0016-5107/92/3806-0645$03.00
GASTROINTESTINAL ENDOSCOPY Copyright 0 1992 by the American Society for Gastrointestinal Endoscopy
Minute non-polypoid adenoma of the colon detected by colonoscopy: correlation between endoscopic and histologic findings Takayuki Matsumoto, MD, Mitsuo lida, MD Yasuyuki Kuwano, MD, Shuji Tada, MD Takashi Yao, MD, Masatoshi Fujishima, MD Fukuoka, Japan
To characterize the endoscopic features of minute non-polypoid neoplastic lesions of the colon, we investigated the endoscopic, macroscopic, and histologic findings in 34 lesions detected by colonoscopy, which were smaller than 5 mm and were endoscopically recognized as flat or depressed lesions. The lesions were divided into two groups according to their endoscopic features; 8 lesions were completely flat and the remaining 26 lesions were flat-topped elevations with a central depression. Macroscopic examinations revealed that the center of the endoscopically flat lesion was slightly elevated, whereas the center of the flattopped elevation was characterized by a central depression. All of the lesions were histologically diagnosed as tubular adenomas. The flat lesions were composed of flatly elevated adenomatous glands, while the flat-topped elevations with a depression were characterized by surrounding hyperplasia arising from normal glands. The whole thickness of the mucosa was replaced by adenomatous glands in the lesions with an obvious central depression, while the adenomas tended to spread superficially in the lesions with a shallow depression. These findings suggest that pre-cancerous lesions other than small polyps do exist in the colon and that colonoscopic examination provides some clue toward a prediction of the histologic architecture of the lesions. (Gastrointest Endosc 1992;38:645-650)
It is now widely accepted that benign adenomatous polyps of the colon and rectum have the potential to develop into cancer,' and that endoscopic removal of these lesions will prevent the development of colorectal ~ a n c e r . ~ Recently, however, small, flat elevated adenomas of the colon were reported as showing a high rate of severe dysplasia by Muto and colleagues3~and Wolber and Owen,5 and they emphasized the necessity to clinically recognize these lesions. In addition, it was also reported that these lesions were frequently found by colonoscopy in subjects belonging to Lynch syndrome families6, and, more recently, it has been pro-
posed that the patients with this type of lesion should be classified as hereditary flat adenoma ~ y n d r o m e . ~ Although many flat or depressed neoplastic lesions detected during colonoscopy have been precisely analyzed by Kudo et al.' in Japan, there have been few reports describing the endoscopic findings of these lesions in the English l i t e r a t ~ r e . ~ .The ~ - ' ~aim of this study was to analyze our 2-year experience concerning minute non-polypoid neoplastic lesions found during colonoscopy, with particular emphasis on clarifying their endoscopic features.
Received January 10,1992. For revision April 1, 1992. Accepted April 23, 1992. From the Second Department of Internal Medicine and Second Department of Pathology, Faculty of Medicine, Kyushu University, Fukuoka, Japan. Reprint requests: Takayuki Matsumoto, MD, Second Department of Internal Medicine, Faculty of Medicine, Kyushu University, Maidashi 3-1-1, Higashi-ku, Fukuoka 812, Japan.
We reviewed colonoscopy records a t our institution between January 1989 and July 1991 and collected 34 lesions from 32 patients, all of which satisfied the following criteria: (I) smaller than 5 mm at the largest diameter; (2) endoscopically recognized as a reddish, flat, or slightly elevated lesion; and (3) histologically confirmed as a neoplastic lesion by
VOLUME 38, NO. 6, 1992
MATERIALS AND METHODS
645
microscopic examination of the specimen obtained by endoscopic forceps biopsy or endoscopic mucosal resection or obtained from surgically resected specimens. The patients were prepared by ingestion of 2 liters of electrolyte lavage solution (Golytely,"l), and colonoscopies were performed using either CF-10I, CFV-lOI, or CFV-200I endoscopes (Olympus Corp., Tokyo, Japan). Total colonoscopy was performed in all of the patients, except for five patients, who had a redundant sigmoid colon or complained of severe abdominal pain during the procedure. When a flat or depressed lesion was suspected endoscopically, 0.2% indigo carmine solution was always sprayed through the colonoscope, and the existence of a central depression was confirmed. Endoscopic forceps biopsy was performed with a standard biopsy forceps (Olympus FB-24Q). Endoscopic mucosal resection was performed modifying the method described by Karita et al. 13 and Kudo et al. 9 In brief, 2 to 4 ml of saline were injected into the submucosa under the tumor prior to resection. The tumor, along with the artificially made elevation, was then polypectomized by bipolar electrocautery snare. The specimen obtained by endoscopic mucosal resection or by surgery was fixed in 10% formalin for 2 days, stained with Alcian blue and Mayer-hematoxylin solution, and then observed under a stereomicroscope at x2 or x5 magnification for measurement of the size and for characterization of the surface of the lesion. All of the specimens, including the ones obtained through forceps biopsy, were cut in half, embedded in paraffin, and then stained with hematoxylin and eosin. Microscopic examination of the specimen was made by a pathologist, who was blind to the endoscopic findings. The grading of dysplasia was defined according to the World Health Organization classification, mainly focusing on nuclear changes and cytoplasmic differentiation. 14 Mild dysplasia was defined as the adenoma with slightly enlarged, elongated, and hyperchromatic nuclei with preserved polarity and with slightly curtailed cytoplasmic maturation. Moderate dysplasia was regarded as the adenoma with further enlarged, and less elongated nuclei with frequent loss of polarity. The adenoma with round or ovoid nuclei with loss of polarity containing prominent nuclei and with basophilic cytoplasm was classified as severe dysplasia. We reviewed the clinical features and the endoscopic and histologic findings of the lesions. RESULTS Clinical features
There were 27 males and 5 females, and the ages of the patients ranged from 48 to 78 years (mean, 64 years). The indications for colonoscopy included positive fecal occult blood in 12 patients, rectal bleeding in 4 patients, and other symptoms such as constipation, diarrhea, and abdominal pain in the remaining 16 patients. Ofthe 27 patients in whom precise family history could be obtained, 3 patients had first-degree relatives who had suffered from colorectal cancer. Figure 1 indicates the location of the minute, flat, or depressed lesions. The lesions were frequently 646
• • •
•
•• •••
•
•
Figure 1. Distribution of non-polypoid adenomas of the colon found during colonoscopy.
Table 1. Other neoplastic lesions found during colonoscopy Lesion
No. of patients (%)
None
6/32 (19)
Single adenomatous polyps
8/32 (25)
Multiple adenomatous polyps
17/32 (53)
Colorectal cancer
6/32 (19)
found in the sigmoid colon and in the transverse colon. Table 1 summarizes other synchronous neoplastic lesions of the colon found during colonoscopy. Single or multiple adenomatous polyps were found in 22 of the 32 patients. In addition, colon cancer was identified in six patients. Thirty-one of the 34 lesions were removed endoscopically; 22 lesions by endoscopic mucosal resection and 9 lesions by endoscopic forceps biopsy, whereas 3 lesions were surgically resected because the patients had colon cancer which was located near the minute lesion. No complications related to endoscopic mucosal resection occurred in any of the patients studied. Endoscopic and macroscopic features
Most of the lesions were initially recognized as slightly reddened mucosa, round or oval in shape (Fig. 2A), except for three cases in which the flat or depressed lesions were not endoscopically detected until GASTROINTESTINAL ENDOSCOPY
Table 2. Endoscopic findings of flat or depressed lesions of the colon Endoscopic features
No. of lesions (%)
Completely flat Flat-topped elevation With shallow depression With deep depression
8/34 (24) 26/34 (76) 20 6
a sprayed dye technique for other lesions was performed. The endoscopic findings and their incidence are summarized in Table 2. Eight of the lesions were completely flat, either with or without a slightly elevated surrounding mucosa of normal appearance (Fig. 2B). Twenty of the lesions were visualized as a flattopped elevation, in the center of which a shallow, reddish depression could be confirmed (Fig. 2C). In the remaining six lesions, the depression, surrounded by an elevation, was obvious (Fig. 2D). Macroscopic appearance of the endoscopically or surgically resected specimen, as confirmed by stereomicroscopy, revealed that the lesions, endoscopically diagnosed as completely flat, were in fact flatly elevated (Fig. 3A), while the endoscopically elevated lesions with a central depression were composed of a depression and a surrounding elevation of normal appearance (Fig. 3B). Histologic features
As shown in Figure 4A, all of the lesions were histologically diagnosed as tubular adenomas with moderate epithelial dysplasia, and no foci of carcinoma or de novo cancer were found in any of the patients. The adenomatous glands were almost flat or slightly elevated, and the center of the adenomatous component was frequently depressed. The surrounding non-neoplastic mucosa was completely flat in six lesions (Fig. 4B), while noticeable hyperplasia arising from glands of normal appearance was observed in the remaining 19 lesions (Fig. 4C). The involvement of neoplastic glands within the mucosa was superficial in 10 lesions (Fig. 4B) and mainly superficial but focally, especially in the center of the lesion, trans-
Figure 2. Endoscopic view of non-polypoid adenomas of the colon. A, Colonoscopy reveals a reddened, oval mucosa in
VOLUME 38, NO.6, 1992
the descending colon (arrow). B, Colonoscopy with sprayed dye technique reveals a completely flat, reddened lesion in the sigmoid colon. The surrounding mucosa is slightly elevated. C, Endoscopic view of the lesion shown in A using sprayed dye technique. A flat-topped elevation, the center of which is slightly depressed, can be seen. D, The central depression of the flat-topped elevation found in the descending colon is more marked than that in the lesion shown in C. 647
Figure 3. Macroscopic view under stereomicroscopy of the
resected lesions. Alcian blue and Mayer-hematoxylin staining can reveal the precise nature of the surface of the lesions. A, The non-polypoid lesion, which is endoscopically flat as shown in Figure 28, is flatly elevated macroscopically. B, The flat-topped elevation, as shown in Figure 2C, is composed of a flat elevation and a central depression.
mucosal in 8 lesions (Fig. 4D), while the whole thickness of the mucosa was replaced by adenomatous glands in 7 lesions (Fig. 4C). Table 3 summarizes the correlation between the endoscopic findings and the histologic features of 25 lesions, which were removed by means other than forceps biopsy. Hyperplasia of the surrounding mucosa was more frequently found in flat-topped elevations than in completely flat lesions. In addition, the involvement of adenoma within the mucosa was more extensive in flat-topped elevations with an obvious central depression than in flat-topped elevations with a shallow depression or than in completely flat lesions. DISCUSSION
Small "flat adenoma" of the colon was first described in the literature by Muto et a1.,3 as a flatly elevated lesion measuring less than 10 mm in diameter 648
with a central depression. Despite the size of these lesions, they were reported to show high-grade dysplasia, and it was speculated that they rapidly developed into invasive carcinoma. 3,5,15 Recently, however, the word "depressed adenoma," the endoscopic view of which seems to be similar to those reported by Muto et a1. 3 was used in another article by Kuramoto et alY This insufficient standardization of terminology, as suggested by Smyrk et a1.,16 seems to arise from the continuing obscure biological nature of these lesions. In this study, we analyzed minute neoplastic nonpolypoid lesions of the colon, which measured less than 5 mm in diameter. The endoscopic features were conspicuously different from those ordinarily found in colonic polyps, in respect to the central depression, whether with or without a surrounding flat elevation. Most of the lesions were initially found as reddened mucosa, and a sprayed dye technique, which was primarily developed for the diagnosis of small gastric cancers,17 was of great value in confirming the existence of these lesions. Although the endoscopic findings in three-fourths of the lesions reported in this study were almost equal to those reported previously,3,5.11 the remaining lesions were completely flat or slightly depressed and were lacking in obvious surrounding elevations. These lesions were considered to conform to previously described completely flat adenomas found in surgically resected specimens. 4 The endoscopically recognized depth of central depression in a flat-topped elevation has been reported to be enhanced when less air is insufflated into the lumen through the colonoscope. 3, 9, 11 Our results indicated that the central depression was more obvious in lesions in which the adenomatous component involved the whole thickness of the mucosa than in lesions with a superficial spread ofthe adenoma. Thus, it can be speculated that the degree of central depression detected by colonoscopy may be an indicator of the depth of involvement within the mucosa. All of the lesions in this study were histologically diagnosed as tubular adenomas. Interestingly, further histologic examination of the completely removed lesions revealed that the adenomatous component was almost flat or else slightly depressed, and that the surrounding elevation in cases of flat-topped elevation was mainly composed of hyperplasia of normal glands, which circumscribed the depressed adenomatous glands. Although synchronous adenomatous polyps were frequently found in our patients, both the endoscopic and histologic features of the non-polypoid adenomas, especially the flat-topped elevation with an obvious depression, suggest that the lesions are unlikely to be the precursor of the usual adenomatous polyps, because diminutive adenomas in familial polyposis patients are convex discoid in shape and horizontal or radial in growth. 18 GASTROINTESTINAL ENDOSCOPY
c
o
Figure 4. Histologic features of the resected lesions. A, High-power view of a flat-topped elevation with a central depression reveals a crowding of small adenomatous tubules (H & E; original magnification x100). B, The flat lesion, as shown in Figure 28, is composed of flatly elevated neoplastic glands which involve the superficial layer within the mucosa. The surrounding mucosa is not hyperplastic (H & E; original magnification x36). C, The center of the lesion, as shown in Figure 2D, is obviously depressed from the surroundings which are elevated because of hyperplasia arising from glands of normal appearance. The adenomatous glands involve the whole thickness of the mucosa (H & E; original magnification x36). D, The lesion shown in Figure 2C is composed of mainly superficial and focally transmucosal proliferation of adenomatous glands, which is surrounded by hyperplasia of normal glands (H & E; original magnification x36).
There still remains some controversy as to whether colorectal cancer arises from adenomatous polyps1, 19 or de novo. 20 Recently, small de novo cancers of the colon have been found in surgically resected specimens21 -24 and, in addition, they have been found by colonoscopy.9, 10, 13,24 In contrast with such evidence suggesting the de novo hypothesis, the adenoma-carcinoma sequence has been supported by the finding that small flat adenomas of the colon frequently contain high-grade dysplasia or focal cancer. 3,5 In this study, there were neither de novo cancer nor foci of carcinoma cells within non-polypoid adenomas. VOLUME 38, NO.6, 1992
These observations do not support the speculation that flat adenomas possess the ability to rapidly transform into frank carcinoma,3,5 or that the recognition of depressed adenomas may lead to the detection of minute de novo cancers. l l This discrepancy can be explained by the small size of the lesions analyzed in this study and, possibly, by the difference in the individual criteria of histologic grading for adenomas and carcinomas between observers. Thus, it would seem to be mandatory to detect and evaluate more cases with progressive lesions and to follow-up minute non-polypoid adenomas, using the same histologic 649
Table 3. Correlation between endoscopic and histologic features in minute non-polypoid adenoma of the colon Histologic features
Endoscopic feature
Hyperplasia of surrounding mucosa (+)
Completely flat (W Flat-topped elevation (19) With shallow depression (13) With deep depression (6)
Involvement of adenomatous glands within mucosa
(-)
Superficial
Intermediate"
Whole thickness
1/6
5/6
4/6
1/6
1/6
12/13 6/6
1/13 0/6
6/13 0/6
6/13 1/6
1/13 5/6
" Focally, especially in the center of the lesion, the whole thickness of the mucosa was replaced by adenomatous glands. b Numbers in parentheses, number of lesions.
criteria, in order to establish the practical biologic nature of these lesions. In such circumstances, it may be important to know that non-polypoid adenomas manifest different characteristics morphologically, in respect to the central depression and the surrounding elevation, even when they are very small in size. There may be some argument concerning the management of such lesions. Forceps biopsy or hot biopsyll and snare polypectomy3 have been recommended in the case of flat or depressed adenomas, whereas Kudo et a1. 9 and Karita et alY recently stressed the diagnostic and therapeutic value and the safety of endoscopic mucosal resection defined as complete excision of the lesion along with surrounding mucosa and submucosa. In this study, most of the lesions were successfully removed by endoscopic mucosal resection and, as a result, the endoscopic, macroscopic, and histologic features of the lesions were able to be investigated comparatively. Although there remains the dilemma that complete resection of these minute lesions, which seem to be benign in nature, results in the inability to determine their natural course, such an approach in greater numbers of lesions will provide some evidence concerning the pathogenesis of colorectal neoplasms.
5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17.
ACKNOWLEDGMENT
18.
The authors are grateful for the assistance of Miss K. Miller.
19.
REFERENCES
20.
1. Muto T, Bussey HJR, Morson BC. The evolution of cancer of the colon and rectum. Cancer 1975;36:2251-70. 2. Shinya H, Wolff WI. Morphology, anatomic distribution and cancer potential of colonic polyps. An analysis of 7,000 polyps endoscopically removed. Ann Surg 1979;190:679-83. 3. Muto T, Kamiya J, Sawada T, et al. Small "flat adenoma" of the large bowel with special reference to its clinico-pathologic features. Dis Colon Rectum 1985;28:847-51. 4. Adachi M, Muto T, Morioka Y, Ikenaga T, Hara M. Flat adenoma and flat mucosal carcinoma (IIb type). A new precur-
21.
650
22. 23. 24.
sor of colorectal carcinoma? Report of two cases. Dis Colon Rectum 1988;31:236-43. Wolber RA, Owen DA. Flat adenoma of the colon. Human PathoI1991;22:70-4. Lynch HT, Smyrk TC, Lanspa SJ, et al. Flat adenoma in a colon cancer-prone kindred. J Nat! Cancer Inst 1988;80:27882. Lanspa SJ, Smyrk TC, Lynch HT. The colonoscopist and the Lynch syndromes. Gastrointest Endosc 1990;36:156-8. Lynch HT, Lanspa SJ, Smyrk TC, et al. The hereditary flat adenoma syndrome (HFAS). Clinical, pathological, and gene linkage update. Gastroenterology 1991;100:A382. Kudo S, Miura K, Takano Y, et al. Detection of colorectal minute cancer. Stomach Intestine 1990;25:801-11 (in Japanese with English abstract). Desigan G, Wang M, Alberti-Flor J, Dunn GD, Halter S, Vaughan S. De novo carcinoma of the rectum. A case report. Am J Gastroenterol 1985;80:553-6. Kuramoto S, Ihara 0, Sakai S, Shimizu R, Kaminishi M, Oohara T. Depressed adenoma in the large intestine. Dis Colon Rectum 1990;33:108-12. Hunt DR, Cherian M. Endoscopic diagnosis of small flat carcinoma of the colon. Dis Colon Rectum 1990;33:143-7. Karita M, Tada M, Okita K, Kodama T. Endoscopic therapy for early colon cancer: the strip biopsy resection technique. Gastrointest Endosc 1991;37:128-32. Morson BC, Dawson IMP. Benign epithelial tumors and polyps. In: Morson BC, Dawson, eds. Gastrointestinal pathology. Oxford: Blackwell Scientific Publications, 1990. Muto T, Masaki T, Suzuki K. DNA ploidy pattern of flat adenomas of the large bowel. Dis Colon Rectum 1991;34:696-8. Smyrk TC, Lanspa SJ, Lynch HT. Small, nonpolypoid colonic neoplasms. Dis Colon Rectum 1990;33:814. Tada M. Endoscopy using dye-spraying method. Stomach Intest 1987;22:1321-4 (in Japanese with English abstract). Chang WWL, Whitener CJ. Histogenesis of tubular adenomas in hereditary colonic adenomatosis polyposis. Arch Pathol Lab Med 1989;113:1042-9. Morson BC. Evolution of cancer of the colon and rectum. Cancer 1974;34:845-9. Spratt JS, Ackerman LV. Small primary adenocarcinomas of the colon and rectum. JAMA 1962;179:125-34. Lev R, Grover R. Precursors of human colon carcinoma. A serial section study of colectomy specimens. Cancer 1981;47:2007-15. Kuramoto S, Oohara T. Minute cancers arising de novo in the human large intestine. Cancer 1988;61:829-34. Shimoda T, Ikegami M, Fujisaki J, Matsui T, Aizawa S, Ishikawa E. Early colorectal carcinoma with special reference to its development de novo. Cancer 1989;64:1138-46. Crawford BE, Stromeyer FW. Small nonpolypoid carcinomas of the large intestine. Cancer 1983;51:1760-3.
GASTROINTESTINAL ENDOSCOPY
GASTROINTESTINAL ENDOSCOPY Copyright 0 1992 by the American Society for Gastrointestinal Endoscopy
Minute non-polypoid adenoma of the colon detected by colonoscopy: correlation between endoscopic and histologic findings Takayuki Matsumoto, MD, Mitsuo lida, MD Yasuyuki Kuwano, MD, Shuji Tada, MD Takashi Yao, MD, Masatoshi Fujishima, MD Fukuoka, Japan
To characterize the endoscopic features of minute non-polypoid neoplastic lesions of the colon, we investigated the endoscopic, macroscopic, and histologic findings in 34 lesions detected by colonoscopy, which were smaller than 5 mm and were endoscopically recognized as flat or depressed lesions. The lesions were divided into two groups according to their endoscopic features; 8 lesions were completely flat and the remaining 26 lesions were flat-topped elevations with a central depression. Macroscopic examinations revealed that the center of the endoscopically flat lesion was slightly elevated, whereas the center of the flattopped elevation was characterized by a central depression. All of the lesions were histologically diagnosed as tubular adenomas. The flat lesions were composed of flatly elevated adenomatous glands, while the flat-topped elevations with a depression were characterized by surrounding hyperplasia arising from normal glands. The whole thickness of the mucosa was replaced by adenomatous glands in the lesions with an obvious central depression, while the adenomas tended to spread superficially in the lesions with a shallow depression. These findings suggest that pre-cancerous lesions other than small polyps do exist in the colon and that colonoscopic examination provides some clue toward a prediction of the histologic architecture of the lesions. (Gastrointest Endosc 1992;38:645-650)
It is now widely accepted that benign adenomatous polyps of the colon and rectum have the potential to develop into cancer,' and that endoscopic removal of these lesions will prevent the development of colorectal ~ a n c e r . ~ Recently, however, small, flat elevated adenomas of the colon were reported as showing a high rate of severe dysplasia by Muto and colleagues3~and Wolber and Owen,5 and they emphasized the necessity to clinically recognize these lesions. In addition, it was also reported that these lesions were frequently found by colonoscopy in subjects belonging to Lynch syndrome families6, and, more recently, it has been pro-
posed that the patients with this type of lesion should be classified as hereditary flat adenoma ~ y n d r o m e . ~ Although many flat or depressed neoplastic lesions detected during colonoscopy have been precisely analyzed by Kudo et al.' in Japan, there have been few reports describing the endoscopic findings of these lesions in the English l i t e r a t ~ r e . ~ .The ~ - ' ~aim of this study was to analyze our 2-year experience concerning minute non-polypoid neoplastic lesions found during colonoscopy, with particular emphasis on clarifying their endoscopic features.
Received January 10,1992. For revision April 1, 1992. Accepted April 23, 1992. From the Second Department of Internal Medicine and Second Department of Pathology, Faculty of Medicine, Kyushu University, Fukuoka, Japan. Reprint requests: Takayuki Matsumoto, MD, Second Department of Internal Medicine, Faculty of Medicine, Kyushu University, Maidashi 3-1-1, Higashi-ku, Fukuoka 812, Japan.
We reviewed colonoscopy records a t our institution between January 1989 and July 1991 and collected 34 lesions from 32 patients, all of which satisfied the following criteria: (I) smaller than 5 mm at the largest diameter; (2) endoscopically recognized as a reddish, flat, or slightly elevated lesion; and (3) histologically confirmed as a neoplastic lesion by
VOLUME 38, NO. 6, 1992
MATERIALS AND METHODS
645
microscopic examination of the specimen obtained by endoscopic forceps biopsy or endoscopic mucosal resection or obtained from surgically resected specimens. The patients were prepared by ingestion of 2 liters of electrolyte lavage solution (Golytely,"l), and colonoscopies were performed using either CF-10I, CFV-lOI, or CFV-200I endoscopes (Olympus Corp., Tokyo, Japan). Total colonoscopy was performed in all of the patients, except for five patients, who had a redundant sigmoid colon or complained of severe abdominal pain during the procedure. When a flat or depressed lesion was suspected endoscopically, 0.2% indigo carmine solution was always sprayed through the colonoscope, and the existence of a central depression was confirmed. Endoscopic forceps biopsy was performed with a standard biopsy forceps (Olympus FB-24Q). Endoscopic mucosal resection was performed modifying the method described by Karita et al. 13 and Kudo et al. 9 In brief, 2 to 4 ml of saline were injected into the submucosa under the tumor prior to resection. The tumor, along with the artificially made elevation, was then polypectomized by bipolar electrocautery snare. The specimen obtained by endoscopic mucosal resection or by surgery was fixed in 10% formalin for 2 days, stained with Alcian blue and Mayer-hematoxylin solution, and then observed under a stereomicroscope at x2 or x5 magnification for measurement of the size and for characterization of the surface of the lesion. All of the specimens, including the ones obtained through forceps biopsy, were cut in half, embedded in paraffin, and then stained with hematoxylin and eosin. Microscopic examination of the specimen was made by a pathologist, who was blind to the endoscopic findings. The grading of dysplasia was defined according to the World Health Organization classification, mainly focusing on nuclear changes and cytoplasmic differentiation. 14 Mild dysplasia was defined as the adenoma with slightly enlarged, elongated, and hyperchromatic nuclei with preserved polarity and with slightly curtailed cytoplasmic maturation. Moderate dysplasia was regarded as the adenoma with further enlarged, and less elongated nuclei with frequent loss of polarity. The adenoma with round or ovoid nuclei with loss of polarity containing prominent nuclei and with basophilic cytoplasm was classified as severe dysplasia. We reviewed the clinical features and the endoscopic and histologic findings of the lesions. RESULTS Clinical features
There were 27 males and 5 females, and the ages of the patients ranged from 48 to 78 years (mean, 64 years). The indications for colonoscopy included positive fecal occult blood in 12 patients, rectal bleeding in 4 patients, and other symptoms such as constipation, diarrhea, and abdominal pain in the remaining 16 patients. Ofthe 27 patients in whom precise family history could be obtained, 3 patients had first-degree relatives who had suffered from colorectal cancer. Figure 1 indicates the location of the minute, flat, or depressed lesions. The lesions were frequently 646
• • •
•
•• •••
•
•
Figure 1. Distribution of non-polypoid adenomas of the colon found during colonoscopy.
Table 1. Other neoplastic lesions found during colonoscopy Lesion
No. of patients (%)
None
6/32 (19)
Single adenomatous polyps
8/32 (25)
Multiple adenomatous polyps
17/32 (53)
Colorectal cancer
6/32 (19)
found in the sigmoid colon and in the transverse colon. Table 1 summarizes other synchronous neoplastic lesions of the colon found during colonoscopy. Single or multiple adenomatous polyps were found in 22 of the 32 patients. In addition, colon cancer was identified in six patients. Thirty-one of the 34 lesions were removed endoscopically; 22 lesions by endoscopic mucosal resection and 9 lesions by endoscopic forceps biopsy, whereas 3 lesions were surgically resected because the patients had colon cancer which was located near the minute lesion. No complications related to endoscopic mucosal resection occurred in any of the patients studied. Endoscopic and macroscopic features
Most of the lesions were initially recognized as slightly reddened mucosa, round or oval in shape (Fig. 2A), except for three cases in which the flat or depressed lesions were not endoscopically detected until GASTROINTESTINAL ENDOSCOPY
Table 2. Endoscopic findings of flat or depressed lesions of the colon Endoscopic features
No. of lesions (%)
Completely flat Flat-topped elevation With shallow depression With deep depression
8/34 (24) 26/34 (76) 20 6
a sprayed dye technique for other lesions was performed. The endoscopic findings and their incidence are summarized in Table 2. Eight of the lesions were completely flat, either with or without a slightly elevated surrounding mucosa of normal appearance (Fig. 2B). Twenty of the lesions were visualized as a flattopped elevation, in the center of which a shallow, reddish depression could be confirmed (Fig. 2C). In the remaining six lesions, the depression, surrounded by an elevation, was obvious (Fig. 2D). Macroscopic appearance of the endoscopically or surgically resected specimen, as confirmed by stereomicroscopy, revealed that the lesions, endoscopically diagnosed as completely flat, were in fact flatly elevated (Fig. 3A), while the endoscopically elevated lesions with a central depression were composed of a depression and a surrounding elevation of normal appearance (Fig. 3B). Histologic features
As shown in Figure 4A, all of the lesions were histologically diagnosed as tubular adenomas with moderate epithelial dysplasia, and no foci of carcinoma or de novo cancer were found in any of the patients. The adenomatous glands were almost flat or slightly elevated, and the center of the adenomatous component was frequently depressed. The surrounding non-neoplastic mucosa was completely flat in six lesions (Fig. 4B), while noticeable hyperplasia arising from glands of normal appearance was observed in the remaining 19 lesions (Fig. 4C). The involvement of neoplastic glands within the mucosa was superficial in 10 lesions (Fig. 4B) and mainly superficial but focally, especially in the center of the lesion, trans-
Figure 2. Endoscopic view of non-polypoid adenomas of the colon. A, Colonoscopy reveals a reddened, oval mucosa in
VOLUME 38, NO.6, 1992
the descending colon (arrow). B, Colonoscopy with sprayed dye technique reveals a completely flat, reddened lesion in the sigmoid colon. The surrounding mucosa is slightly elevated. C, Endoscopic view of the lesion shown in A using sprayed dye technique. A flat-topped elevation, the center of which is slightly depressed, can be seen. D, The central depression of the flat-topped elevation found in the descending colon is more marked than that in the lesion shown in C. 647
Figure 3. Macroscopic view under stereomicroscopy of the
resected lesions. Alcian blue and Mayer-hematoxylin staining can reveal the precise nature of the surface of the lesions. A, The non-polypoid lesion, which is endoscopically flat as shown in Figure 28, is flatly elevated macroscopically. B, The flat-topped elevation, as shown in Figure 2C, is composed of a flat elevation and a central depression.
mucosal in 8 lesions (Fig. 4D), while the whole thickness of the mucosa was replaced by adenomatous glands in 7 lesions (Fig. 4C). Table 3 summarizes the correlation between the endoscopic findings and the histologic features of 25 lesions, which were removed by means other than forceps biopsy. Hyperplasia of the surrounding mucosa was more frequently found in flat-topped elevations than in completely flat lesions. In addition, the involvement of adenoma within the mucosa was more extensive in flat-topped elevations with an obvious central depression than in flat-topped elevations with a shallow depression or than in completely flat lesions. DISCUSSION
Small "flat adenoma" of the colon was first described in the literature by Muto et a1.,3 as a flatly elevated lesion measuring less than 10 mm in diameter 648
with a central depression. Despite the size of these lesions, they were reported to show high-grade dysplasia, and it was speculated that they rapidly developed into invasive carcinoma. 3,5,15 Recently, however, the word "depressed adenoma," the endoscopic view of which seems to be similar to those reported by Muto et a1. 3 was used in another article by Kuramoto et alY This insufficient standardization of terminology, as suggested by Smyrk et a1.,16 seems to arise from the continuing obscure biological nature of these lesions. In this study, we analyzed minute neoplastic nonpolypoid lesions of the colon, which measured less than 5 mm in diameter. The endoscopic features were conspicuously different from those ordinarily found in colonic polyps, in respect to the central depression, whether with or without a surrounding flat elevation. Most of the lesions were initially found as reddened mucosa, and a sprayed dye technique, which was primarily developed for the diagnosis of small gastric cancers,17 was of great value in confirming the existence of these lesions. Although the endoscopic findings in three-fourths of the lesions reported in this study were almost equal to those reported previously,3,5.11 the remaining lesions were completely flat or slightly depressed and were lacking in obvious surrounding elevations. These lesions were considered to conform to previously described completely flat adenomas found in surgically resected specimens. 4 The endoscopically recognized depth of central depression in a flat-topped elevation has been reported to be enhanced when less air is insufflated into the lumen through the colonoscope. 3, 9, 11 Our results indicated that the central depression was more obvious in lesions in which the adenomatous component involved the whole thickness of the mucosa than in lesions with a superficial spread ofthe adenoma. Thus, it can be speculated that the degree of central depression detected by colonoscopy may be an indicator of the depth of involvement within the mucosa. All of the lesions in this study were histologically diagnosed as tubular adenomas. Interestingly, further histologic examination of the completely removed lesions revealed that the adenomatous component was almost flat or else slightly depressed, and that the surrounding elevation in cases of flat-topped elevation was mainly composed of hyperplasia of normal glands, which circumscribed the depressed adenomatous glands. Although synchronous adenomatous polyps were frequently found in our patients, both the endoscopic and histologic features of the non-polypoid adenomas, especially the flat-topped elevation with an obvious depression, suggest that the lesions are unlikely to be the precursor of the usual adenomatous polyps, because diminutive adenomas in familial polyposis patients are convex discoid in shape and horizontal or radial in growth. 18 GASTROINTESTINAL ENDOSCOPY
c
o
Figure 4. Histologic features of the resected lesions. A, High-power view of a flat-topped elevation with a central depression reveals a crowding of small adenomatous tubules (H & E; original magnification x100). B, The flat lesion, as shown in Figure 28, is composed of flatly elevated neoplastic glands which involve the superficial layer within the mucosa. The surrounding mucosa is not hyperplastic (H & E; original magnification x36). C, The center of the lesion, as shown in Figure 2D, is obviously depressed from the surroundings which are elevated because of hyperplasia arising from glands of normal appearance. The adenomatous glands involve the whole thickness of the mucosa (H & E; original magnification x36). D, The lesion shown in Figure 2C is composed of mainly superficial and focally transmucosal proliferation of adenomatous glands, which is surrounded by hyperplasia of normal glands (H & E; original magnification x36).
There still remains some controversy as to whether colorectal cancer arises from adenomatous polyps1, 19 or de novo. 20 Recently, small de novo cancers of the colon have been found in surgically resected specimens21 -24 and, in addition, they have been found by colonoscopy.9, 10, 13,24 In contrast with such evidence suggesting the de novo hypothesis, the adenoma-carcinoma sequence has been supported by the finding that small flat adenomas of the colon frequently contain high-grade dysplasia or focal cancer. 3,5 In this study, there were neither de novo cancer nor foci of carcinoma cells within non-polypoid adenomas. VOLUME 38, NO.6, 1992
These observations do not support the speculation that flat adenomas possess the ability to rapidly transform into frank carcinoma,3,5 or that the recognition of depressed adenomas may lead to the detection of minute de novo cancers. l l This discrepancy can be explained by the small size of the lesions analyzed in this study and, possibly, by the difference in the individual criteria of histologic grading for adenomas and carcinomas between observers. Thus, it would seem to be mandatory to detect and evaluate more cases with progressive lesions and to follow-up minute non-polypoid adenomas, using the same histologic 649
Table 3. Correlation between endoscopic and histologic features in minute non-polypoid adenoma of the colon Histologic features
Endoscopic feature
Hyperplasia of surrounding mucosa (+)
Completely flat (W Flat-topped elevation (19) With shallow depression (13) With deep depression (6)
Involvement of adenomatous glands within mucosa
(-)
Superficial
Intermediate"
Whole thickness
1/6
5/6
4/6
1/6
1/6
12/13 6/6
1/13 0/6
6/13 0/6
6/13 1/6
1/13 5/6
" Focally, especially in the center of the lesion, the whole thickness of the mucosa was replaced by adenomatous glands. b Numbers in parentheses, number of lesions.
criteria, in order to establish the practical biologic nature of these lesions. In such circumstances, it may be important to know that non-polypoid adenomas manifest different characteristics morphologically, in respect to the central depression and the surrounding elevation, even when they are very small in size. There may be some argument concerning the management of such lesions. Forceps biopsy or hot biopsyll and snare polypectomy3 have been recommended in the case of flat or depressed adenomas, whereas Kudo et a1. 9 and Karita et alY recently stressed the diagnostic and therapeutic value and the safety of endoscopic mucosal resection defined as complete excision of the lesion along with surrounding mucosa and submucosa. In this study, most of the lesions were successfully removed by endoscopic mucosal resection and, as a result, the endoscopic, macroscopic, and histologic features of the lesions were able to be investigated comparatively. Although there remains the dilemma that complete resection of these minute lesions, which seem to be benign in nature, results in the inability to determine their natural course, such an approach in greater numbers of lesions will provide some evidence concerning the pathogenesis of colorectal neoplasms.
5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17.
ACKNOWLEDGMENT
18.
The authors are grateful for the assistance of Miss K. Miller.
19.
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20.
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