0016-5107/79/2503-0096$02.00/0 GASTROINTESTINAL ENDOSCOPY Copyright © 1979 by the American Society for Gastrointestinal Endoscopy
The endoscopic diagnosis of early gastric cancer Yoshiaki Ito, MD Michael O. Blackstone, MD Robert H. Riddell, MD Joseph B. Kirsner, MD, PhD Chicago, Illinois
Among 168 patients with adenocarcinoma of the stomach, 14 (8.3%) fulfilled the criteria for "early gastric cancer." Endoscopy in all cases permitted visual appraisal and opportunity for biopsy and cytologic examination. A correct endoscopic diagnosis was made in 6; biopsy disclosed carcinoma in 12; cytology was positive in only 7. The authors caution that diagnosis may be difficult when lesions are observed with forward-viewing endoscopes but that perspicacity and repeated examinations should sharpen diagnostic accuracy. Gastric cancer, while slowly decreasing in annual incidence, continues to be a major cause of cancer death in the United States. The overall prognosis following diagnosis is grim, with a 5-year survival generally of under 15%. A subgroup of patients has been identified by Japanese workers with an immensely better prognosis, namely, early gastric cancer. This has been defined as gastric cancer which is found to be confined to the mucosa or within the submucosa and does not extend into the muscularis propia. The lesion is considered early gastric cancer if it meets these criteria irrespective of any lymph node involvement. Its recognition in Japan has led to the identification of patients where curative resection and a 5-year survival can be expected in over 90% of surgically treated patients. 1 ,2 This can be compared to an overall 5-year survival of 30% or less in patients with advanced cancer following gastrectomy.3 In Japan, before the early 1960's and the introduction of a gastrocamera, a fiberoptic instrument with a wide angle, miniaturized camera mounted in its distal end, the frequency of lesions meeting the criteria of early gastric cancer was generally under 5%. Since that time, the figure has risen to as high as 33% in 1 series. 4 With the widespread use of fiberoptic endoscopy as a routine diagnostic procedure for gastric cancer in other parts of the world, early gastric cancer has now been recognized outside of Japan, but in no more than 10% to 15% of patients with gastric cancer, 5-7 a figure substantially less than that noted in Japanese studies 1 •2 ,4 where the principal endoscope used was the side-viewing gastrocamera or other instruments in which the gastrocamera lens system had been integrated. In most other parts of the world, especially in the United States, forward-viewing instruments are generally employed which are not principally designed for gastric examination. The use of these
instruments may present certain technical difficulties in the complete evaluation of suspicious lesions and contribute to the lower frequency of early gastric cancer actually diagnosed. Wishing to know specifically what technical problems might be associated with the use of these instruments, we have reviewed our experience with early gastric cancer, drawn from 168 cases of gastric cancers seen over a 10-year period where the principal endoscopes used were of the forward-viewing type.
MATERIALS AND METHODS During the period from September 1968 through August 1978, 6169 peroral endoscopic examinations were performed by the gastroenterology service at the University of Chicago Hospitals and Clinics. Fourteen malignancies of the stomach meeting the histologic criteria for early gastric cancer were found (8.3%) among 168 cases of gastric cancers studied over this period. The endoscopes used for the gastric cancer cases were mainly of the forward-viewing type, either the Olympus GIF-D or the subsequent GIF-D3 model. The GIF-P or GIFP2 endoscope was used in only a few instances because of its smaller biopsy channel. Three of the 14 cases studied before 1971 were examined with a fiberoptic gastrocamera, the Olympus GTF-A model with histologic and cytologic material being obtained in these cases using several other available instruments. In all cases, a minimum of 3 directed biopsies were obtained, although usually more than 5 biopsies were taken. These were placed directly in 10% formalin (1968-1974) or placed on Millipore® filter paper (1975-1978) before being immersed in formalin. At least one brushing cytology was obtained. The brushed material was immediately smeared on glass slides and fixed in 95% ethyl alcohol and stained by the Papanicolaou method. All histologic material was reviewed by one pathologist
From the Departments of Medicine and Pathology, University of Chicago Pritzker School of Medicine, Chicago, Illinois. Reprint requests: Michael O. Blackstone, MD, Department of Medicine, University of Chicago, Box 400, 950 East 59th Street, Chicago, Illinois 60637. 96
GASTROINTESTINAL ENDOSCOPY
(R.H.R.). To qualify as early gastric cancer, the lesion had to be confined to the mucosa or submucosa and not directly involve the muscularis propria. As in the original definition, the term was used irrespective of whether lymph node metastasis was present (2 patients). The cancers were typed according to the standard 1962 classification for early gastric cancer of the Japanese Society of Gastroenterological Endoscopy (Table I). Typing was based on an analysis of the photographs taken of the resected specimen. In addition, the histology in all cases was reviewed to determine the depth of the cancer as well as the presence of metastasis. To assess the diagnostic efficacy of endoscopy in these cases, the formal endoscopy report was reviewed as to final diagnosis. These diagnoses were considered as indicating one of the following: (1) early gastric cancer diagnosed, (2) gastric cancer diagnosed, (3) an indeterminate lesion with cancer not being excluded, or (4) no cancer found including either no lesion being seen or a diagnosis of benign ulcer. Histologic and cytologiC material obtained at endoscopy was reviewed by the pathologist, although, for purposes of analysis, the final diagnosis at the time of the endoscopy was used even if on subsequent review this proved to be in error as it did in 1 case (the biopsy obtained in case 6). The efficacy of biopsy and cytology in the cases of early gastric cancer was compared with the yield from these modalities in the remaining 150 patients with advanced gastric cancer in the series for whom the results of biopsy or cytology were available. The relationship between the appearance and location of the early gastric cancers and the efficacy of endoscopy, biopsy, and cytology was examined separately. Table I. The Japanese classification of early gastric cancer (bold segments indicate cancer).
SINGLE TYPES Type I TypeII
Protruded Superficial
IIa
(Elevated) ( Flat)
IIb lIc Type
(Depressed)--~--Jr---
m:
Excavated COMBIN ATIONS
Type lIc
:m:
•
+m +IIc
Shaded areas indicate cancer
VOLUME 25, NO. 3, 1979
Table II. Types of early gastric cancer for the 14 cases in the present series. single types
I Iia tic Total
n
1 1
3 5
combined types
n
lIa + Ilc Ilc + III til + tic Total
2 5 2
9
Table III. Endoscopic diagnosis in 14 cases of early gastric cancer. endoscopic diagnosis Gastric cancer early gastric cancer advanced gastric cancer Indeterminate lesion ulcer polyp Benign gastric ulcer No lesion
no. of patients
6 3 3 4
3 1
3 1 TOTAL 14
RESULTS The types of early gastric cancer for the 14 patients in the present series are presented in Table II. The combined types predominated, being found in 9 of the 14 cases. Of these, 7 were associated with a peptic ulceration (type III lesion). For the group as a whole, the type lie lesion was found alone or in combination in 12 of the 14 cases. The protruded type lesions either as I or lIa were seen in only 2 of the 14 patients. Endoscopic diagnosis. A correct diagnosis of gastric cancer was provided in only 6 of the 14 cases (Table III). In 3 of these, a diagnosis of early gastric cancer was made. In 1 (case 10), a type 11e+llllesion, a linear ulcer of the angulus was observed to be surrounded by a large, well-demarcated zone of discolored, irregular mucosa (Figure 1A) which extended proximally into the lower body. In another (case 6), the Ilc lesion appeared as a malignant ulcer with raised, friable margins. In the third case, a type I lesion (case 1) was recognized as a sessile polyp with a nodular surface. In 3 others (cases 3, 9, and 13), the endoscopic diagnosis was gastric cancer. Typical of this was the lIa+11e lesion of case 3 where a lesion consisting of raised folds, surrounding a large central depression was endoscopically observed on the greater curve of the midantrum. In the other 2 (cases 9 and 13), both combined types involving the peptic ulcerlike type III, the endoscopic diagnosis was malignant ulcer on the basis of either an irregular margin or converging folds becoming nodular at the margin of the ulcer. In 4 cases, the endoscopic diagnosis was an indeterminate lesion. In 3 (cases 8, 11, and 12), all type IIc+llllesions, ulcers surrounded by a regular or discolored margin were observed. Typical of this is the lesion seen in case 11 (Figure 3) where the disrupted fold at the margin of erythema raised the possibility of early gastric cancer, yet a definite diagnosis was not made. While in this case a gastrocamera photograph shows the lesion to greatest advantage, in the other cases this was not so, as in case 12 (Figure 4A) where only an irregular ulcer with marginal hemorrhage and nodularity was seen and called indeter97
figure 1. Endoscopic view of a IIc + III lesion (case 10) showing a large area of discolored and slightly depressed mucosa which surrounds an ulcer (arrow) in the proximal antrum (A) and extends up to the distal body of the stomach (8).
figure 2. Resected IIc + III lesion (case 10); note the large depressed mucosal lesion with disruption of radiating folds (the IIc component of the lesion).
Figure 3. Gastrocamera photograph of a IIc + III lesion (case 11) showing an ulcer (small arrows) surrounded by marginal erythema with a disrupted fold (large arrow); despite these findings, the lesion was considered indeterminate. Figure 4. Endoscopic view of a IIc + III lesion (case 12) called indeterminate. This shows only a tangential view of the ulcer with a somewhat irregular margin and disrupted converging folds (A); note the appearance of the resected lesion seen straight on (8) wherein the margin of the ulcer is clearly depressed and the folds around it disrupted. Figure 5. Forward-viewing endoscopic photograph of a III + /lc lesion (case 13) showing an ulcer on the gastric angulus with a nodular, friable margin (A); this was called malignant, but biopsy and cytology were negative. Endoscopy repeated 2 weeks later with a side-viewing instrument showed reduction in size of the base, illustrating partial "healing," and the ulcer was called benign (8); however, biopsy and cytology were both positive for malignancy. Figure 6. Representative gastrocamera views of 2 early gastric cancers (courtesy of Dr. T. Kasugai, Aichi Cancer Center, Nagoya, Japan). In the IIc lesion (A) there is an irregular shallow depression with clubbing of the converging folds. In the IIc + III lesion (8), there is a typical IIc area (arrow) surrounding a central ulcer. Abrupt thinning of the mucosal folds can also be seen. Note the complete view of the lesion and surrounding mucosa provided by the wide angle gastrocamera.
minate. Here, a complete, en face view might have shown more of the lesion ultimately found in the resected specimen (Figure 48). The 1 remaining patient with an endoscopic diagnosis of an indeterminate lesion (case 2) had a lIa lesion consisting of a small, slightly elevated mucosal excrescence of the cardia.
98
In the remaining 4 cases, the endoscopic diagnosis was either a benign gastric ulcer or the lesion was entirely missed. The lesions called benign gastric ulcer (cases 4, 5, and 14) were all either Ilc singly (case 5) or in combination (case 4, type Ila+11e and case 14, type IIl+lIc). In one instance (case 7) a lie lesion was entirely missed. GASTROINTESTINAL ENDOSCOPY
Endoscopic biopsy and cytology. The results are presented in Table IV. In contrast to visual diagnosis, biopsy was positive in 12 of the 14 cases (86%) while cytology was positive in only 7 of 13 (54%). By contrast, for 150 advanced cancers seen over the same period, biopsy was positive in 116 of 143 patients (81%) and cytology was positive in 116 of 143 cases (81%). While biopsy results in either type of gastric cancer were comparable, the yield from cytology was greater in advanced cancer than in early cancer. The combination of biopsy and cytology raised the yield in advanced gastric cancer from 81% for biopsy alone to 92% for the combination while no such increased yield was noted for early gastric cancer. Appearance and location of the lesion in relation to the success of endoscopic diagnosis, biopsy, and cytology (Table V). For purposes of analysis, types I and lIa lesions were considered polypoid while the remainder, principally lie and III, were considered ulcerative. For the 2 polypoid lesions both of the cardia, biopsy was positive in both whereas endoscopic and cytologic diagnosis was positive in only 1. The ulcerative lesions were divided into those of the body and antrum. Endoscopic diagnosis was correctly made in 4 of 6 lesions of the body but in only 1 of 6 antral lesions. Biopsy was successful in all but 1 of both body and antral lesions, while cytology was slightly more successful in the body (positive in 4 of 6 lesions) than in the antrum (positive in 2 of 5). Illustrative clinical features. In 3 cases, the course previous to surgery was noteworthy. In 1 (case 6), the initial endoscopic diagnosis was malignant gastric ulcer. The biopsies taken were reported as benign, whereas, in fact, on subsequent review for inclusion in the present series, cancer was found. Three years later, endoscopy again reTable IV.
Results of biopsy and cytology in 164 patients with gastric cancer. n Biopsy Cytology Combination
14 13
14
early cancer positive 12 (86%) 7 (54%) 12 (86%)
advanced cancer n positive
143 143 150
116 (81%) 116 (81%) 138 (92%)
Table V.
The principal appearance and location of early gastric cancers in relation to visual diagnosis and results of biopsy and cytology.• polypoid
ulcerative
Cardia
Body
• • • • 00
&&&&&6 • • 00 • • Antrum
.00000
&&&&&6 0 • • 00 • KEY: endoscopy: e, positive; 0, negative or indeterminate; biopsy: .., positive; 6, negative; cytology: _, positive; 0, negative.
VOLUME 25, NO. 3, 1979
vealed a malignant ulcer and the lesion was finally resected. Histologically, it was still early gastric cancer with invasion confined to only the submucosa with metastasis to none of 80 lymph nodes recovered. In 2 others (cases 12 and 13) apparent healing of a malignant ulcer was observed. In case 13, the ulcer was considered malignant at the first endoscopy because of nodular, friable margins (Figure SA). Biopsy and cytology were both negative. A second endoscopy 2 week later showed apparent reduction in size (Figure 58) with only a slightly depressed area encircling the ulcer as a clue to malignancy (Figure 58). This was ignored, and at endoscopy the ulcer was called benign. Biopsy, however, disclosed poorly differentiated adenocarcinoma. In case 12, an indeterminate ulcer was seen at endoscopy. By the time the patient came to resection 2 weeks later, the ulcer base was covered by a small rim of regenerative mucosa and appeared to be almost healed. DISCUSSION In most reported series outside of Japan, the frequency of gastric carcinoma fulfilling the criteria for early gastric cancer remains under 15%, despite an increased awareness of the lesion. 5 - 7 By contrast, Japanese workers in 1 series identified up to one third of all gastric cancers as uearly.u4 Some have attributed this to a difference in gastric cancer seen in Japan and elsewhere in the world; however, there appears to be no demonstrable difference in the gross or histologic appearance, site, rate of resectability, or high percent of 5-year survivals to suggest that early gastric cancer in Japan is different from that found elsewhere. 5 ,a-12 Regardless of where early gastric cancer occurs, as in our series, the depressed lie lesion predominates, usually in association with ulceration (lIc+III). These lesions closely simulate peptic ulcers, clinically, radiologically, and even at endoscopy.13.14 In 1 Japanese study of 300 cases of early gastric cancer, 211 (70.3%) were found to be adjacent to ulcers. 13 Typically the ulcers were entirely benign, with the cancer being located within the surrounding mucosa and submucosa. The endoscopic clues indicating an ulcer's association with early gastric cancer are, therefore, obtained from a complete examination of its margin in relationship to the remainder of the stomach. As indicated in Table VI, these include: (1) disruption and clubbing of the surrounding mucosal folds, (2) a dirty appearance of the surrounding mucosa with adherent mucous or exudate, (3) irregular margins of the ulcer itself, or .(4) island-like residues of intact mucosa within the depressed area. These features clearly call for a complete examination not only of the base of the ulcer but the surrounding 2 to 3 em of gastric mucosa. This has, in the past, best been afforded by the use of the gastrocamera, the principal instrument used in all Japanese series. In fact, the endoscopic criteria for early gastric cancer (Table VI) are derived from these gastrocamera studies. If forward-viewing endoscopes are used, a lesion may be seen only tangentially (Figure 4A) and then incompletely, so that important features such as the disruption of the fold pattern and depression of the ulcer margin may not be apparent until the resected specimen is examined (Figure 48). This may explain why, in our 99
Table VI.
Clues to the endoscopic recognition of early gastric cancer. type lesion
principal endoscopic features 1. 2. 3. 4.
irregular contour bleeding sessile greater than 2 cm
Iia
1. elevated area does not disappear with inflaticn 2. "flower-bed" appearance
lib
1. discoloration of surrounding mucosa
Ilc
1. slightly depressed with disruption and clubbing of surrounding mucosal folds 2. dirty appearance of depressed area with adherent mucus or exudate 3. irregular margins 4. island-like residues of intact mucosa within the depressed area
III
1. similar in appearance to benign gastric ulcer
IIc
+ III
1. ulcer may appear entirely benign 2. depressed area with disruption of folds adjacent to the ulcer, as well as other IIc features
III
+ IIc
1. definite depression confined to margins of the ulcer 2. rigidity and clubbing of tips of any converging mucosa folds 3. discoloration and adherent necrotic material and blood in the depressed zone
series, only 6 of 14 (42.8%) lesions were correctly identified endoscopically as gastric cancer compared with 70.6% in a representative Japanese series where the gastrocamera was exclusively used.'6 With the gastrocamera, it is usually possible to photograph the lesion, en face, in relation to a wide area of stomach (Figure 6A), especially in areas such as the antrum where it is difficult with a forward-viewing endoscope to obtain a complete view in anyone position. In our own series, lesions of the antrum proved particularly difficult, so that a correct endoscopic diagnosis was made in only 1 of 6 cases, contrasted with the region of the gastric angle where 4 of 6 lesions were correctly identified as malignant (Table V). Despite the failure of endoscopic visual diagnosis in over half the cases, biopsy was successful in 86% (Table IV). This, we attribute to our policy of obtaining multiple biopsies (usually more than 3) for any gastric lesion, especially ulcers. Others have found that, for endoscopic biopsy to have its greatest accuracy, 8 or more biopsies must be taken from any suspicious lesion, especially an ulcer where the question of malignancy is raised. 17o '8 This becomes especially important where, in the case of ulcerlike early gastric cancer, inadequate visualization of the lesion with forward-viewing endoscopes may prevent correct endoscopic interpretation and full utilization of brush cytology'S (Table V). The lack of any contribution of cy-
100
tology in our series of early gastric cancer may be contrasted with its performance in advanced cancers, where its role, especially in the diagnosis of the infiltrative type, has been noted by others.'8 Apart from the difficulty of endoscopic visualization of these lesions because, we believe, of the instruments used, the recognition of early gastric cancer is hindered by its close similarity both in appearance and in course with benign peptic ulcers. The natural history of early gastric cancer appears to be one of healing and ulceration, often in a cyclical fashion, providing a malignant ulcer "life cycle," previously noted.'4 Apparent healing of the early gastric cancer ulcer, as in our case 13 (Figure 58), adds to the confusion of these lesions with benign peptic ulcers. In addition, the lesions grow slowly, as in our case 6 where early gastric cancer was still found 3 years after biopsies were misread as benign. One suspects that such a lesion would change little in appearance over such period of time and thus escape diagnosis unless a high index of suspicion was maintained. Because of the difficulties in both visualization and correct identification of early gastric cancers, we recommend a vigorous approach to biopsy with at least 6, and preferably 8 or more, biopsy specimens being taken from any of the following: (1) an ulcer whose base or margin is irregular and where the surrounding mucosa is discolored or depressed, and (2) a discrete area where gastric folds are elevated, discolored, disrupted, or have in any other wayan irregular appearance. Cytology is a complementary procedure to biopsy. It may not actually increase the overall yield in early gastric cancer, but it may be used to supplement biopsy when the endoscopist feels that an optimal position for biopsy cannot be achieved.'s Besides this approach to biopsy and cytology, we further urge that a carefully planned follow-up be provided for any suspicious gastric ulcer to the point of complete healing, with endoscopy and biopsy being performed at 4- to 6-week intervals. After apparent healing, endoscopic follow-up should be provided at an interval of 6 months to a year. Even with apparent healing, early gastric cancer may still be present which may become only apparent on su bseq uent endoscopy.'4 While, in the end, none of these measures may actually increase the frequency of early gastric cancer in western countries to that reported in Japan, still an increased awareness of endoscopic factors which may limit diagnosis, as well as the necessity for obtaining multiple biopsies from any ulcer, especially with suspicious or atypical features, may increase the endoscopist's effectiveness in the diagnosis of these lesions.
REFERENCES 1. HAYASHIDA T, KIDOKORO S: End results of early gastric cancer collected from 22 institutions. Stomach and Intestine 4:1077, 1969 2. YAMADA E, NAKAZATO H, KOIKE A, SUZUKI K, KATO K, KITO T: Surgical results for early gastric cancer. Surg 59:7,1974 3. KASUGAI T: Prognosis of early gastric cancer. Gastroenterology 58:429, 1970 4. KAWAI K: Diagnosis of early gastric cancer. Endoscopy 1:23, 1971 GASTROINTESTINAL ENDOSCOPY
5. EVANS DMD, CRAVEN )L, MURPHY F, CLEARY BK: Comparison of "early gastric cancer" in Britain and Japan. Gut 19:1,1978 6. MACHADO G, DAVIES )D, TODWAY AjC, WALMON PR, REED AE: Superficial carcinoma of the stomach. Br Med J 2:77, 1976 7. STADELMANN 0, MIEDERER SE, LOFFLER A, MULLER R, KAUFER C, ELSTER K: So-called early gastric cancer and its detection. Endoscopy 5:70, 1973 8. ELSTER K, KOLACZEK F, SHIMAMOTO K, FREITAG H: Early gastric cancer: experience in Germany. Endoscopy 7:5, 1975 9. QIZILBASH A, HARNARINE C, CASTELLI M: Early gastric carcinoma. Arch Pathol Lab Med 101:610,1977 10. FEVRE DI, GREEN HR, BARRATT PI, NAGY GS: Review of five cases of early gastric carcinoma. Gut 17:41, 1976 11. KOBAYASHI 5, PROLLA jC, YAGI M, KASUGAI J: Gastroscopic diagnosis of early gastric carcinoma based on Japanese classification. Gastrointestinal Endoscopy 16:92, 1969 12. KUBO T: Geographical pathology of gastric carcinoma. Acta Pathol Jpn 24:465, 1974 13. SANO R: Pathological analysis of 300 cases of early gastric cancer, in Early Gastric Cancer, T, Murakami ed. Tokyo, University of Tokyo Press, 1971, p. 81
VOLUME 25, NO. 3, 1979
14. SAKITA T, OGURO Y, TAKASU 5, FUKUTOMI H, MIWA T, YOSHIMORI M: Observation on the healing of ulcerations in early gastric cancer; the life cycle of the malignant ulcer. Gastroenterology 60:835, 1971 15. KOBAYASHI 5, YOSHII Y, KASUGAI T: Biopsy and cytology in the diagnosis of early gastric cancer, 10-year experience with direct vision techniques at a Japanese institution. Endoscopy 8:53, 1976 16. KOBAYASHI 5, SUGIURA H, KASUGAI T: Reliability of endoscopic observation in the diagnosis of early gastric carcinoma of the stomach. Endoscopy 4:61, 1972 17. DEKKER W, TYTGAT GN: Diagnostic accuracy of fiberendoscopy in the detection of upper intestinal malignancy: a follow-up analysis. Gastroenterology 73:710, 1977 18. SANCHO-POCH FL BALANZO I, OCANA I, PRESA E, SALA-CLADERA E, Cusso X, VILARDELL F: An evaluation of gastric biopsy in the diagnosis of gastric cancer. Gastrointestinal Endoscopy 24:281, 1978 19. LANDRES RT, STRUM WB: Endoscopic techniques in the diagnosis of gastric adenocarcinoma. Gastrointestinal Endoscopy 23:203, 1977
101
The endoscopic diagnosis of early gastric cancer Yoshiaki Ito, MD Michael O. Blackstone, MD Robert H. Riddell, MD Joseph B. Kirsner, MD, PhD Chicago, Illinois
Among 168 patients with adenocarcinoma of the stomach, 14 (8.3%) fulfilled the criteria for "early gastric cancer." Endoscopy in all cases permitted visual appraisal and opportunity for biopsy and cytologic examination. A correct endoscopic diagnosis was made in 6; biopsy disclosed carcinoma in 12; cytology was positive in only 7. The authors caution that diagnosis may be difficult when lesions are observed with forward-viewing endoscopes but that perspicacity and repeated examinations should sharpen diagnostic accuracy. Gastric cancer, while slowly decreasing in annual incidence, continues to be a major cause of cancer death in the United States. The overall prognosis following diagnosis is grim, with a 5-year survival generally of under 15%. A subgroup of patients has been identified by Japanese workers with an immensely better prognosis, namely, early gastric cancer. This has been defined as gastric cancer which is found to be confined to the mucosa or within the submucosa and does not extend into the muscularis propia. The lesion is considered early gastric cancer if it meets these criteria irrespective of any lymph node involvement. Its recognition in Japan has led to the identification of patients where curative resection and a 5-year survival can be expected in over 90% of surgically treated patients. 1 ,2 This can be compared to an overall 5-year survival of 30% or less in patients with advanced cancer following gastrectomy.3 In Japan, before the early 1960's and the introduction of a gastrocamera, a fiberoptic instrument with a wide angle, miniaturized camera mounted in its distal end, the frequency of lesions meeting the criteria of early gastric cancer was generally under 5%. Since that time, the figure has risen to as high as 33% in 1 series. 4 With the widespread use of fiberoptic endoscopy as a routine diagnostic procedure for gastric cancer in other parts of the world, early gastric cancer has now been recognized outside of Japan, but in no more than 10% to 15% of patients with gastric cancer, 5-7 a figure substantially less than that noted in Japanese studies 1 •2 ,4 where the principal endoscope used was the side-viewing gastrocamera or other instruments in which the gastrocamera lens system had been integrated. In most other parts of the world, especially in the United States, forward-viewing instruments are generally employed which are not principally designed for gastric examination. The use of these
instruments may present certain technical difficulties in the complete evaluation of suspicious lesions and contribute to the lower frequency of early gastric cancer actually diagnosed. Wishing to know specifically what technical problems might be associated with the use of these instruments, we have reviewed our experience with early gastric cancer, drawn from 168 cases of gastric cancers seen over a 10-year period where the principal endoscopes used were of the forward-viewing type.
MATERIALS AND METHODS During the period from September 1968 through August 1978, 6169 peroral endoscopic examinations were performed by the gastroenterology service at the University of Chicago Hospitals and Clinics. Fourteen malignancies of the stomach meeting the histologic criteria for early gastric cancer were found (8.3%) among 168 cases of gastric cancers studied over this period. The endoscopes used for the gastric cancer cases were mainly of the forward-viewing type, either the Olympus GIF-D or the subsequent GIF-D3 model. The GIF-P or GIFP2 endoscope was used in only a few instances because of its smaller biopsy channel. Three of the 14 cases studied before 1971 were examined with a fiberoptic gastrocamera, the Olympus GTF-A model with histologic and cytologic material being obtained in these cases using several other available instruments. In all cases, a minimum of 3 directed biopsies were obtained, although usually more than 5 biopsies were taken. These were placed directly in 10% formalin (1968-1974) or placed on Millipore® filter paper (1975-1978) before being immersed in formalin. At least one brushing cytology was obtained. The brushed material was immediately smeared on glass slides and fixed in 95% ethyl alcohol and stained by the Papanicolaou method. All histologic material was reviewed by one pathologist
From the Departments of Medicine and Pathology, University of Chicago Pritzker School of Medicine, Chicago, Illinois. Reprint requests: Michael O. Blackstone, MD, Department of Medicine, University of Chicago, Box 400, 950 East 59th Street, Chicago, Illinois 60637. 96
GASTROINTESTINAL ENDOSCOPY
(R.H.R.). To qualify as early gastric cancer, the lesion had to be confined to the mucosa or submucosa and not directly involve the muscularis propria. As in the original definition, the term was used irrespective of whether lymph node metastasis was present (2 patients). The cancers were typed according to the standard 1962 classification for early gastric cancer of the Japanese Society of Gastroenterological Endoscopy (Table I). Typing was based on an analysis of the photographs taken of the resected specimen. In addition, the histology in all cases was reviewed to determine the depth of the cancer as well as the presence of metastasis. To assess the diagnostic efficacy of endoscopy in these cases, the formal endoscopy report was reviewed as to final diagnosis. These diagnoses were considered as indicating one of the following: (1) early gastric cancer diagnosed, (2) gastric cancer diagnosed, (3) an indeterminate lesion with cancer not being excluded, or (4) no cancer found including either no lesion being seen or a diagnosis of benign ulcer. Histologic and cytologiC material obtained at endoscopy was reviewed by the pathologist, although, for purposes of analysis, the final diagnosis at the time of the endoscopy was used even if on subsequent review this proved to be in error as it did in 1 case (the biopsy obtained in case 6). The efficacy of biopsy and cytology in the cases of early gastric cancer was compared with the yield from these modalities in the remaining 150 patients with advanced gastric cancer in the series for whom the results of biopsy or cytology were available. The relationship between the appearance and location of the early gastric cancers and the efficacy of endoscopy, biopsy, and cytology was examined separately. Table I. The Japanese classification of early gastric cancer (bold segments indicate cancer).
SINGLE TYPES Type I TypeII
Protruded Superficial
IIa
(Elevated) ( Flat)
IIb lIc Type
(Depressed)--~--Jr---
m:
Excavated COMBIN ATIONS
Type lIc
:m:
•
+m +IIc
Shaded areas indicate cancer
VOLUME 25, NO. 3, 1979
Table II. Types of early gastric cancer for the 14 cases in the present series. single types
I Iia tic Total
n
1 1
3 5
combined types
n
lIa + Ilc Ilc + III til + tic Total
2 5 2
9
Table III. Endoscopic diagnosis in 14 cases of early gastric cancer. endoscopic diagnosis Gastric cancer early gastric cancer advanced gastric cancer Indeterminate lesion ulcer polyp Benign gastric ulcer No lesion
no. of patients
6 3 3 4
3 1
3 1 TOTAL 14
RESULTS The types of early gastric cancer for the 14 patients in the present series are presented in Table II. The combined types predominated, being found in 9 of the 14 cases. Of these, 7 were associated with a peptic ulceration (type III lesion). For the group as a whole, the type lie lesion was found alone or in combination in 12 of the 14 cases. The protruded type lesions either as I or lIa were seen in only 2 of the 14 patients. Endoscopic diagnosis. A correct diagnosis of gastric cancer was provided in only 6 of the 14 cases (Table III). In 3 of these, a diagnosis of early gastric cancer was made. In 1 (case 10), a type 11e+llllesion, a linear ulcer of the angulus was observed to be surrounded by a large, well-demarcated zone of discolored, irregular mucosa (Figure 1A) which extended proximally into the lower body. In another (case 6), the Ilc lesion appeared as a malignant ulcer with raised, friable margins. In the third case, a type I lesion (case 1) was recognized as a sessile polyp with a nodular surface. In 3 others (cases 3, 9, and 13), the endoscopic diagnosis was gastric cancer. Typical of this was the lIa+11e lesion of case 3 where a lesion consisting of raised folds, surrounding a large central depression was endoscopically observed on the greater curve of the midantrum. In the other 2 (cases 9 and 13), both combined types involving the peptic ulcerlike type III, the endoscopic diagnosis was malignant ulcer on the basis of either an irregular margin or converging folds becoming nodular at the margin of the ulcer. In 4 cases, the endoscopic diagnosis was an indeterminate lesion. In 3 (cases 8, 11, and 12), all type IIc+llllesions, ulcers surrounded by a regular or discolored margin were observed. Typical of this is the lesion seen in case 11 (Figure 3) where the disrupted fold at the margin of erythema raised the possibility of early gastric cancer, yet a definite diagnosis was not made. While in this case a gastrocamera photograph shows the lesion to greatest advantage, in the other cases this was not so, as in case 12 (Figure 4A) where only an irregular ulcer with marginal hemorrhage and nodularity was seen and called indeter97
figure 1. Endoscopic view of a IIc + III lesion (case 10) showing a large area of discolored and slightly depressed mucosa which surrounds an ulcer (arrow) in the proximal antrum (A) and extends up to the distal body of the stomach (8).
figure 2. Resected IIc + III lesion (case 10); note the large depressed mucosal lesion with disruption of radiating folds (the IIc component of the lesion).
Figure 3. Gastrocamera photograph of a IIc + III lesion (case 11) showing an ulcer (small arrows) surrounded by marginal erythema with a disrupted fold (large arrow); despite these findings, the lesion was considered indeterminate. Figure 4. Endoscopic view of a IIc + III lesion (case 12) called indeterminate. This shows only a tangential view of the ulcer with a somewhat irregular margin and disrupted converging folds (A); note the appearance of the resected lesion seen straight on (8) wherein the margin of the ulcer is clearly depressed and the folds around it disrupted. Figure 5. Forward-viewing endoscopic photograph of a III + /lc lesion (case 13) showing an ulcer on the gastric angulus with a nodular, friable margin (A); this was called malignant, but biopsy and cytology were negative. Endoscopy repeated 2 weeks later with a side-viewing instrument showed reduction in size of the base, illustrating partial "healing," and the ulcer was called benign (8); however, biopsy and cytology were both positive for malignancy. Figure 6. Representative gastrocamera views of 2 early gastric cancers (courtesy of Dr. T. Kasugai, Aichi Cancer Center, Nagoya, Japan). In the IIc lesion (A) there is an irregular shallow depression with clubbing of the converging folds. In the IIc + III lesion (8), there is a typical IIc area (arrow) surrounding a central ulcer. Abrupt thinning of the mucosal folds can also be seen. Note the complete view of the lesion and surrounding mucosa provided by the wide angle gastrocamera.
minate. Here, a complete, en face view might have shown more of the lesion ultimately found in the resected specimen (Figure 48). The 1 remaining patient with an endoscopic diagnosis of an indeterminate lesion (case 2) had a lIa lesion consisting of a small, slightly elevated mucosal excrescence of the cardia.
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In the remaining 4 cases, the endoscopic diagnosis was either a benign gastric ulcer or the lesion was entirely missed. The lesions called benign gastric ulcer (cases 4, 5, and 14) were all either Ilc singly (case 5) or in combination (case 4, type Ila+11e and case 14, type IIl+lIc). In one instance (case 7) a lie lesion was entirely missed. GASTROINTESTINAL ENDOSCOPY
Endoscopic biopsy and cytology. The results are presented in Table IV. In contrast to visual diagnosis, biopsy was positive in 12 of the 14 cases (86%) while cytology was positive in only 7 of 13 (54%). By contrast, for 150 advanced cancers seen over the same period, biopsy was positive in 116 of 143 patients (81%) and cytology was positive in 116 of 143 cases (81%). While biopsy results in either type of gastric cancer were comparable, the yield from cytology was greater in advanced cancer than in early cancer. The combination of biopsy and cytology raised the yield in advanced gastric cancer from 81% for biopsy alone to 92% for the combination while no such increased yield was noted for early gastric cancer. Appearance and location of the lesion in relation to the success of endoscopic diagnosis, biopsy, and cytology (Table V). For purposes of analysis, types I and lIa lesions were considered polypoid while the remainder, principally lie and III, were considered ulcerative. For the 2 polypoid lesions both of the cardia, biopsy was positive in both whereas endoscopic and cytologic diagnosis was positive in only 1. The ulcerative lesions were divided into those of the body and antrum. Endoscopic diagnosis was correctly made in 4 of 6 lesions of the body but in only 1 of 6 antral lesions. Biopsy was successful in all but 1 of both body and antral lesions, while cytology was slightly more successful in the body (positive in 4 of 6 lesions) than in the antrum (positive in 2 of 5). Illustrative clinical features. In 3 cases, the course previous to surgery was noteworthy. In 1 (case 6), the initial endoscopic diagnosis was malignant gastric ulcer. The biopsies taken were reported as benign, whereas, in fact, on subsequent review for inclusion in the present series, cancer was found. Three years later, endoscopy again reTable IV.
Results of biopsy and cytology in 164 patients with gastric cancer. n Biopsy Cytology Combination
14 13
14
early cancer positive 12 (86%) 7 (54%) 12 (86%)
advanced cancer n positive
143 143 150
116 (81%) 116 (81%) 138 (92%)
Table V.
The principal appearance and location of early gastric cancers in relation to visual diagnosis and results of biopsy and cytology.• polypoid
ulcerative
Cardia
Body
• • • • 00
&&&&&6 • • 00 • • Antrum
.00000
&&&&&6 0 • • 00 • KEY: endoscopy: e, positive; 0, negative or indeterminate; biopsy: .., positive; 6, negative; cytology: _, positive; 0, negative.
VOLUME 25, NO. 3, 1979
vealed a malignant ulcer and the lesion was finally resected. Histologically, it was still early gastric cancer with invasion confined to only the submucosa with metastasis to none of 80 lymph nodes recovered. In 2 others (cases 12 and 13) apparent healing of a malignant ulcer was observed. In case 13, the ulcer was considered malignant at the first endoscopy because of nodular, friable margins (Figure SA). Biopsy and cytology were both negative. A second endoscopy 2 week later showed apparent reduction in size (Figure 58) with only a slightly depressed area encircling the ulcer as a clue to malignancy (Figure 58). This was ignored, and at endoscopy the ulcer was called benign. Biopsy, however, disclosed poorly differentiated adenocarcinoma. In case 12, an indeterminate ulcer was seen at endoscopy. By the time the patient came to resection 2 weeks later, the ulcer base was covered by a small rim of regenerative mucosa and appeared to be almost healed. DISCUSSION In most reported series outside of Japan, the frequency of gastric carcinoma fulfilling the criteria for early gastric cancer remains under 15%, despite an increased awareness of the lesion. 5 - 7 By contrast, Japanese workers in 1 series identified up to one third of all gastric cancers as uearly.u4 Some have attributed this to a difference in gastric cancer seen in Japan and elsewhere in the world; however, there appears to be no demonstrable difference in the gross or histologic appearance, site, rate of resectability, or high percent of 5-year survivals to suggest that early gastric cancer in Japan is different from that found elsewhere. 5 ,a-12 Regardless of where early gastric cancer occurs, as in our series, the depressed lie lesion predominates, usually in association with ulceration (lIc+III). These lesions closely simulate peptic ulcers, clinically, radiologically, and even at endoscopy.13.14 In 1 Japanese study of 300 cases of early gastric cancer, 211 (70.3%) were found to be adjacent to ulcers. 13 Typically the ulcers were entirely benign, with the cancer being located within the surrounding mucosa and submucosa. The endoscopic clues indicating an ulcer's association with early gastric cancer are, therefore, obtained from a complete examination of its margin in relationship to the remainder of the stomach. As indicated in Table VI, these include: (1) disruption and clubbing of the surrounding mucosal folds, (2) a dirty appearance of the surrounding mucosa with adherent mucous or exudate, (3) irregular margins of the ulcer itself, or .(4) island-like residues of intact mucosa within the depressed area. These features clearly call for a complete examination not only of the base of the ulcer but the surrounding 2 to 3 em of gastric mucosa. This has, in the past, best been afforded by the use of the gastrocamera, the principal instrument used in all Japanese series. In fact, the endoscopic criteria for early gastric cancer (Table VI) are derived from these gastrocamera studies. If forward-viewing endoscopes are used, a lesion may be seen only tangentially (Figure 4A) and then incompletely, so that important features such as the disruption of the fold pattern and depression of the ulcer margin may not be apparent until the resected specimen is examined (Figure 48). This may explain why, in our 99
Table VI.
Clues to the endoscopic recognition of early gastric cancer. type lesion
principal endoscopic features 1. 2. 3. 4.
irregular contour bleeding sessile greater than 2 cm
Iia
1. elevated area does not disappear with inflaticn 2. "flower-bed" appearance
lib
1. discoloration of surrounding mucosa
Ilc
1. slightly depressed with disruption and clubbing of surrounding mucosal folds 2. dirty appearance of depressed area with adherent mucus or exudate 3. irregular margins 4. island-like residues of intact mucosa within the depressed area
III
1. similar in appearance to benign gastric ulcer
IIc
+ III
1. ulcer may appear entirely benign 2. depressed area with disruption of folds adjacent to the ulcer, as well as other IIc features
III
+ IIc
1. definite depression confined to margins of the ulcer 2. rigidity and clubbing of tips of any converging mucosa folds 3. discoloration and adherent necrotic material and blood in the depressed zone
series, only 6 of 14 (42.8%) lesions were correctly identified endoscopically as gastric cancer compared with 70.6% in a representative Japanese series where the gastrocamera was exclusively used.'6 With the gastrocamera, it is usually possible to photograph the lesion, en face, in relation to a wide area of stomach (Figure 6A), especially in areas such as the antrum where it is difficult with a forward-viewing endoscope to obtain a complete view in anyone position. In our own series, lesions of the antrum proved particularly difficult, so that a correct endoscopic diagnosis was made in only 1 of 6 cases, contrasted with the region of the gastric angle where 4 of 6 lesions were correctly identified as malignant (Table V). Despite the failure of endoscopic visual diagnosis in over half the cases, biopsy was successful in 86% (Table IV). This, we attribute to our policy of obtaining multiple biopsies (usually more than 3) for any gastric lesion, especially ulcers. Others have found that, for endoscopic biopsy to have its greatest accuracy, 8 or more biopsies must be taken from any suspicious lesion, especially an ulcer where the question of malignancy is raised. 17o '8 This becomes especially important where, in the case of ulcerlike early gastric cancer, inadequate visualization of the lesion with forward-viewing endoscopes may prevent correct endoscopic interpretation and full utilization of brush cytology'S (Table V). The lack of any contribution of cy-
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tology in our series of early gastric cancer may be contrasted with its performance in advanced cancers, where its role, especially in the diagnosis of the infiltrative type, has been noted by others.'8 Apart from the difficulty of endoscopic visualization of these lesions because, we believe, of the instruments used, the recognition of early gastric cancer is hindered by its close similarity both in appearance and in course with benign peptic ulcers. The natural history of early gastric cancer appears to be one of healing and ulceration, often in a cyclical fashion, providing a malignant ulcer "life cycle," previously noted.'4 Apparent healing of the early gastric cancer ulcer, as in our case 13 (Figure 58), adds to the confusion of these lesions with benign peptic ulcers. In addition, the lesions grow slowly, as in our case 6 where early gastric cancer was still found 3 years after biopsies were misread as benign. One suspects that such a lesion would change little in appearance over such period of time and thus escape diagnosis unless a high index of suspicion was maintained. Because of the difficulties in both visualization and correct identification of early gastric cancers, we recommend a vigorous approach to biopsy with at least 6, and preferably 8 or more, biopsy specimens being taken from any of the following: (1) an ulcer whose base or margin is irregular and where the surrounding mucosa is discolored or depressed, and (2) a discrete area where gastric folds are elevated, discolored, disrupted, or have in any other wayan irregular appearance. Cytology is a complementary procedure to biopsy. It may not actually increase the overall yield in early gastric cancer, but it may be used to supplement biopsy when the endoscopist feels that an optimal position for biopsy cannot be achieved.'s Besides this approach to biopsy and cytology, we further urge that a carefully planned follow-up be provided for any suspicious gastric ulcer to the point of complete healing, with endoscopy and biopsy being performed at 4- to 6-week intervals. After apparent healing, endoscopic follow-up should be provided at an interval of 6 months to a year. Even with apparent healing, early gastric cancer may still be present which may become only apparent on su bseq uent endoscopy.'4 While, in the end, none of these measures may actually increase the frequency of early gastric cancer in western countries to that reported in Japan, still an increased awareness of endoscopic factors which may limit diagnosis, as well as the necessity for obtaining multiple biopsies from any ulcer, especially with suspicious or atypical features, may increase the endoscopist's effectiveness in the diagnosis of these lesions.
REFERENCES 1. HAYASHIDA T, KIDOKORO S: End results of early gastric cancer collected from 22 institutions. Stomach and Intestine 4:1077, 1969 2. YAMADA E, NAKAZATO H, KOIKE A, SUZUKI K, KATO K, KITO T: Surgical results for early gastric cancer. Surg 59:7,1974 3. KASUGAI T: Prognosis of early gastric cancer. Gastroenterology 58:429, 1970 4. KAWAI K: Diagnosis of early gastric cancer. Endoscopy 1:23, 1971 GASTROINTESTINAL ENDOSCOPY
5. EVANS DMD, CRAVEN )L, MURPHY F, CLEARY BK: Comparison of "early gastric cancer" in Britain and Japan. Gut 19:1,1978 6. MACHADO G, DAVIES )D, TODWAY AjC, WALMON PR, REED AE: Superficial carcinoma of the stomach. Br Med J 2:77, 1976 7. STADELMANN 0, MIEDERER SE, LOFFLER A, MULLER R, KAUFER C, ELSTER K: So-called early gastric cancer and its detection. Endoscopy 5:70, 1973 8. ELSTER K, KOLACZEK F, SHIMAMOTO K, FREITAG H: Early gastric cancer: experience in Germany. Endoscopy 7:5, 1975 9. QIZILBASH A, HARNARINE C, CASTELLI M: Early gastric carcinoma. Arch Pathol Lab Med 101:610,1977 10. FEVRE DI, GREEN HR, BARRATT PI, NAGY GS: Review of five cases of early gastric carcinoma. Gut 17:41, 1976 11. KOBAYASHI 5, PROLLA jC, YAGI M, KASUGAI J: Gastroscopic diagnosis of early gastric carcinoma based on Japanese classification. Gastrointestinal Endoscopy 16:92, 1969 12. KUBO T: Geographical pathology of gastric carcinoma. Acta Pathol Jpn 24:465, 1974 13. SANO R: Pathological analysis of 300 cases of early gastric cancer, in Early Gastric Cancer, T, Murakami ed. Tokyo, University of Tokyo Press, 1971, p. 81
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14. SAKITA T, OGURO Y, TAKASU 5, FUKUTOMI H, MIWA T, YOSHIMORI M: Observation on the healing of ulcerations in early gastric cancer; the life cycle of the malignant ulcer. Gastroenterology 60:835, 1971 15. KOBAYASHI 5, YOSHII Y, KASUGAI T: Biopsy and cytology in the diagnosis of early gastric cancer, 10-year experience with direct vision techniques at a Japanese institution. Endoscopy 8:53, 1976 16. KOBAYASHI 5, SUGIURA H, KASUGAI T: Reliability of endoscopic observation in the diagnosis of early gastric carcinoma of the stomach. Endoscopy 4:61, 1972 17. DEKKER W, TYTGAT GN: Diagnostic accuracy of fiberendoscopy in the detection of upper intestinal malignancy: a follow-up analysis. Gastroenterology 73:710, 1977 18. SANCHO-POCH FL BALANZO I, OCANA I, PRESA E, SALA-CLADERA E, Cusso X, VILARDELL F: An evaluation of gastric biopsy in the diagnosis of gastric cancer. Gastrointestinal Endoscopy 24:281, 1978 19. LANDRES RT, STRUM WB: Endoscopic techniques in the diagnosis of gastric adenocarcinoma. Gastrointestinal Endoscopy 23:203, 1977
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