Depressed Adenomas Research Articles

East Meets West: What Is Early Cancer?

It has become increasingly apparent that the Japanese and Western systems of classifying dysplasia and carcinoma in the gastrointestinal tract are not the same. The implication of these differences is that in an article in a Western journal on gastrointestinal 'cancer' originating from Japan, it is often impossible to repeat the study to confirm or refute it because of these differences in definitions. 'Carcinoma' is diagnosed in Japan by virtue of its structural and cytological features but by invasion in the Western system. Adenoma does not mean a dysplastic lump in the Japanese system (although it can), but in most cases is similar to low grade dysplasia irrespective of the macroscopic and/or endoscopic appearances (hence flat and depressed adenomas in the Japanese system); however, most examples of high grade dysplasia in the Western system, as well as some low grade dysplasia, are 'cancer' in the Japanese system. Conversely, both have conceptual areas that are useful in the other's system.

Problems arising from eastern and western classification systems for gastrointestinal dysplasia and carcinoma: are they resolvable?

It has become increasingly apparent that the Japanese and Western systems of classifying dysplasia and carcinoma in the gastrointestinal tract are not the same. The implication of these differences is that in an article in a Western journal on gastrointestinal 'cancer' originating from Japan, it is often impossible to repeat the study to confirm or refute it, because of these differences in definitions. Although there is no reason why it should not be just as much of a problem if Western research is published in Japanese journals, this is currently not a major problem. The terminological differences do not mean that one is right and one wrong; they are simply different. We had an opportunity to look at these differences in detail in a series of 100 gastric biopsies. In this review, we outline these differences and indicate the similarities, differences and problems between these two systems. 'Carcinoma' is diagnosed in Japan by virtue of its structural and cytological features, but by invasion in the Western system. Adenoma does not mean a dysplastic lesion in the Japanese system (although it can) but in most cases is similar to low-grade dysplasia irrespective of the macroscopic/endoscopic appearances (hence flat and depressed adenomas in the Japanese system); however, most examples of high-grade dysplasia in the Western system, as well as some low-grade dysplasia, becomes 'cancer' in the Japanese system. Conversely, both have conceptual areas that are useful in the other's systems. Because we were ultimately able to use each other's systems, we were able to show where these systems come together and diverge. These provide hope that a common classification encompassing both systems that allows communication between both systems is feasible.

Flat adenomas in the United Kingdom: are treatable cancers being missed?

The recognized pathway for colorectal malignancies is the adenoma-carcinoma sequence. It is estimated that up to two-thirds of colorectal carcinomas arise from adenomatous polyps. In recent years, Japanese workers have suggested that early colorectal malignancies may arise as "flat" or "depressed" rather than as polypoid lesions. Such flat or depressed adenomas and adenocarcinomas have not been widely recognized in the West. A prospective study was carried out to search for flat and depressed adenomas in a British population, using Japanese colonoscopic techniques. In this prospective study at a British centre, 210 consecutive patients attending for routine colonoscopy were examined for flat or depressed lesions. The examinations were carried out using Japanese techniques by an experienced Japanese endoscopist (T.F.). Overall, 68 adenomas were found, of which 40 (59%) were polypoid, 26 (38%) were flat, and two (3%) appeared depressed. The majority of the adenomas contained areas of mild or moderate dysplasia, but four were severely dysplastic. Two of these were large polypoid tubulovillous adenomas, the third was a 7-mm protruding polyp, and the fourth was a depressed adenoma 6 mm in diameter. Three Dukes' stage A adenocarcinomas were also found. Of these, one was a 20-mm polyp, one a 15-mm flat elevation of the mucosa with a central depression, and the third a 6-mm depression of the mucosa. Finally, four Dukes' B or more advanced adenocarcinomas were found. The polyp-carcinoma hypothesis prompts colonoscopists to search only for polypoid lesions when screening for malignancy. A significant proportion of early colorectal neoplasms may therefore be missed. European colonoscopists require training in the recognition of flat elevated and depressed lesions in order to detect colorectal malignancies in their early stages.

Gastric epithelial dysplasia and adenoma: Historical review and histological criteria for grading

Gastric epithelial dysplasia (GED) hypothetically is a straight-forward concept: dysplastic epithelium replacing the normal gastric epithelium of the stomach. However, since its inception several decades ago, the term GED has become progressively complex and confusing because of differences in definitions and nomenclature that have been based on cytological, microscopic, endoscopic, or gross features. This has resulted in the terms “dysplasia,” “adenoma,” “flat adenoma,” and “depressed adenoma.” Some authors have also included reactive changes under the term “dysplasia.”

P53 expression patterns in colorectal adenomas and early carcinomas: a special reference to depressed adenoma and non-polypoid carcinoma.

The purpose of the present study was to investigate the role of p53 in tumor progression of colorectal adenomas and early carcinomas, while especially focusing on flat tumors (depressed adenomas and non-polypoid carcinomas). Paraffin sections of 61 pure adenomas (33 polypoid, 28 depressed), 26 carcinomas in polypoid adenoma (CIA) and 63 pure carcinomas (36 polypoid, 27 non-polypoid) were examined for immunostaining using p53 monoclonal antibody (PAb 1801). All of the carcinomas were restricted to the mucosa. The number and distribution of the p53 positive tumor cells was evaluated, and then compared with tumor growth patterns and histological features. The incidence of p53 expression in carcinomas (58% in CIA and 51% in pure carcinomas) was significantly higher than that in polypoid adenoma (27% in CIA and 21% in pure adenomas). However, the same incidence in depressed adenomas (51%) was significantly higher than in polypoid adenomas. No correlation in carcinomas was observed between p53 expression and clinicopathologic data except for age. The distribution of p53 positive cells was different between adenomas and carcinomas. There tended to be fewer p53 positive cells in adenomas, even in depressed ones, than in carcinomas and they also tended to be confined to the superficial areas in adenomas, while they were diffusely distributed in carcinomas. Interestingly, the p53 positive cells were more frequently present in the deep mucosal areas than in the superficial areas of some non-polypoid carcinomas. In conclusion, the following hypotheses are suggested: (i) the increase of p53 expression from adenoma to carcinoma supports the hypothesis of an adenoma-carcinoma sequence in a polypoid tumor; (ii) the unique p53 expression in non-polypoid carcinoma suggests the existence of another type of carcinogenesis; and (iii) depressed adenomas are thus considered to have a high potential risk of carcinoma.

Nonpolypoid adenomas and adenocarcinomas found in background mucosa of surgically resected colons.

Nonpolypoid (depressed or flat) neoplasias are rarely seen in the colon and rectum. We previously reported their histogenesis and characteristics in patients with familial adenomatous polyposis (FAP), but their development in patients without FAP has not been studied systematically. Three hundred specimens of large intestinal mucosa surgically resected from patients with cancers or other diseases, excluding FAP, were examined with a dissecting microscope. The morphologic types, sizes, locations, and frequencies of detectable colorectal neoplasias, and their histologic features, were analyzed. A total of 297 adenomas (240 polypoid, 32 flat, and 25 depressed type) were obtained. Nonpolypoid adenomas were most frequently found in the transverse and descending colon. Almost all depressed adenomas (24 of 25; 96%) were less than 3 mm in greatest dimension and almost all flat adenomas (31 of 32; 96.9%) were less than 3.5 mm in greatest dimension. Three minute, nonpolypoid adenocarcinomas (mean size, 2.6 mm; range, 2.4-2.9 mm) were also detected, two of them already invaded the submucosal layer. Minute nonpolypoid type adenomas may be present in the background mucosa of patients without FAP. This study suggests that even minute nonpolypoid adenocarcinomas have an increased potential for endophytic growth.

Depressed Adenomas of the Colon in Familial Adenomatous Polyposis Histology, Immunohistochemical Detection of Proliferating Cell Nuclear Antigen (PCNA), and Analysis of the Background Mucosa

Depressed adenomas of the colon have been reported more often during the past several years, but there are few reports on the details of their characteristics or behavior. In this study, depressed and ordinary polypoid adenomas, especially those in an early stage, in the large intestine of 28 patients with familial adenomatous polyposis (FAP) were examined macroscopically, by dissecting microscope, and histologically. Proliferating cell nuclear antigen (PCNA) and the density of crypts in the background mucosa around depressed and polypoid adenomas were also compared. Depressed adenomas of < 1.0 mm in diameter showed horizontal growth between the normal adjacent crypts, which often left the normal crypts as islands, whereas polypoid adenomas grow expansively without including remnants of normal crypts. In depressed adenomas, PCNA shifted to the upper part of the crypts, and the background mucosa in their vicinity showed a low density of crypts. These findings indicate that a unique characteristic of growth of depressed adenomas at an early stage is superficial proliferation.

Clinicopathological Characteristics of Superficial Type Colorectal Adenomas Obtained by Endoscopic Resection

Colorectal adenomas may be either protruding type or superficial type lesions. To delineate the clinicopathological characteristics of the latter, 153 superficial type adenomas (including the surrounding mucosa) obtained by endoscopic resection were studied morphologically. Superficial type adenomas were defined as flat or flat depressed adenomas with a height of ≤3 mm; histologically, the tubules proliferated horizontally without vertical overlap. The location of tubules in the mucosa was classified as: involvement of the surface layer only (m1), deeper invasion not reaching the muscularis mucosae (m2), or invasion to the muscularis mucosae (m3). The results of analysis indicated: 1) there was no relationship between atypia and size; 2) although macroscopic features (depression, etc.) were associated with the grade of atypia, a closer association was obtained for the location in the mucosa; 3) based on our classification system for tubule location, (m2) and (m3) adenomas had a significantly higher frequency of depressed type lesions than did m1 lesions; and 4) the height of superficial type adenomas was 295 to 413 μm. Height was lowest in the m3 group followed by, in ascending order, the m2 and m1 groups. These morphological and histological characteristics are expected to contribute to improved diagnosis of superficial type adenomas.

Depressed adenoma of the colorectum: Analysis of proliferative activity using immunohistochemical staining for proliferating cell nuclear antigen (PCNA)

Recently, depressed adenomas (DA) of the colorectum have been frequently detected in Japan. The natural history and carcinogenesis of these DA remain unclear. The histological features and cell kinetics of 13 DA were analyzed, using proliferating cell nuclear antigen (PCNA), and compared with 24 non-depressed adenomas (NDA), 12 non-neoplastic mucosa and 12 adenocarcinomas. The DA had a characteristic architecture when compared with the NDA, as demonstrated by a crowded collection of adenomatous tubules with small diameters. The adenomatous tubules tended to occupy the full thickness of the lamina propria at the center with superficial growth to the periphery. The PCNA-positive cells were mostly restricted to the lower half of the crypts in the non-neoplastic mucosa, and were distributed predominantly across the upper half area of the crypts in both the DA and NDA, whereas they were randomly distributed across any area in the adenocarcinomas. The mean labeling index of PCNA in the DA (43.2%) was significantly higher than that in the non-neoplastic mucosa (26.5%) and NDA (29.3%), but lower than that in the intramucosal component of the adenocarcinomas (70.0%). The DA should be seriously considered as a precancerous lesion because of its unusual histologic architecture and high proliferative activity.

Colorectal Counterpart of Gastric Depressed Adenoma

The histological features of 28 depressed adenomas (DAs) were compared with those of 40 flat adenomas (FAs) without a central depression and those of 29 polypoid adenomas (PAs), with special reference to the development of pericryptal fibroblasts (PCFs), using immunohistochemical staining for muscle-specific actin (HHF-35). The DAs were composed of a crowded collection of adenomatous tubules with smaller diameters than those of the PAs. With regard to PCF development, the DAs had poorly developed PCFs; PCF (-), (+), and (++) numbered 12 (43%), 16 (57%), and 0 (0%), respectively. On the other hand, the nondepressed adenomas (PAs and FAs) had well-developed PCF; PCF (-), (+), and (++) numbered 5 (7%), 35 (51%), and 29 (42%), respectively. In addition, the number of PCFs seemed to decrease in the sequence of PAs, followed by FAs and DAs. According to our results, the DAs had a characteristic histological architecture together with poorly developed PCFs features, which distinguished them from the PAs. In conclusion, the depressed adenomas were considered a subtype of the flat adenomas. The depletion of PCFs seems to correlate with the depressed growth of the adenoma.

A morphometrical analysis of minute depressed adenomas in familial polyposis coli

In a morphometrical study of minute adenomas in familial polyposis coli (FPC), ranging from 0.8 mm to 1.5 mm in diameter, five parameters of depressed adenomas were compared with those of ordinary polypoid adenomas. The density of glands (DG), an index of structural atypia, and the nuclear-cytoplasmic (N/C) ratio, an index of cellular atypia, were higher in depressed adenomas than in polypoid adenomas (74.8% vs 66.8% and 37.8% vs 32.7%, respectively). The cell area (C-area) of depressed adenomas was less than that of polypoid adenomas (107.3 microns 2 vs 121.1 microns 2), but there was no significant difference in values for the nuclear area (N-area) in the two types (40.0 microns 2 vs 39.2 microns 2). The higher N/C ratio of depressed adenomas was, therefore, not caused by enlargement of the nuclei but by reduction of the cell size. In addition, values of the sphericity of nuclei (SN) (3.14 vs 3.65) indicated rounder nuclei in depressed adenomas than in ordinary ones. The higher DG and N/C ratio of the depressed adenomas indicates their higher grade of atypia than that of ordinary polypoid adenomas.

Minute adenomas of the depressed type in familial adenomatous polyposis of the colon. A pathway to ordinary polypoid adenomas.

It has been thought that colorectal adenomas are polypoid from their beginning. Although depressed adenomas have been described, they have been considered an unusual form and have not been studied systemically. More than 5000 colorectal adenomas in 24 resected large intestines of patients with familial adenomatous polyposis were examined by dissecting microscopic study. These adenomas were classified by their surface appearance as depressed, flat, or polypoid type. The frequencies and sizes of the three types were determined. In addition to ordinary polypoid adenomas, many adenomas of the depressed type were found. Of the 5287 adenomas detected, 635 (12.0%) were depressed, 967 (18.3%) were flat, and 3685 (69.7%) were polypoid. Depressed adenomas constituted approximately 15% of all adenomas smaller than 1.5 mm diameter. However, they were rare in those of 1.5-2.0 mm diameter and were not found among those of more than 2.0 mm in diameter. These findings suggest that some ordinary polypoid adenomas originate from minute depressed adenomas.

Minute nonpolypoid adenomas of the colon depicted with barium enema examination.

To evaluate the usefulness of barium enema examination for detection of small nonpolypoid adenomas, the barium enema study findings were reviewed in patients with flat or depressed adenomas of the colon 3-5 mm in diameter that had been initially found during colonoscopy and that had been diagnosed as adenomas at histologic analysis. Eleven of the 21 nonpolypoid adenomas were depicted on radiographs; they tended to be located on the left side of the colon. The 10 other lesions were not detected retrospectively on barium enema radiographs. The radiographic findings in the depicted lesions included smooth, round, radiolucent areas; in seven of these lesions, round or irregular barium flecks were also seen. The radiolucent areas were attributed either to slightly elevated growth of adenomas or to surrounding hyperplasia of nonneoplastic glands; the central barium fleck seemed to conform to depressed areas within adenomas. Barium enema examination can demonstrate nonpolypoid adenomas of the colon, even though colonoscopy seems superior to barium enema examination for detection of these lesions.

Depressed Adenoma of the Stomach

Depressed gastric adenoma is a recently featured lesion, distinguished by a depression in the gastric mucosa, with histologic changes of conventional adenomatous polyp. We observed five cases of depressed gastric adenoma, one of them associated with a peptic ulcer, another with a gastric stump, and yet another with an early gastric carcinoma. None of the cases was detected clinically by radiology or endoscopic study. Endoscopically, this lesion stimulates a peptic ulcer at a re-epithelialization stage or an early carcinoma of the depressed type. Histologically, all the cases showed dysplastic changes of varying degrees, with a relevant risk of malignancy. A similarity is shown to other lesions described in the gastric mucosa.

Depressed adenoma of the stomach, revisited. Histologic, histochemical, and immunohistochemical profiles

For 52 patients with depressed adenomas of the stomach, histopathologic studies were done on 56 tumors and for 43 of them, histochemical and immunohistochemical features were examined. In addition, nondepressed adenomas (n = 57) and the depressed type of early gastric adenocarcinomas of the well-differentiated variety (n = 44) were studied as the controls. Depressed adenomas in the majority (73%) involved the entire thickness of the mucous membrane of the stomach with tubules of atypical epithelium, presenting a severe grade in many of the cases (41%). Paneth's cells were found in cases of a depressed adenoma, in significantly higher percentages (61%) than in those with a nondepressed adenoma (P less than 0.01). The frequency of cases with argyrophil cells was also higher in depressed adenoma (63%) than in nondepressed adenoma (36%) or in cases of early gastric carcinoma (32%). Carcinoembryonic antigen (CEA) and carbohydrate antigen (CA) 19-9 were noticed in tumor cells, immunohistochemically in 28% of the cases with depressed adenoma, the frequency being intermediate between cases of a benign nondepressed adenoma (6% for both CEA and CA 19-9) and cases of early gastric carcinoma (71% for CEA and 66% for CA 19-9). No difference was noticed in lectin reactivity and mucin content between depressed and nondepressed adenomas, whereas tumor cells in the early depressed carcinoma had a higher lectin reactivity and less mucin content than those seen in the adenomas. It would thus appear that depressed adenoma is a benign neoplastic lesion; however, the malignant potential of this lesion is somewhat higher than the nondepressed counterpart, as indicated by the immunoreactivity to tumor markers and follow-up results reported by colleagues previously.

Depressed tubular adenoma of the stomach: pathological and immunohistochemical features

We examined 12 depressed tubular adenomas of the stomach pathologically and immunohistochemically in order to clarify the difference between the depressed type and the elevated type. Depressed tubular adenomas showed shallow mucosal depression and, of the 12, nine were endoscopically diagnosed as early gastric cancer. Histologically, the adenoma cells showed dysplasia in varying degree and focal adenocarcinoma occurred in two adenomas measuring over 2 cm. The mean height of the adenoma glands was 0.63 +/- 0.31 mm in the 12 depressed adenomas and 1.32 +/- 0.43 mm in 44 elevated adenomas, while the mean heights of the subjacent mucosa were 0.18 +/- 0.19 mm and 1.07 +/- 0.71 mm, respectively. Thus, depressed adenomas resulted from paucity of the mucosa subjacent to the adenoma glands and the height of the adenomatous glands was half that found in the elevated type. Goblet cells, a variety of endocrine cells and lysozyme-containing cells were found in nine, nine and eight depressed adenomas, respectively, in variable numbers. Hyperplasia of these cells was also detected in depressed adenomas showing mild or moderate dysplasia. Immunohistochemical examination revealed no difference in the phenotypic expression of adenoma cells as between the depressed and the elevated type.

Depressed adenoma in the large intestine

To clarify the presence of depressed adenomas in the human large intestine, a prospective study was performed from January 1986 to December 1987. During these two years, 997 colonoscopies were conducted in patients, excluding cases of familial adenomatosis coli. Of 32 small, depressed lesions biopsied, seven were depressed adenomas, demonstrating that depressed adenomas do exist in the colon and rectum, and can be detected endoscopically. Resembling a sucker, they are easily detected through inflation and deflation.

Do all colorectal carcinomas arise in preexisting adenomas?

In this article, the underlying nature of the adenoma is defined and evidence in support of the adenoma-carcinoma sequence is presented. Emphasis is placed on recent findings from the field of molecular biology which fortify the concept of the adenoma as a step in the evolution of large bowel cancer. Despite the considerable body of indirect evidence in support of the adenoma-carcinoma sequence, the de novo theory still has some support. Although differences between the de novo and adenoma carcinoma concept are largely semantic, the fact that infiltrating carcinoma can arise within small, flat foci of severely dysplastic epithelium (indistinguishable from carcinoma in situ) may be of considerable clinical importance. Other routes of morphogenesis exist also, but these make a relatively small contribution to the overall incidence of colorectal cancer. Even if it is accepted that the majority of colorectal cancers develop in a preexisting adenoma, the systematic removal of adenomas would pose a number of practical difficulties. First, adenomas are extremely common, particularly in populations at high risk of colorectal cancer. A second factor is the recently recognized existence of flat or depressed adenomas which may be small and difficult to visualize endoscopically. A simple screening program based on our knowledge of the evolution of colorectal cancer is outlined.

Depressed adenoma of the stomach.

A "depressed adenoma" was detected in surgically removed stomachs. There were 40 such lesions (11%) of a total of 357 lesions of gastric adenomas. Macroscopically, these lesions often occurred along the lesser curvature of the stomach, had shallow depressions of a light-brown color, a round or oval shape with irregular margins, and could hardly be distinguished from a depressed early carcinoma. Although 14 of the lesions were detected preoperatively with confirmation by endoscopic biopsy, the other 26 remained unrecognized until the gross examination of the formalin-fixed specimens. Histologically, all were tubular adenomas of the intestinal type with varying degrees of epithelial atypia. Carcinoma in adenoma was present in 5% of these depressed lesions, in contrast to 2.5% of the conventional protruded adenoma. Thus, depressed adenoma seems to be a variant of gastric adenoma which has a somewhat higher malignant potential.