normal tissue and benign lesions without atypism; group II, benign lesions with slight atypism; group III, borderline between benign and malignant lesions; group IV, cancer is strongly suspected; group V, cancer. Of 54 cases, 35 were hyperplastic or adenomatous polyps (group I), 17 showed atypical hyperplasia (group Ill), and 2 were cases of early gastric cancer, type Ila (group V). In cases which showed lesions of groups III and V, complete eradication was confirmed by biopsy from the margin of the resulting ulcer. The 17 cases of atypical hyperplasia were all successfully removed.
126
OTANI ETAL.
Wide- based sessile FIG .
N arrow - based sessile
P eduncul ated
3. Injection sites for the three categories of
polyp. TABLE
3. Histology of the protruberant lesio n
Grade of atypism
Widebased
Group V: Ila early 2 (1) " gastric cancer Group Ill: atypical 17 (2) hyperplasia Group 1: hyperplastic polyp Total a
25 (3)
Narrowbased
Pedunculated
Total
2 17 8
21
35
8
21
54
Numbers in parentheses are operated cases.
Details of the 2 cases of early gastric cancer will be discussed later in the paper. Table 4 shows the number of treatments needed for complete removal. As might be expected, wide- based sessile growths required a greater number of injections and t he treatment occasionally had to be repeated, but this depended very much on the experience of the endoscopist. Three treatments were required to remove the two largest wide-based growths which were more than 3 em in diameter. With both pedunculated and wide-based lesions, removal during the first treatment is, of course, desirable. This can be achieved by adjusting the injection dose and by properly selecting the injection sites. Intramural injection of ethanol usually causes marginal elevation, a few days later, around t he resultant ulcer, which often makes it difficult to discern the border of the original lesion. Table 5 shows the healing time of the resultant ulcers in 43 cases. Complete healing with scar formation was seen within 6 weeks in every case, including large widebased atypical hyperplasia of more than 3 em in diameter (figs. 4-6).
widely accepted, although the evidence is debatable. 8 • 9 On the other hand, t he risk of cancer in gastric polyps seems to be extremely small, 10 - 13 so that it is questionable whether an asymptomatic polyp of the stomach should be excised. McNeer, 14 however, has maintained that the safest procedure to follow in the management of polyps in low risk patien ts is removal. With the availabi lity of electrodiathermy snares for use with fiberoptic endoscopes, excision biopsy is the treatment of choice for narrow-based sessile and pedunculated polyps, because the lesion can be recovered for histological examination in good condition . Polyp removal by intramural injection of ethanol is appropriate for the management of early gastric cancer in poor ri sk patients who have other diseases and for elderly patients with a short life expectancy. Experiments with intramural injections to remove gastric polypoid lesions have been reported using antitumor agents' or acetic acid. 5 Antitumor agents, however, seem to cause not only slower repair of the resultant ulcer, but also diffiTABLE 4.
Numb er of treatments for eradication Size Total
Treatment' -1.0
1
w N
p 2
w p
3
5 5 1
-
1
-
4
w
-
3
-
4
-
1
8
1 1
N
p
1.1 - 2.0 2.1 - 3.0 3. 1-
-
N
1
-
-
5
4
1
9
2
7
-
1
2
-
3
1
-
3 1 3
1
9 5
3
1
-
-
4
w
1 1
N
p Tota l
Discussion The concept that adenomatous polyps of the colon are precancerous growt h s is
Vol . 69, No.1
16
1
-
2
1
24
9
2
51
a W, wide-based sessile growth (24 cases); N , narrow-based sessile polyp (8 cases); P, pedun cu lated polyp (19 cases) .
July 1975
REMOVAL OF GASTRIC POLYPS HY ETHANOL
TABLE
5. Healin{< time of resultant ulcer Size
Term
Toto) - 1.0
1.1 - 2.0 2.1-3.0
3.1-
wks
2-3
w N p
2 -
-
-
I
3
-
6 (14 %)
-
16 (:l7 %)
-
13 (:lO%)
3-4
w
2
N p
4 1
3
-
I
-
4
I
4-5
w N p
1 4
-
2
2
-
-
2
2
5-6
w N p Total
-
-
14
19
2
1 4
-
1
9
127
sile polyp it is better to produce necrosis of the whole lesion at the first treatment, giving several injections from the surface. Otherwise, it becomes difficult to discern the actual border of the lesion from the marginal elevation of the artificial ulcer. Using Okuda's criteria. endoscopic dia~ nosis of the depth of involvement of the cancerous lesion in early gastric cancer is reasonably reliable. Therefore, in cases of small early ~astr i c cancer, whose depth of involvement is rest ricted within the submucosa, it is reasonable to eradicate the cancer tissue by producing an artificial ulcer of the degree Ul. II. if the patient is a bad risk for surgery. Complete eradication should be confirmed by post-treatment biopsy and follow-up. One cancer case was a 65-year-old male with a small gastric cancer type IIa (0.5 em
8 (19 %)
1
43
"W, wide-based sessile growth (15 cases); N, narrow-based sessile polyp (8 cases); P, pedunculated polyp ( 18 cases).
culty in controllin~ its size because of the absence of immediate change in the injected mucosa. Accurate measurement of the injected doses is difficult because of the possibility of leaka~e of the injected material. Acetic acid showed some immediate change in the intramural injection , but it was not as clearly defined as that produced by ethanol. It was also inferior in localization, as indicated by tests of the extent of diffusion with methylene blue. Ethanol injection seems to produce a sharp delineation between the necrotized area and the surrounding tissue by a hyperemic reaction. Injection sites for the three categories of polyp are indicated in figure 3. Although a pedunculated polyp may be eradicated by injection at the middle of the stalk, the base of the stalk still resembles a small sessile polyp. Therefore, the best method is to inject a root of the stalk. A successful injection can be recognized by the discoloration of the tip of polyp which becomes dark red when necrosis by ethanol involves the main vessels of the stalk. For a wide-based ses-
F1c:. 4. A case of pedunculated pol yp. A. gas trocamera findings beli>re treatment; B. sequential ulcers I week after injection; C. complete scarring several weeks lat er.
128
OTANI ETAL.
Vol . 69, No.1
diameter) situated close to the cardiac orifice . Total gastrectomy was contraindicated because of poor respiratory function due to emphysema. The biopsy examination from the margin of the resultant ulcer was negative on the 3rd day after the first treatment by ethanol injection, but evidence of malignancy was demonstrated again in the follow-up examination by biopsy 1 month later. This may have been due to a reduction in the ethanol dose which was made in an attempt to avoid the production of stenosis of the gastroesophageal junction which might result if a large ulceration was formed. Another ethanol injection was given and a biopsy was taken after complete repair of the second artificial ulcer 3 months later was negative. The
FIG. 6. A case of atypical hyperplasia. A, gastrocamera findings before treatment; B, sequential ulcers I week after injection; C, complete scarring several weeks later.
FIG . 5. A case of narrow-based sessile polyp . A, gastrocamera findings before treatment; B, sequential ulcers I week after injection ; C, complete scarring several weeks late r .
condition of the patient's stomach is now satisfactory and he does not have dysphagia. The other cancer case was a 74-year-old female with IIa type early gastric cancer of approximately 2.0 em in diameter on the lesser curvature of the middle portion of the stomach. She underwent operation 3 days after the first ethanol injection. To our disappointment, postoperative histological examination of the resected stomach still revealed some residual cancer tissue on the anal side of the artificial ulcer. This is the only unsuccessful case in the wide-based sessile growths shown in table 2; complete eradication might have been achieved by another ethanol injection. With additional trials of preoperative
July 1975
REMOVAL OF GASTRIC POLYPS BY ETHANOL
treatment by ethanol injection, followed by postoperative histological examination, it is expected that a more precise evaluation of this technique will be achieved. REFERENCES 1. Akasaka Y, Kawai K, Nakajima M, et al: Endo· scopic polypectomy with diathermy snare EPD . Gastroenterol Enclose 15: 389-393, 1973 2. Classen M, Demling L: Operative Gastroskopie, fiberendoskopische Polypenabtragung in Magen. Deutsche Med W, 96:1466-1467, 1971. 3. Wolff WI, Shinya H: Colonofiberscopic management of colonic polyps. Dis Colon Rectum 16:87-93, 1973 4. Ujiie T, Ikeda S, et al: Studies on intramural stomach injection under direct gastrofiberscope observation. Proceedings of the 2nd World Congress of Gastrointestinal Endoscopy in Rome and Copenhagen. Piccin Medical Books, 1970, p 197202 5. Ak asa ka Y, K awa i K, Toriie S, et al : Endoscopi· cal local injection method (ELl) for cancer and polypous lesion . J Kyoto Prefect Univers Med 8 1:365-381 , 1972 6. Murakami T , Matsui T , Koide H, et al: Operative indication of gastric ulcer: from the point of view of pathology. (in Japanese). Saishin lgaku 14:1013-1017. 1959 7. Nagayo T, Mochizuki T, Sano R, et al: A draft for histological grouping of biopsied materials of the
8.
9.
10.
11. 12. 13. 14.
15.
16.
129
stomach for diagnosis of gastric carcinoma. J ap J Cancer Clinics 15:937-952, 1969 Rinder JA, Kirsner JB, Moeller HC, et al: Polyps of the colon and rectum. Their incidence and relationship to carcinoma. Am J Med 16:555-564, 1954 Spratt JS Jr, Ackerman LV , Moter CA: Relationship of polyps of the colon to colonic cancer. Ann Surg 148:682-698, 1958 Monaco AP, Roth SI: Adenomatous polyps of the stomach. A clinical and pathological study of 153 cases. Cancer 15: 456-467, 1962 Marshak RH , Feldman F: Gastric polyps. Am J Dig Dis 10:909-935, 1965 Yarnis H , Marshak RH: Gastric polyps. JAMA 148:1088-1094, 1952 Carey JB , Hay LJ: Gastric polyps . Gastroenterology 14:280-286, 1950 McNeer G: The diagnosis and treatment of early and established cancer of the stomach. Fourth National Cancer Conference Proceedings. Phila· delphia, JB Lippincott Co, 1960, p 413 Okuda S : Differential dia!(nosis of early J.(astric carcinoma from advanced carcinoma. Gann Monograph on Cancer Research 11: Early gastric cancer. University of Tokyo Press, 1971, p 283301 Murakami T : Pathomorphological dia!(nosis. Def· inition and gross classification of early gastric cancer. Gann Mono!(raph on Cancer Resea rch 11: Early ga;tric ca ncer. University of Tokyo Press, 1971, p 53-55