World J. Surg. 3, 693-700, 1979
of Stirgery
Diagnosis of Advanced Gastric Cancer Fusahiro Nagao, M.D., and N o b u h i r o Takahashi, M.D. Second Department of Surgery, Jikei University School of Medicine, Tokyo, Japan surgical s p e c i m e n s were examined, and a survey was made regarding the patients' s y m p t o m s and the results of diagnostic procedures that the patients underwent. Cases of " e a r l y gastric c a n c e r " (defined as c a n c e r limited to the m u c o s a or s u b m u c o s a ) were excluded. C o m p a r i s o n s were made with cases of early gastric cancer, simple l a p a r o t o m y , and benign gastric diseases. All the patients were treated during the l l - y e a r period from 1965 to 1975 in the Second D e p a r t m e n t of Surgery of the Jikei University School o f Medicine in T o k y o .
A series of 536 patients who underwent gastric resections for advanced gastric cancer has been reviewed with regard to the diagnostic procedures for detecting gastric cancer. There were no characteristic symptoms of gastric cancer, but weight loss was a frequent complaint. Variation in the type and frequency of symptoms did not appear to depend on the presence or absence of metastases. Patients whose operations were delayed more than one year after the onset of symptoms accounted for 33% of the series, and 38% of these had visited their physicians within 6 months after the onset of symptoms but were misdiagnosed as having chronic gastritis or benign ulcer. The results of various laboratory examinations were not specific. Gastric acidity was found to be distinctly lower than in patients with benign gastric disease. Techniques of radiology, endoscopy, and endoscopic biopsy of the stomach have greatly improved, and the overall rates of correct diagnosis of gastric cancer were 96% by x-ray, 98% by endoscopy, and 90% by biopsy. These rates were slightly lowered when only Borrmann type IV lesions were considered. Celiac angiography was useful to determine the extent or depth of cancerous invasion and to detect liver metastases. The frequency of positive PPD or DNCB skin tests appeared to decrease as the stage of cancer advanced, indicating immunologic impairment in advanced gastric cancer.
Symptomatology
When gastric cancer has r e a c h e d a s y m p t o m a t i c stage, the s y m p t o m s are usually multiple. To detect the m o s t specific s y m p t o m of gastric cancer, if there is any, the earliest s y m p t o m s were reviewed and c o m p a r e d with those of patients with benign ulcer. It was found that there are m a n y s y m p t o m s comm o n to gastric cancer and benign ulcer, although their f r e q u e n c y is not analogous (Table 1). Weight loss was a frequent early s y m p t o m of gastric c a n c e r when the patients first s o u g h t medical advice, and m a n y patients were bothered b y a feeling o f emaciation. On the other hand, patients with benign ulcer more frequently complained o f nausea, vomiting, and heartburn, the s y m p t o m s suggestive o f an acute exacerbation. S o m e gastric c a n c e r patients had a course similar to that of patients with benign ulcer for a period of time and e v e n r e s p o n d e d to conservative treatment. The s y m p t o m s of gastric cancer varied according to the stage of the disease, but there were no distinct differences b e t w e e n patients who had a d v a n c e d cancers and those who had lesions that were not far advanced. The term " f a r ad-
Diagnosis o f gastric cancer in J a p a n has greatly imp r o v e d in the past 10-20 years and, consequently, detection o f early gastric c a n c e r has b e c o m e m o r e frequent. N e v e r t h e l e s s , o v e r 80% of patients who visit clinics b e c a u s e o f gastric c a n c e r are reported to have a d v a n c e d cancer [1, 2], and there is not great likelihood of improving this situation in the future, b e c a u s e gastric cancer does not p r o d u c e s y m p t o m s until it reaches an a d v a n c e d stage. In the present study, a total of 536 patients who underw e n t either curative or palliative gastric resections for a d v a n c e d gastric cancer were reviewed. T h e
0364-2313/79/0003-0693 $01.60 9 1979 Soci6t6 Internationale de Chirurgie
Reprint requests: Professor Fusahiro Nagao, 3-25-8, Nishishinbashi, Minato-ku, Tokyo, Japan. 693
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World J. Surg. Vol. 3, No. 6, 1979
Table 1. Frequency (in percent of patients) of earliest symptoms of gastric cancer in 536 patients.
Gastric cancer Location of Cancer Symptoms
Overall
Far advanced
Not far advanced
Weight loss Pain Anorexia Nausea Vomiting Abdominal fullness Heartburn General fatigability Eructation Dysphagia Constipation Epigastric discomfort Hematemesis Tarry stool Others
50 44 21 16 19 8 6 9 7 5 3 5 5 5 12
59 41 26 4 11 26 7 11 7 4 7 4 0 8 19
46 45 19 20 21 15 6 8 6 5 1 5 7 12 10
v a n c e d " indicates dissemination o f gastric c a n c e r with liver metastases, infiltration to other organs, and/or distant l y m p h node metastases. Patients with lesions around the cardia of the s t o m a c h had a higher incidence of dysphagia, whereas those with lesions in the antrum had a higher incidence of s y m p t o m s of pyloric stenosis, namely, nausea, vomiting, abdominal fullness, and eructation. O f the cases of " f a r a d v a n c e d " cancer, 7% were without s y m p t o m s . On the other hand, some patients with small lesions had severe obstructive s y m p t o m s . Thus, it is likely that the s y m p t o m s of gastric c a n c e r are related more to the location of the t u m o r than to the stage of malignancy. Furthermore, none o f the s y m p t o m s can be considered diagnostic of gastric cancer. Diagnosis based on a c o m p u t e r i z e d analysis of d y s p e p s i a has been att e m p t e d [3], but the validity remains to be established. The interval b e t w e e n the onset of s y m p t o m s and operation was less than 6 months in 61% of patients
Cardia
Body
Antrum
Benign ulcer
55 64 18 9 9 9 9 18 7 27
44 48 26 15 15 7 7 4 8 0
47 44 22 25 22 34 9 '6 16 0
0 0 0 18
0 15 7 11
6 3 3 9
38 51 27 37 36 32 50 32 34 1 31 24 21 25 12
and was o v e r 1 year in 33% (Table 2). O f the patients whose treatment was delayed more than 1 year, 62% did not seek medical advice despite the fact that they had s y m p t o m s , but 32% visited their physician within 6 months after the onset of symptoms and were erroneously diagnosed as having chronic gastritis or gastric ulcer, usually because of misinterpretation of x-rays. Patients with and without " f a r a d v a n c e d " cancer were c o m p a r e d with regard to the extent of delay in treatment, but no clear difference was found, indicating that the time of onset or severity of s y m p t o m s were not proportional to the extent of cancer growth. All of the patients had a battery o f blood studies and a blood count prior to operation. The results of these studies were generally within the normal range. T h e r e was no relationship of the sedimentation rate, s e r u m protein concentration, results of liver function tests, or blood count to the presence or stage of gastric cancer.
Gastric A c i d i t y Table 2. Percent of patients experiencing delay in treat-
ment after the appearance of symptoms in 536 patients with gastric cancer. Delay in treatment
Stage of gastric cancer
6 months or less
More than 6 months, less than 1 year
Overall Far advanced Not far advanced
61 64 59
6 12 4
1 year or more 33 24 37
In a previous study 108 patients with various gastric diseases c h o s e n at r a n d o m underwent measurements o f gastric acidity in r e s p o n s e to histamine stimulation. The results are shown in Table 3. Secretory volume, maximal acidity, and maximal acid output o f gastric cancer patients were all markedly lower than those of patients in any other category. Thus, patients with hypoacidity or anacidity should be suspected of having gastric c a n c e r if they have a d e m o n s t r a b l e gastric lesion. H o w e v e r , lesions of the s t o m a c h which are sufficiently large to reduce
F. Nagao and N. Takahashi: Diagnosis of Advanced Gastric Cancer
695
Table 3. Gastric acidity after histamine stimulation of 108 patients with various gastric diseases. Gastric acidity
Gastric diseases
No. of cases
Mean maximal gastric volume secretion (ml)
Mean maximal acidity (clinical units)
Mean maximal hydrochloric acid output--mEq
Duodenal ulcer Combined ulcer Gastric ulcer Gastritis Gastric cancer
21 7 24 24 32
61.6 46.4 46.7 45.1 22.5
99.0 82.5 71.7 62.8 6.3
5.99 3.65 2.51 2.44 0.36
Table 4. Accuracy of preoperative diagnosis of gastric cancer. Rates of correct diagnosis of gastric cancer--% of patients Located in:
Method of diagnosis
Overall
Borrmann types II and lII
Borrmann type IV
Cardia
Corpus or antrum
X-ray Gastroscopy Gastroscopic biopsy
96 98 90
97 98 89
92 87 87
100 100 91
98 98 90
gastric secretion usually are easily detected by xray or endoscopy. The question is: is gastric analysis helpful in the diagnosis of early gastric cancer? In 46 patients with "early gastric cancer," we observed that more than 50% had gastric acid secretion within the same range as patients with benign gastric ulcer. Thus, in early gastric cancer, x-ray studies and endoscopy appear to be more reliable than measurement of gastric acid secretion in making the diagnosis.
X-Ray Examination and Endoscopy The techniques of x-ray examination of the stomach have improved greatly in the past decade. Combination of compression and double contrast methods has made it possible to visualize the fine intragastric structure, leaving no blind areas. The use of television and image intensification [4, 5] represent important advances in the radiographic diagnosis of gastric lesions. The technique of gastroscopy has also undergone great improvement. Development of the fiberscope has made it possible to visualize and biopsy lesions arising anywhere in the gastric mucosa. A technique involving application of indigocarmine or methylene blue to the gastric mucosa has been developed to detect early cancerous changes, atypical epithelium, intestinal metaplasia, and the extent of malignant infiltration [6, 7]. Today, the diagnosis of
gastric cancer is highly accurate. We reviewed our cases of proven gastric cancer with regard to the accuracy of preoperative diagnosis. The rate of correct diagnosis was 96% by x-ray, 98% by endoscopy, and 90% by endoscopic biopsy (Table 4). Similar rates have been reported by others [8-10]. Analysis of the cases of misdiagnosis showed some problems common to both radiography and endoscopy, namely: (a) problems with the local condition of the lesion at the time of examination, (b) difficulty of differentiation of malignant from benign ulcers, (c) diagnosis of Borrmann type IV lesion in which the growth was not tumorous but diffusely invasive, and (d) diagnosis of lesions near the cardia. Each of these problems will be considered briefly. When the expansion of the gastric wall is restricted for some reason or when there are food elements or blood clots at the site of a suspected abnormality, the features may become exaggerated, leading to a false-positive diagnosis of cancer. Conversely, the lesion may be masked by the local conditions, resulting in a false-negative diagnosis. In our series, ulcerating cancers were diagnosed correctly as malignant lesions in 99% of the cases by x-ray examination, in 97% by endoscopy, and in 89% by endoscopic biopsy. The ulcerating gastric cancer is said to have an irregular niche protruding like a breakwater into the filling defect (Schattenplus im Schattenminus), and the niche is usually surrounded by hard and nodular changes. The con-
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diagnosing this type of lesion, probably because the mucosal surface was not regularly involved with cancer. The Borrmann type IV lesion grows mainly within the submucosal layer and is not always apparent on gross inspection of the mucosa. In the past it has been difficult to correctly diagnose high gastric lesions [13, 14]. On x-ray examination, it is difficult to apply compression to the region of the cardia or to nicely induce a niche from a small crater. It has also been difficult to visualize high lesions by gastroscopy. These difficulties have been largely o v e r c o m e , and today they exist only in cases o f small early lesions. In our series, advanced gastric c a n c e r around the cardia was diagnosed correctly by x-ray examination in 94% of patients, and by e n d o s c o p y in 99%. Angiography deserves mention since it may be helpful in the detection of early gastric cancer and in demonstrating the extramucosal and extragastric extension of the tumor [15-17]. We have performed both selective celiac angiography and superselective left gastric arteriography as an adjunct to the radiologic and endoscopic examinations.
Fig. 1. Barium contrast x-ray of ulcerating gastric cancer incorrectly diagnosed as benign ulcer. There is a niche at the angulus and the niche is smoothly outlined. The adjacent mucosal surface has no gross change, and the mucosal folds extend up to the niche, so the radiologic diagnosis was benign ulcer. However, the diagnosis was correctly changed to cancer of Borrmann type III after gastroscopic examination and biopsy.
vergent mucosal folds are often interrupted. The niche of a benign ulcer is round and bulkier than that of a malignant lesion and its edges are smooth and soft, probably from the local edema. The outline of the niche delineates an eccentric excavation, which is distinctly different from the outline of the cancer niche [11]. However, the findings are not always so clear-cut. Figure 1 shows an ulcerating cancer that had all of the features o f a benign ulcer on barium contrast x-ray examination. Endoscopy and biopsy demonstrated the true malignant nature of the ulcer. Occasionally, the diagnosis of Borrmann type IV cancer is difficult. In our series, a correct diagnosis was made in 92% of patients by x-ray examination and in 87% by gastroscopy (Table 4). X-ray diagnosis in our hands was quite successful, probably because the stomachs in the majority of our patients had b e c o m e tubular in shape because of diffuse infiltration. If the stomachs had been soft and of normal contour, diagnosis would have been much more difficult [12]. E n d o s c o p y was not as successful in
Prediction of Resectability of Gastric Cancer The resectability of gastric cancer ranges from 60 to 90% of the cases. In our series, resection was performed in 326 (65%) of 502 primary operations for gastric cancer. The remainder of our series consisted of 72 cases (14%) of gastrojejunostomy and 105 cases (21%) of exploratory laparotomy. The incidence o f nonresectable cancer was quite high, so it would be worthwhile to determine how to predict resectability before operation. Resectable and nonresectable cases were compared with regard to results of preoperative laboratory examinations. The nonresectable patients more frequently had abnormalities of serum alkaline phosphatase and blood sedimentation rate. There were no differences in the results of the other tests. The resectable and nonresectable cases were reviewed with regard to the x-ray findings, such as deformity o f the angulus, extent of the gastric deformation, shortening of the lesser curvature, and shifting o f the stomach by posture. The rate of resectability was much lower when the angulus was deformed in both the proximal and distal directions or when a deformity involved more than a/2 of the entire c o n t o u r of the stomach. Endoscopic findings were reviewed with regard to the extent of the cancerous lesions, of mucosal discolorations, and o f abnormal flattening or stretching o f the mucosa. It was found that resectability was much lower when the extent o f these
F. Nagao and N. Takahashi: Diagnosis of Advanced Gastric Cancer
697
Table 5. Results of PPD and DNCB skin tests in patients with various gastric diseases.
Gastric diseases--% of patients Skin tests
Gastric cancer
Gastric ulcer
Duodenal ulcer
Normal
Positive PPD Positive DNCB
38 27
64 73
63 100
80 92
Table 6. Relationship of preoperative PPD and DNCB skin tests to resectability of gastric cancer.
Skin tests
Resectability of gastric cancer--% of patients
PPD
DNCB
Curative resection
Palliative resection
Unresectable
Positive Positive Negative Negative
Positive Negative Positive Negative
79 37
20 25
1 38
14
27
59
changes covered more than 1/2 of the entire gastric area. Skin Tests and Gastric Cancer
It is generally known that immunologic activity, especially of cellular immunity, is reduced in cancer patients. To test cellular immunity, skin reactions to PPD and DNCB were checked and the subpopulations o f T cells and B cells were measured [18, 19] in our patients with gastric cancer and other gastric diseases. PPD tests were performed in 40 healthy subjects, 96 patients with benign gastric or duodenal ulcers, and 140 patients with gastric cancer. DNCB tests were performed in 25 healthy subjects, 44 patients with benign gastric or duodenal ulcers, and 97 patients with gastric cancer. As shown in Table 5, the frequency of positive PPD and DNCB skin tests was markedly lower in patients with gastric cancer. Among the gastric cancer patients, positive PPD and DNCB tests were observed, respectively, in 75% and 65% of patients who underwent curative resection, 36% and 33% of patients who underwent palliative resection, and 25% and 5% of patients with nonresectable lesions. Skin test responsiveness was directly related to the extent of the gastric malignancy. This relationship was even more striking when the two skin tests were given in combination to the same patient (Table 6). Measurement of the subpopulations of T cells and B cells failed to correlate with the stage o f gastric cancer. R6sum6
L a valeur des m6thodes de diagnostic du cancer
gastrique a 6t6 revue dans une analyse de 536 cas de gastrectomie pour cancer avanc6. I1 n'y a pas de symptome caract6ristique du c a n c e r gastrique; la perte de poids est fr6quente. Les variations de type et de fr6quence des symptomes semblent 6tre ind6pendantes de la pr6sence ou de l'absence de m6tastases. Dans la s6rie, 33% des malades ont 6t6 op6r6s plus d ' u n an apr6s le d6but des symptomes: 38% d'entre eux avaient consult6 leur m6decin moins de 6 mois apr6s les premiers symptomes, mais un diagnostic erron6 de gastrite chronique ou d'ulc~re b6nin avait 6t6 pos6. Les r6sultats des examens de laboratoire n'ont rien de sp6cifique. L'acidit6 gastrique est nettement plus basse dans le cancer que dans les 16sions b6nignes de l'estomac. Les techniques de la radiographie, de l'endoscopie et de la biopsie endoscopique se sont fort am6lior6es et donnent actuellement 96% de diagnostics exacts pour la radiographie, 98% pour l'endoscopie et 90% pour la biopsie. Ces pourcentages sont un peu moins favorables pour les 16sions de type Borrmann IV. L'art6riographie coeliaque est utile pour pr6ciser l'6tendue et la profondeur de l'extension du cancer et pour d6celer les m6tastases h6patiques. L a fr6quence de tests positifs au PPD ou DNCB semble se r6duire pour les cancers aux stades avanc6s, sugg6rant l'existence d'alt6rations immunologiques. References
1. Miwa, K.: National Registration of Gastric Cancer, 6th issue. Tokyo, Japanese Research Society of Gastric Cancer and National Cancer Center of Japan, 1975, pp. 66-68 2. Gray, D.B., Ward, G.E.: Delay in diagnosis of carcinoma of the stomach--an analysis of 104 cases. Am. J. Surg. 83:524, 1952
World J. Surg. Vol. 3, No. 6, 1979
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3. Horrocks, J.C., Dombal, F.T.: Computer-aided diagnosis of"dyspepsia." Am. J. Dig. Dis. 20:397, 1975 4. Kumakura, K., Maruyama, M., Sugiyama, M., Takeda, R., Ochiai, H.: Detailed diagnosis of lesions on the anterior wall of the stomach. Stomach and Intestine (I to Cho) 6:1405, 1971 5. Shirakabe, H., Takeda, Y., Hayakawa, Y., Kurosawa, K., Yamanaka, K., Nishizawa, M., Nomoto, K.: Problems in x-ray diagnosis of gastric cancer. Jpn. J. Clin. Exp. Med. 50:302, 1973 6. Suzuki, S., Ono, K., Yamada, A., Suzuki, H., Endo, M., Takemoto, T., Nakayama, K.: Recognition of invasive extent of gastric cancer by an endoscopic dyeing method and its application to surgery. J. Clin. Surg. 29:159, 1974 7. Hashimoto, Y., Takeda, S., Kohli, Y., Ide, K., Kawai, K.: Dye scattering method in endoscopy for diagnosing early gastric cancer. Stomach and Intestine (I-to-Cho) 10:1157, 1975 8. Kirsh, I.E.: Radiological aspects of cancer after apparent healing. Gastroenterology 61:601, 1971 9. Mitty, W.F., Rousselot, L.M., Grace, W.J.: Carcinoma of the stomach. Am. J. Dig. Dis. 5:249, 1960 10. Morrissey, J.F.: Gastrointestinal endoscopy. Gastroenterology 62:1241, 1972 11. Ichikawa, H., Yamada, T., Doi, T.: Practice of Gastric Radiology, l lth edition. Tokyo, Kobundo, 1972, pp. 222-246 12. Takeuchi, T., Ishii, K., Sakita, T., Miwa, K., Sano,
Invited Commentary Laurence M. Blendis, M.D. Toronto General Hospital, Toronto, Ontario, Canada
The authors describe their extensive experience in the diagnosis o f advanced gastric cancer, a condition with a very poor prognosis. T h e y rightly point out the nonspecificity of symptoms o f this condition and the importance of physician awareness, since a third of the patients in whom the diagnosis was delayed, or more than 40 patients, were initially misdiagnosed [1]. This situation may be aggravated by the recent advances in therapy with histamine-2-receptor antagonists. At least one paper has reported cases of gastric cancers which healed on cimetidine therapy, thus misleading the clinicians into the belief that they were dealing with benign gastric ulcers [1]. Paradoxically, patients with the longest prediagnostic history may have the better prognosis, presumably because they have a more slowly growing tumor [2]. Certainly, obstructive upper gastrointestinal symptoms should always cause suspicion and, prognostically, lesions near the pylorus have a better o u t c o m e than cardiac lesions [2]. It was surprising, however, that the blood counts
13. 14.
15. 16.
17.
18. 19.
R., Shimoda, T.: Study on mechanism of development of Borrmann IV type gastric cancer. Jpn. J. Gastroenterol. (Nippon Shokakibyo Gakkai Zasshi) 69:951, 1972 Kumakura, K., Takagi, K.: Diagnosis of high gastric cancer. Jpn. J. Clin. Med. (Nippon Rinsho)25:1369, 1967 Matsui, H., Tobayashi, K., Yamada, T., Doi, I., Noguchi, M., Suko, H., Ichikawa, H.: X-ray diagnosis of high gastric lesions. Stomach and Intestine (1-toCho) 5:107t, 1970 Shibata, S.: Angiographic findings in disease of the stomach. Am. J. Roentgenol. 110:322, 1970 Sasaki, T., Kido, C., Kaneko, M.: Study on stomach disease from blood vessel image--selective angiography of abdominal aorta. Jpn. J. Clin. Radiol. (Rinsho Hoshasen) 12:48, 1967 Kitajima, M., Uematsu, Y., Ochiai, M., Maruyama, K., Hiramatsu, K.: A comparative study on superselective angiography and microangiography of the gastric cancer. Stomach and Intestine (I-to-Cho) 10:913, 1975 Filber, F.R., Morton, D.L.: Impaired immunologic reactivity and recurrence following cancer surgery. Cancer 25:362, 1970 Bolton, P.M., James, S.L., Davidson, J., Hughes, L.E.: Diagnostic and prognostic significance of delayed hypersensitivity skin testing in patients with malignant neoplasma. Br. J. Cancer 28:80, 1973
on this group of patients were generally within the normal range, since chronic blood loss is a c o m m o n complication of gastric cancer, and achlorhydria and pre-pernicious anemia may occur in up to 44% of cases [3]. The presence of achlorhydria has been a useful " s e c o n d a r y " investigation in patients with suspicious gastric ulcers [4]. The authors' conclusion that x-ray studies or endoscopy are more reliable than secretion studies answers a question that need hardly be raised. Unfortunately, the authors did not address themselves to the more difficult question of how they would manage a patient with an ulcer in which the principle tests were negative or suspicious and with achlorhydria. As a believer in the dictum " n o acid, no ulcer, therefore c a n c e r , " my view would be presumptive cancer and to r e c o m m e n d surgery. The authors describe in considerable detail the diagnosis o f gastric cancer by inspection. It is disappointing, therefore, that they do not discuss either the position o f the ulcerating cancers in their series or the size. The long-held belief that the position of the ulcer gives a good indication of its nature was shattered by a recent study in which all 29 ulcers on the greater curvature were benign, and most cancerous ulcers were on the lesser curve [5]. In the same study, however, the size of the ulcer did appear to be important, with ulcers of an area greater than 300 mm z being more likely to be malignant.
of Stirgery
Diagnosis of Advanced Gastric Cancer Fusahiro Nagao, M.D., and N o b u h i r o Takahashi, M.D. Second Department of Surgery, Jikei University School of Medicine, Tokyo, Japan surgical s p e c i m e n s were examined, and a survey was made regarding the patients' s y m p t o m s and the results of diagnostic procedures that the patients underwent. Cases of " e a r l y gastric c a n c e r " (defined as c a n c e r limited to the m u c o s a or s u b m u c o s a ) were excluded. C o m p a r i s o n s were made with cases of early gastric cancer, simple l a p a r o t o m y , and benign gastric diseases. All the patients were treated during the l l - y e a r period from 1965 to 1975 in the Second D e p a r t m e n t of Surgery of the Jikei University School o f Medicine in T o k y o .
A series of 536 patients who underwent gastric resections for advanced gastric cancer has been reviewed with regard to the diagnostic procedures for detecting gastric cancer. There were no characteristic symptoms of gastric cancer, but weight loss was a frequent complaint. Variation in the type and frequency of symptoms did not appear to depend on the presence or absence of metastases. Patients whose operations were delayed more than one year after the onset of symptoms accounted for 33% of the series, and 38% of these had visited their physicians within 6 months after the onset of symptoms but were misdiagnosed as having chronic gastritis or benign ulcer. The results of various laboratory examinations were not specific. Gastric acidity was found to be distinctly lower than in patients with benign gastric disease. Techniques of radiology, endoscopy, and endoscopic biopsy of the stomach have greatly improved, and the overall rates of correct diagnosis of gastric cancer were 96% by x-ray, 98% by endoscopy, and 90% by biopsy. These rates were slightly lowered when only Borrmann type IV lesions were considered. Celiac angiography was useful to determine the extent or depth of cancerous invasion and to detect liver metastases. The frequency of positive PPD or DNCB skin tests appeared to decrease as the stage of cancer advanced, indicating immunologic impairment in advanced gastric cancer.
Symptomatology
When gastric cancer has r e a c h e d a s y m p t o m a t i c stage, the s y m p t o m s are usually multiple. To detect the m o s t specific s y m p t o m of gastric cancer, if there is any, the earliest s y m p t o m s were reviewed and c o m p a r e d with those of patients with benign ulcer. It was found that there are m a n y s y m p t o m s comm o n to gastric cancer and benign ulcer, although their f r e q u e n c y is not analogous (Table 1). Weight loss was a frequent early s y m p t o m of gastric c a n c e r when the patients first s o u g h t medical advice, and m a n y patients were bothered b y a feeling o f emaciation. On the other hand, patients with benign ulcer more frequently complained o f nausea, vomiting, and heartburn, the s y m p t o m s suggestive o f an acute exacerbation. S o m e gastric c a n c e r patients had a course similar to that of patients with benign ulcer for a period of time and e v e n r e s p o n d e d to conservative treatment. The s y m p t o m s of gastric cancer varied according to the stage of the disease, but there were no distinct differences b e t w e e n patients who had a d v a n c e d cancers and those who had lesions that were not far advanced. The term " f a r ad-
Diagnosis o f gastric cancer in J a p a n has greatly imp r o v e d in the past 10-20 years and, consequently, detection o f early gastric c a n c e r has b e c o m e m o r e frequent. N e v e r t h e l e s s , o v e r 80% of patients who visit clinics b e c a u s e o f gastric c a n c e r are reported to have a d v a n c e d cancer [1, 2], and there is not great likelihood of improving this situation in the future, b e c a u s e gastric cancer does not p r o d u c e s y m p t o m s until it reaches an a d v a n c e d stage. In the present study, a total of 536 patients who underw e n t either curative or palliative gastric resections for a d v a n c e d gastric cancer were reviewed. T h e
0364-2313/79/0003-0693 $01.60 9 1979 Soci6t6 Internationale de Chirurgie
Reprint requests: Professor Fusahiro Nagao, 3-25-8, Nishishinbashi, Minato-ku, Tokyo, Japan. 693
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World J. Surg. Vol. 3, No. 6, 1979
Table 1. Frequency (in percent of patients) of earliest symptoms of gastric cancer in 536 patients.
Gastric cancer Location of Cancer Symptoms
Overall
Far advanced
Not far advanced
Weight loss Pain Anorexia Nausea Vomiting Abdominal fullness Heartburn General fatigability Eructation Dysphagia Constipation Epigastric discomfort Hematemesis Tarry stool Others
50 44 21 16 19 8 6 9 7 5 3 5 5 5 12
59 41 26 4 11 26 7 11 7 4 7 4 0 8 19
46 45 19 20 21 15 6 8 6 5 1 5 7 12 10
v a n c e d " indicates dissemination o f gastric c a n c e r with liver metastases, infiltration to other organs, and/or distant l y m p h node metastases. Patients with lesions around the cardia of the s t o m a c h had a higher incidence of dysphagia, whereas those with lesions in the antrum had a higher incidence of s y m p t o m s of pyloric stenosis, namely, nausea, vomiting, abdominal fullness, and eructation. O f the cases of " f a r a d v a n c e d " cancer, 7% were without s y m p t o m s . On the other hand, some patients with small lesions had severe obstructive s y m p t o m s . Thus, it is likely that the s y m p t o m s of gastric c a n c e r are related more to the location of the t u m o r than to the stage of malignancy. Furthermore, none o f the s y m p t o m s can be considered diagnostic of gastric cancer. Diagnosis based on a c o m p u t e r i z e d analysis of d y s p e p s i a has been att e m p t e d [3], but the validity remains to be established. The interval b e t w e e n the onset of s y m p t o m s and operation was less than 6 months in 61% of patients
Cardia
Body
Antrum
Benign ulcer
55 64 18 9 9 9 9 18 7 27
44 48 26 15 15 7 7 4 8 0
47 44 22 25 22 34 9 '6 16 0
0 0 0 18
0 15 7 11
6 3 3 9
38 51 27 37 36 32 50 32 34 1 31 24 21 25 12
and was o v e r 1 year in 33% (Table 2). O f the patients whose treatment was delayed more than 1 year, 62% did not seek medical advice despite the fact that they had s y m p t o m s , but 32% visited their physician within 6 months after the onset of symptoms and were erroneously diagnosed as having chronic gastritis or gastric ulcer, usually because of misinterpretation of x-rays. Patients with and without " f a r a d v a n c e d " cancer were c o m p a r e d with regard to the extent of delay in treatment, but no clear difference was found, indicating that the time of onset or severity of s y m p t o m s were not proportional to the extent of cancer growth. All of the patients had a battery o f blood studies and a blood count prior to operation. The results of these studies were generally within the normal range. T h e r e was no relationship of the sedimentation rate, s e r u m protein concentration, results of liver function tests, or blood count to the presence or stage of gastric cancer.
Gastric A c i d i t y Table 2. Percent of patients experiencing delay in treat-
ment after the appearance of symptoms in 536 patients with gastric cancer. Delay in treatment
Stage of gastric cancer
6 months or less
More than 6 months, less than 1 year
Overall Far advanced Not far advanced
61 64 59
6 12 4
1 year or more 33 24 37
In a previous study 108 patients with various gastric diseases c h o s e n at r a n d o m underwent measurements o f gastric acidity in r e s p o n s e to histamine stimulation. The results are shown in Table 3. Secretory volume, maximal acidity, and maximal acid output o f gastric cancer patients were all markedly lower than those of patients in any other category. Thus, patients with hypoacidity or anacidity should be suspected of having gastric c a n c e r if they have a d e m o n s t r a b l e gastric lesion. H o w e v e r , lesions of the s t o m a c h which are sufficiently large to reduce
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695
Table 3. Gastric acidity after histamine stimulation of 108 patients with various gastric diseases. Gastric acidity
Gastric diseases
No. of cases
Mean maximal gastric volume secretion (ml)
Mean maximal acidity (clinical units)
Mean maximal hydrochloric acid output--mEq
Duodenal ulcer Combined ulcer Gastric ulcer Gastritis Gastric cancer
21 7 24 24 32
61.6 46.4 46.7 45.1 22.5
99.0 82.5 71.7 62.8 6.3
5.99 3.65 2.51 2.44 0.36
Table 4. Accuracy of preoperative diagnosis of gastric cancer. Rates of correct diagnosis of gastric cancer--% of patients Located in:
Method of diagnosis
Overall
Borrmann types II and lII
Borrmann type IV
Cardia
Corpus or antrum
X-ray Gastroscopy Gastroscopic biopsy
96 98 90
97 98 89
92 87 87
100 100 91
98 98 90
gastric secretion usually are easily detected by xray or endoscopy. The question is: is gastric analysis helpful in the diagnosis of early gastric cancer? In 46 patients with "early gastric cancer," we observed that more than 50% had gastric acid secretion within the same range as patients with benign gastric ulcer. Thus, in early gastric cancer, x-ray studies and endoscopy appear to be more reliable than measurement of gastric acid secretion in making the diagnosis.
X-Ray Examination and Endoscopy The techniques of x-ray examination of the stomach have improved greatly in the past decade. Combination of compression and double contrast methods has made it possible to visualize the fine intragastric structure, leaving no blind areas. The use of television and image intensification [4, 5] represent important advances in the radiographic diagnosis of gastric lesions. The technique of gastroscopy has also undergone great improvement. Development of the fiberscope has made it possible to visualize and biopsy lesions arising anywhere in the gastric mucosa. A technique involving application of indigocarmine or methylene blue to the gastric mucosa has been developed to detect early cancerous changes, atypical epithelium, intestinal metaplasia, and the extent of malignant infiltration [6, 7]. Today, the diagnosis of
gastric cancer is highly accurate. We reviewed our cases of proven gastric cancer with regard to the accuracy of preoperative diagnosis. The rate of correct diagnosis was 96% by x-ray, 98% by endoscopy, and 90% by endoscopic biopsy (Table 4). Similar rates have been reported by others [8-10]. Analysis of the cases of misdiagnosis showed some problems common to both radiography and endoscopy, namely: (a) problems with the local condition of the lesion at the time of examination, (b) difficulty of differentiation of malignant from benign ulcers, (c) diagnosis of Borrmann type IV lesion in which the growth was not tumorous but diffusely invasive, and (d) diagnosis of lesions near the cardia. Each of these problems will be considered briefly. When the expansion of the gastric wall is restricted for some reason or when there are food elements or blood clots at the site of a suspected abnormality, the features may become exaggerated, leading to a false-positive diagnosis of cancer. Conversely, the lesion may be masked by the local conditions, resulting in a false-negative diagnosis. In our series, ulcerating cancers were diagnosed correctly as malignant lesions in 99% of the cases by x-ray examination, in 97% by endoscopy, and in 89% by endoscopic biopsy. The ulcerating gastric cancer is said to have an irregular niche protruding like a breakwater into the filling defect (Schattenplus im Schattenminus), and the niche is usually surrounded by hard and nodular changes. The con-
696
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diagnosing this type of lesion, probably because the mucosal surface was not regularly involved with cancer. The Borrmann type IV lesion grows mainly within the submucosal layer and is not always apparent on gross inspection of the mucosa. In the past it has been difficult to correctly diagnose high gastric lesions [13, 14]. On x-ray examination, it is difficult to apply compression to the region of the cardia or to nicely induce a niche from a small crater. It has also been difficult to visualize high lesions by gastroscopy. These difficulties have been largely o v e r c o m e , and today they exist only in cases o f small early lesions. In our series, advanced gastric c a n c e r around the cardia was diagnosed correctly by x-ray examination in 94% of patients, and by e n d o s c o p y in 99%. Angiography deserves mention since it may be helpful in the detection of early gastric cancer and in demonstrating the extramucosal and extragastric extension of the tumor [15-17]. We have performed both selective celiac angiography and superselective left gastric arteriography as an adjunct to the radiologic and endoscopic examinations.
Fig. 1. Barium contrast x-ray of ulcerating gastric cancer incorrectly diagnosed as benign ulcer. There is a niche at the angulus and the niche is smoothly outlined. The adjacent mucosal surface has no gross change, and the mucosal folds extend up to the niche, so the radiologic diagnosis was benign ulcer. However, the diagnosis was correctly changed to cancer of Borrmann type III after gastroscopic examination and biopsy.
vergent mucosal folds are often interrupted. The niche of a benign ulcer is round and bulkier than that of a malignant lesion and its edges are smooth and soft, probably from the local edema. The outline of the niche delineates an eccentric excavation, which is distinctly different from the outline of the cancer niche [11]. However, the findings are not always so clear-cut. Figure 1 shows an ulcerating cancer that had all of the features o f a benign ulcer on barium contrast x-ray examination. Endoscopy and biopsy demonstrated the true malignant nature of the ulcer. Occasionally, the diagnosis of Borrmann type IV cancer is difficult. In our series, a correct diagnosis was made in 92% of patients by x-ray examination and in 87% by gastroscopy (Table 4). X-ray diagnosis in our hands was quite successful, probably because the stomachs in the majority of our patients had b e c o m e tubular in shape because of diffuse infiltration. If the stomachs had been soft and of normal contour, diagnosis would have been much more difficult [12]. E n d o s c o p y was not as successful in
Prediction of Resectability of Gastric Cancer The resectability of gastric cancer ranges from 60 to 90% of the cases. In our series, resection was performed in 326 (65%) of 502 primary operations for gastric cancer. The remainder of our series consisted of 72 cases (14%) of gastrojejunostomy and 105 cases (21%) of exploratory laparotomy. The incidence o f nonresectable cancer was quite high, so it would be worthwhile to determine how to predict resectability before operation. Resectable and nonresectable cases were compared with regard to results of preoperative laboratory examinations. The nonresectable patients more frequently had abnormalities of serum alkaline phosphatase and blood sedimentation rate. There were no differences in the results of the other tests. The resectable and nonresectable cases were reviewed with regard to the x-ray findings, such as deformity o f the angulus, extent of the gastric deformation, shortening of the lesser curvature, and shifting o f the stomach by posture. The rate of resectability was much lower when the angulus was deformed in both the proximal and distal directions or when a deformity involved more than a/2 of the entire c o n t o u r of the stomach. Endoscopic findings were reviewed with regard to the extent of the cancerous lesions, of mucosal discolorations, and o f abnormal flattening or stretching o f the mucosa. It was found that resectability was much lower when the extent o f these
F. Nagao and N. Takahashi: Diagnosis of Advanced Gastric Cancer
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Table 5. Results of PPD and DNCB skin tests in patients with various gastric diseases.
Gastric diseases--% of patients Skin tests
Gastric cancer
Gastric ulcer
Duodenal ulcer
Normal
Positive PPD Positive DNCB
38 27
64 73
63 100
80 92
Table 6. Relationship of preoperative PPD and DNCB skin tests to resectability of gastric cancer.
Skin tests
Resectability of gastric cancer--% of patients
PPD
DNCB
Curative resection
Palliative resection
Unresectable
Positive Positive Negative Negative
Positive Negative Positive Negative
79 37
20 25
1 38
14
27
59
changes covered more than 1/2 of the entire gastric area. Skin Tests and Gastric Cancer
It is generally known that immunologic activity, especially of cellular immunity, is reduced in cancer patients. To test cellular immunity, skin reactions to PPD and DNCB were checked and the subpopulations o f T cells and B cells were measured [18, 19] in our patients with gastric cancer and other gastric diseases. PPD tests were performed in 40 healthy subjects, 96 patients with benign gastric or duodenal ulcers, and 140 patients with gastric cancer. DNCB tests were performed in 25 healthy subjects, 44 patients with benign gastric or duodenal ulcers, and 97 patients with gastric cancer. As shown in Table 5, the frequency of positive PPD and DNCB skin tests was markedly lower in patients with gastric cancer. Among the gastric cancer patients, positive PPD and DNCB tests were observed, respectively, in 75% and 65% of patients who underwent curative resection, 36% and 33% of patients who underwent palliative resection, and 25% and 5% of patients with nonresectable lesions. Skin test responsiveness was directly related to the extent of the gastric malignancy. This relationship was even more striking when the two skin tests were given in combination to the same patient (Table 6). Measurement of the subpopulations of T cells and B cells failed to correlate with the stage o f gastric cancer. R6sum6
L a valeur des m6thodes de diagnostic du cancer
gastrique a 6t6 revue dans une analyse de 536 cas de gastrectomie pour cancer avanc6. I1 n'y a pas de symptome caract6ristique du c a n c e r gastrique; la perte de poids est fr6quente. Les variations de type et de fr6quence des symptomes semblent 6tre ind6pendantes de la pr6sence ou de l'absence de m6tastases. Dans la s6rie, 33% des malades ont 6t6 op6r6s plus d ' u n an apr6s le d6but des symptomes: 38% d'entre eux avaient consult6 leur m6decin moins de 6 mois apr6s les premiers symptomes, mais un diagnostic erron6 de gastrite chronique ou d'ulc~re b6nin avait 6t6 pos6. Les r6sultats des examens de laboratoire n'ont rien de sp6cifique. L'acidit6 gastrique est nettement plus basse dans le cancer que dans les 16sions b6nignes de l'estomac. Les techniques de la radiographie, de l'endoscopie et de la biopsie endoscopique se sont fort am6lior6es et donnent actuellement 96% de diagnostics exacts pour la radiographie, 98% pour l'endoscopie et 90% pour la biopsie. Ces pourcentages sont un peu moins favorables pour les 16sions de type Borrmann IV. L'art6riographie coeliaque est utile pour pr6ciser l'6tendue et la profondeur de l'extension du cancer et pour d6celer les m6tastases h6patiques. L a fr6quence de tests positifs au PPD ou DNCB semble se r6duire pour les cancers aux stades avanc6s, sugg6rant l'existence d'alt6rations immunologiques. References
1. Miwa, K.: National Registration of Gastric Cancer, 6th issue. Tokyo, Japanese Research Society of Gastric Cancer and National Cancer Center of Japan, 1975, pp. 66-68 2. Gray, D.B., Ward, G.E.: Delay in diagnosis of carcinoma of the stomach--an analysis of 104 cases. Am. J. Surg. 83:524, 1952
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3. Horrocks, J.C., Dombal, F.T.: Computer-aided diagnosis of"dyspepsia." Am. J. Dig. Dis. 20:397, 1975 4. Kumakura, K., Maruyama, M., Sugiyama, M., Takeda, R., Ochiai, H.: Detailed diagnosis of lesions on the anterior wall of the stomach. Stomach and Intestine (I to Cho) 6:1405, 1971 5. Shirakabe, H., Takeda, Y., Hayakawa, Y., Kurosawa, K., Yamanaka, K., Nishizawa, M., Nomoto, K.: Problems in x-ray diagnosis of gastric cancer. Jpn. J. Clin. Exp. Med. 50:302, 1973 6. Suzuki, S., Ono, K., Yamada, A., Suzuki, H., Endo, M., Takemoto, T., Nakayama, K.: Recognition of invasive extent of gastric cancer by an endoscopic dyeing method and its application to surgery. J. Clin. Surg. 29:159, 1974 7. Hashimoto, Y., Takeda, S., Kohli, Y., Ide, K., Kawai, K.: Dye scattering method in endoscopy for diagnosing early gastric cancer. Stomach and Intestine (I-to-Cho) 10:1157, 1975 8. Kirsh, I.E.: Radiological aspects of cancer after apparent healing. Gastroenterology 61:601, 1971 9. Mitty, W.F., Rousselot, L.M., Grace, W.J.: Carcinoma of the stomach. Am. J. Dig. Dis. 5:249, 1960 10. Morrissey, J.F.: Gastrointestinal endoscopy. Gastroenterology 62:1241, 1972 11. Ichikawa, H., Yamada, T., Doi, T.: Practice of Gastric Radiology, l lth edition. Tokyo, Kobundo, 1972, pp. 222-246 12. Takeuchi, T., Ishii, K., Sakita, T., Miwa, K., Sano,
Invited Commentary Laurence M. Blendis, M.D. Toronto General Hospital, Toronto, Ontario, Canada
The authors describe their extensive experience in the diagnosis o f advanced gastric cancer, a condition with a very poor prognosis. T h e y rightly point out the nonspecificity of symptoms o f this condition and the importance of physician awareness, since a third of the patients in whom the diagnosis was delayed, or more than 40 patients, were initially misdiagnosed [1]. This situation may be aggravated by the recent advances in therapy with histamine-2-receptor antagonists. At least one paper has reported cases of gastric cancers which healed on cimetidine therapy, thus misleading the clinicians into the belief that they were dealing with benign gastric ulcers [1]. Paradoxically, patients with the longest prediagnostic history may have the better prognosis, presumably because they have a more slowly growing tumor [2]. Certainly, obstructive upper gastrointestinal symptoms should always cause suspicion and, prognostically, lesions near the pylorus have a better o u t c o m e than cardiac lesions [2]. It was surprising, however, that the blood counts
13. 14.
15. 16.
17.
18. 19.
R., Shimoda, T.: Study on mechanism of development of Borrmann IV type gastric cancer. Jpn. J. Gastroenterol. (Nippon Shokakibyo Gakkai Zasshi) 69:951, 1972 Kumakura, K., Takagi, K.: Diagnosis of high gastric cancer. Jpn. J. Clin. Med. (Nippon Rinsho)25:1369, 1967 Matsui, H., Tobayashi, K., Yamada, T., Doi, I., Noguchi, M., Suko, H., Ichikawa, H.: X-ray diagnosis of high gastric lesions. Stomach and Intestine (1-toCho) 5:107t, 1970 Shibata, S.: Angiographic findings in disease of the stomach. Am. J. Roentgenol. 110:322, 1970 Sasaki, T., Kido, C., Kaneko, M.: Study on stomach disease from blood vessel image--selective angiography of abdominal aorta. Jpn. J. Clin. Radiol. (Rinsho Hoshasen) 12:48, 1967 Kitajima, M., Uematsu, Y., Ochiai, M., Maruyama, K., Hiramatsu, K.: A comparative study on superselective angiography and microangiography of the gastric cancer. Stomach and Intestine (I-to-Cho) 10:913, 1975 Filber, F.R., Morton, D.L.: Impaired immunologic reactivity and recurrence following cancer surgery. Cancer 25:362, 1970 Bolton, P.M., James, S.L., Davidson, J., Hughes, L.E.: Diagnostic and prognostic significance of delayed hypersensitivity skin testing in patients with malignant neoplasma. Br. J. Cancer 28:80, 1973
on this group of patients were generally within the normal range, since chronic blood loss is a c o m m o n complication of gastric cancer, and achlorhydria and pre-pernicious anemia may occur in up to 44% of cases [3]. The presence of achlorhydria has been a useful " s e c o n d a r y " investigation in patients with suspicious gastric ulcers [4]. The authors' conclusion that x-ray studies or endoscopy are more reliable than secretion studies answers a question that need hardly be raised. Unfortunately, the authors did not address themselves to the more difficult question of how they would manage a patient with an ulcer in which the principle tests were negative or suspicious and with achlorhydria. As a believer in the dictum " n o acid, no ulcer, therefore c a n c e r , " my view would be presumptive cancer and to r e c o m m e n d surgery. The authors describe in considerable detail the diagnosis o f gastric cancer by inspection. It is disappointing, therefore, that they do not discuss either the position o f the ulcerating cancers in their series or the size. The long-held belief that the position of the ulcer gives a good indication of its nature was shattered by a recent study in which all 29 ulcers on the greater curvature were benign, and most cancerous ulcers were on the lesser curve [5]. In the same study, however, the size of the ulcer did appear to be important, with ulcers of an area greater than 300 mm z being more likely to be malignant.
