Analyses of the APC and TGF-β Type II Receptor Genes, and Microsatellite Instability in Mucosal Colorectal Carcinomas

APC and transforming growth factor-β type II receptor (TGF-β RII) gene mutations, and microsatcllitc instability have been found in sporadic colorectal carcinomas. To clarify further the early alterations in colorectal carcinogenesis, we investigated these genetic changes in 23 protruding- and 24 superficial-type mucosal colorectal carcinomas. TGF-β RII gene mutations and microsatellite instability were rarely found in these lesions. Nevertheless, APC was mutated in 16 of the 47 (34.0%) mucosal colorectal carcinomas and was significantly more frequently mutated in protruding- (I) and superficial elevated-type (Ila) (14/32,43.8%) than in other superficial-type (IIa+IIc, IIb, IIc, and IIc+IIa) (2/ 15,13.3%) mucosal colorectal carcinomas (P<0.04). These results indicate that the APC gene may be involved from the beginning in the tumorigenesis of many early colorectal carcinomas, particularly of the protruding and superficial elevated types. However, there might be a distinct pathway for other superficial-type colorectal carcinomas, possibly not involving APC as an initial step of tumorigenesis.     

Analysis of Early Gastric Cancer Cases Collected from Major Hospitals and Intitutes in Japan

An analysis of 17,212 lesions from 15,933 patients with earlygastric cancer collected from 110 major hospitals and institutesin Japan is presented. The percentage of patients with early gastric cancer was highamong persons in their 60s and 50s. The sex ratio (F/M) was0.5 but it was higher for younger people than for old people.Regarding distribution of the types of early gastric cancer,the depressed group (Types IIe, III) accounted for 73.9% andthe elevated group (Types I, IIa) accounted for 15.3%. The elevated group was more frequent in the older age group.In regard to the type and invasion, slight invasion was prominentin types lIb and IIa, while deep invasion was prominent in IIa+ IIc. The metastatic rate was 18.4% for IIa + IIc, 11.8% forI and 11% for IIe. The frequency of lymph node metastasis was+4% in intramucosal cancer, 18.9% in submucosal cancer and 11.4%in total. The type in which multiple cancers were most frequentwas lIb, followed by IIa. The percentage of differentiated adenocarcinoma was 91.9% inthe elevated group and was found more often among the aged. Undifferentiated adenocarcinoma occurred more often among theyoung. The relationship between site and histology, locationand invasion, location and lymph node metastasis etc. were alsoinvestigated. We believe that these results should be very usefulfor detection and treatment of early gastric cancer. The rate of detection of small cancer is increasing year byyear. This increase can be explained by the progress and widespreadapplication of endo-scopy, which will continue to play a largerole in diagnosis and treatment of gastric cancer.     

Treatment of early gastric cancer by endoscopic double snare polypectomy (EDSP)

The indication for EDSP was studied in 75 patients with early gastric cancer diagnosed endoscopically which had been obtained over a period of 11 years (1979 to 1985) at the Cancer Institute Hospital, Tokyo and the following results were obtained. EDSP consists of two procedures using double channel fiberscope; a sessile or depressed lesion pulled upward by one snare cautery (standard EDSP) is transformed into a subpedunculated one, which allows another snare cautery of pseudostalk, and it is excised by using coagulation current. EDSP was performed in 53 cases of IIa type and 22 cases of IIc type. Excision by one snare cautery was possible in 90.9% (40/44) of IIa lesion measuring less than 2 cm and in 100% (14/14) of IIc lesion measuring less than 1 cm, the total being 85.3% (64/75). There was no residual cancer in 41 cases of IIa lesion (93.2%) and 17 cases (85.0%) of IIc lesion with two recurrent cancers confirmed by follow-up endoscopy. Residual cancer was found in 6 cases (9.1%) which were operated on. The results mentioned above show the usefulness of EDSP and selection of case without lymph node metastasis permitting complete excision by one snare cautery is of much importance. EDSP is indicated for IIa lesion of differentiated type measuring less than 2 cm, IIc lesion of differentiated type without ulceration measuring less than 1 cm and IIc lesion of undifferentiated type without ulceration measuring less than 0.5 cm that is not located in the fundic gland area.     

A clinicopathological study of early gastric cancers with a diameter larger than five centimeters

Out of a total of 1,112 resected early gastric carcinomas, 181 that were larger than 5 cm in diameter have been pathologically investigated. Of these, intramucosal and submucosal carcinomas amounted to 68 (37.6%) and 113 (64.4%), respectively. The incidence of their location, shown as a percentage, was 37.8% in the antrum, 57.4% in the corpus, and 4.8% in the fundus (11% in the anterior wall, 13.2% in the posterior wall, 68.1% in the lesser curvature, and 7.7% in the greater curvature). Grossly, the incidence of a type IIc carcinoma was 46.5% and that of a IIc + III type was 20.5%, respectively. Microscopically, in the intramucosal cases, signet ring cell carcinomas were the most frequent histological type, whereas in the invasive submucosal cases, the carcinomas were the intestinal metaplastic type. Lymphatic invasions, venous invasions, and lymph nodal metastases amounted to 32.6%, 6.1%, and 11.6%, respectively. In the early gastric carcinomas, the larger the tumor size, the more likelihood of a signet ring cell carcinoma than a intestinal metaplastic type, and it appeared that a signet ring cell carcinoma had infiltrated the propria mucosae for a longer time when compared to either an intestinal metaplastic type carcinoma or a poorly differentiated tubular adenocarcinoma.     

A case of IIa + IIc type early carcinoma of the rectum, with no invasion of the submucosa

A case of a IIa + IIc type early carcinoma of the rectum is reported. A 62-year-old man, who had been checked by immunological latex agglutination faecal occult blood testing, underwent a colorectal examination at Hakodate Chu-o Hospital. A barium enema revealed a slightly elevated lesion with a central depression in the lower rectum. Colonoscopic examination showed a IIa + IIc type of early rectal carcinoma. Study of the resected specimen also confirmed a IIa + IIc type early rectal carcinoma, 17 x 15 mm in diameter. Histologically, a lesion was located within the mucosa and consisted of both a carcinoma and an adenoma. Immunological latex agglutination faecal occult blood testing was thought to be useful for mass screening detection of a colorectal carcinoma.     

Initial radiographic findings of early gastric cancer detected in health check programs and human "dry dock" collective health checks and treated by endoscopic mucosal resection

Abstract. Background: The purpose of this study was to evaluate the capacity of detection (detectability), by radiographic examination, of minute gastric cancer that was indicated for endoscopic mucosal resection (EMR). Methods: Fifty-five lesions in 55 patients with minute gastric cancer were endoscopically resected between 1992 and 2000 at the Foundation for Detection of Early Gastric Carcinoma. Of these 55 patients, 33 patients underwent indirect (with image intensifier and 100-mm roll film) and/or direct radiographic examination of the upper gastrointestinal tract as the initial screening examination, and subsequent upper gastrointestinal endoscopy. The remaining 22 patients underwent upper gastrointestinal endoscopy as the initial screening examination. As the first step, radiographic (indirect and direct) images were reviewed, and the abnormalities which had eventually led to the detection of the minute early gastric cancer (EGC) were reconfirmed. Then, they were analyzed in terms of the reproducibility of abnormal findings which enabled the detection of such a minute EGC, and in terms of whether they could be treated by EMR. The size, morphology, and location of the radiographically detected lesions were analyzed. Results: Seventeen lesions of EGC were detected in the group in which indirect radiography was initially performed. Of these 17 lesions, some abnormality corresponding to the site of the lesion was pointed out in 7 lesions (2 lesions of type IIa and 5 lesions of type IIc). On the other hand, the remaining 10 lesions (type IIa, 3; type IIc, 5; type IIa + IIc, 1; and type IIb, 1) were detected by endoscopy, which was carried out to confirm the other abnormalities in the indirect radiographic images. Sixteen lesions of EGC were detected in the group in which direct radiography was initially performed. Of these 16 lesions, some abnormality corresponding to the site of the lesion was pointed out in 8 lesions (4 lesions of type IIa and 4 lesions of type IIc). The remaining 8 lesions (3 lesions of type IIa and 5 lesions of type IIc) were not detected by direct radiography. Conclusion: Indirect and direct radiographic examination enabled the detection of approximately 50% of EGCs which could be treated by endoscopic resection. The significance of radiographic examination should not be underestimated, even in the detection of EGCs which can be endoscopically resected. Received: June 18, 2001 / Accepted: December 7, 2001     

Endoscopic mucosal resection for early gastric cancer.

Progress in the detection of early gastric cancer has made endoscopic mucosal resection (EMR) possible for the treatment of gastric cancer instead of only conventional surgical resection. The most commonly employed modalities include strip biopsy, double snare polypectomy, and resection with combined use of highly concentrated saline and epinephrine, and resection using a cap. The indications should be strictly limited to the differentiated IIa type (the slightly elevated type) that is smaller than 2 cm, or the differentiated IIc type (slightly depressed type) without ulcer formation and smaller than 1 cm. Both of these entities are thought to have a negligible risk of lymph node metastasis. Prognosis after this treatment is comparable that of surgical resection for early gastric cancer in completely resected cases. EMR also permits local resection in elderly patients with various complications who would be at risk for conventional surgical operations. EMR should be encouraged for treatment of gastric cancer if the indications are strictly chosen.     

Endoscopic diagnosis of gastric cancer of a benign appearance

From April, 1982 to March, 1987, we have performed 36,566 gastrofiberscopic examinations and have detected 793 gastric cancers among 7,618 biopsies. Of these 55 cancerous lesion (6.9%) diagnosed as benign at the time of endoscopic examinations were analyzed and the following results were noted. 1. Most such lesions were small in size and superficial in nature. 2. The gross appearances of the cancers were mainly IIc, IIc + III or IIa. 3. The lesions were most frequently located on the gastric angulus or the side with a lesser curvature. 4. Histologically, well differentiated adenocarcinomas were relatively frequent. 5. False-negative cases determined by endoscopic examination were not infrequent in cases of lesions involving an ulcer, or showed redness, erosion or a polyp.     

Two cases of histopathologically advanced (stage IV) early gastric cancers

We report two cases of early gastric cancer with distant metastases (stage IV). At our institute 1428 cases of primary gastric cancer were resected between 1980 and 1997; 536 were diagnosed as early gastric cancer based on the resected specimens (304 cases of mucosal cancer, Tis--TNM classification--and 232 of submucosal cancer, T1). 528 of these 536 cases were classified as histological stage I, six as stage II, none as stage III and two as stage IV. The incidence of stage IV early gastric cancer was 0.14% of all gastric cancers and 0.37% of the early gastric cancers. The two patients with stage IV early gastric cancer were women. Both tumors were defined as early cancer because they were confined to the submucosa. One was a type 0 IIc + III early cancer, histologically classifiable as a small, moderately differentiated adenocarcinoma (tub2 according to the Japanese Classification of Gastric Carcinoma, G2; TNM classification: ICD-O C16), size 10 x 8 mm; the other was a surface spreading type 0 IIc, classifiable as a signet-ring cell carcinoma (sig, G3), size 50 x 35 mm. Stage IV factors were N3 in the first and ovarian metastasis (Krukenberg tumor) in the second case.     

Initial phase of Borrmann type-IV carcinoma of the stomach suggested from observations of early gastric carcinoma arising in breast cancer patients

Borrmann Type-IV carcinomas were frequently found in advanced carcinoma of the stomach arising in breast cancer patients as a second malignancy. We assumed that some of the early gastric carcinomas in with breast cancer patients would develop into Borrmann Type-IV carcinoma. According to histopathological studies involving 10 cases, six were presumed to be initial lesions of Borrmann Type-IV carcinoma. All lesions in the six cases were macroscopically Type-IIc of early gastric cancer. A shallow ulcer scar, such as UL-1 or UL-II was mostly observed in IIc lesions.     

Possibility of performing a modified operation on the depressed type early gastric carcinoma

To study of the possibility of performing a modified operation in cases of a depressed early gastric carcinoma, we have investigated the possibility of stage I early gastric carcinoma detection. Examined were 196 cases of depressed early gastric carcinomas out of a total of 394 cases of a depressed gastric carcinoma. Further, the relationship between lymph node metastasis and the clinicopathological indicators was the following: 1) the macroscopical type grade was simple IIc; 2) the size of tumor was less than 50 mm; 3) the ulceration in the cancerous lesion was under (a) shallow Ul-II; and 4) the depressed floor showed a granular pattern. According to these indicators, we feel that it is possible to detect stage I early depressed carcinoma prior to operation.     

A case report of early rectal carcinoma, IIa + IIc type, with no invasion of the submucosa

A 66-year-old woman was admitted to the Hakodate Chuo Hospital because of abdominal discomfort. A barium enema study revealed a deformity of the middle Houston's valve of the rectum and granular lesions at the Rb region of the rectum. A colonoscopic examination showed the IIa + IIc type of early rectal carcinoma. A resected specimen also revealed IIa + IIc type early rectal carcinoma, 8 X 13 mm in diameter, and well-differentiated adenocarcinoma with no invasion of the submucosa. Infiltration into the lymphatic vessels and regional lymph node metastasis were not encountered. The deformity of the rectal Houston's valve was checked by a barium enema study. It should be emphasized that early detection of colorectal carcinoma with no invasion of the submucosa, requires careful barium enema studies and colonoscopic examination.     

A clinicopathological study of early mucinous adenocarcinoma of the stomach

From 1963 to 1986, 1126 cases (1300 lesions) of early gastric carcinoma were treated at Fukui Prefectural Hospital. Mucinous adenocarcinomas comprised 16 lesions in this series. These cases of mucinous adenocarcinoma were younger than all the other early carcinomas of the stomach and they often were locted in the lower third of the stomach. Macroscopically, most were types "Iia + IIc". Dividing them into 3 grouping: papillary, tubular, and signet ring cell types, depending on the microscopic appearance of the intramucosal carcinoma, the signet ring cell group differed from the other two as to age, macroscopic appearance, and region it occupied. An immunochemical study showed that CA19-9 stained positively in a mucous lake, much like a carcinoma cell, but that CEA stained little.     

Gastric cancer presenting a variety of macroscopic and histopathological findings

A 68-year-old man was admitted to hospital because of nausea and vomiting. Examination of the upper digestive tract led to a total gastrectomy. A histopathological examination revealed a Borrmann type 3 advanced cancer in the prepyloric antrum that showed a moderately differentiated adenocarcinoma. Found on the anterior wall of the middle corpus was an advanced cancer, mimicking a type IIc early cancer, that was poorly differentiated with dispersed signet ring cells. Between these two advanced cancers, another superficially extended cancer, consisting of a type IIa and IIb early cancer, was found. The type IIa cancer, located on the posterior wall of the angle, was a papillary adenocarcinoma and the type IIb cancer on the lesser curvature of the antrum was moderately differentiated. Therefore this patient displayed not only a type IIa and a type IIb cancer, but also a Borrmann type 3 cancer and an advanced cancer, mimicking type IIc, that were linked into one large lesion. Although the present case was not determined as being a multiple gastric cancer, it suggests the likelihood of a multicentric generation, growth, and extension of synchronous multiple cancers, in view of the variety of macroscopic and histopathological findings presented.     

Multiple simultaneous gastric carcinomas.

A total of 1664 patients with gastric cancer were examined to evaluate the rate of multiple synchronous primary tumours. In cases of multiple synchronous cancer (MSC), the tumours were analysed immunohistochemically for their expression pattern of p53, c-erbB2, ras, E-cadherin and proliferative activity. Multiple synchronous gastric carcinomas (MSCs) were observed in 61 out of 1664 patients (3.7%), with a total of 134 carcinomas. In our series, early carcinoma was observed more frequently in MSC than in solitary cancers. The comparison of tumour stage in MSC and solitary tumours revealed that multiple early gastric cancers were significantly more often of type I (protruded type) and IIa (superficial elevated type) than solitary early cancer. Multiple advanced carcinomas were more often of a lower pT category than solitary advanced gastric cancer. Performing immunohistochemistry for p53, c-erbB2 and ras in 134 tumours with MSCs, we observed positivity rates of 33%, 59% and 87% respectively. In 43 patients, the multiple tumours in each individual patient demonstrated an identical status of p53 and c-erbB2, and in 42 patients a similar pattern of E-cadherin expression was observed. The proliferative index, determined by proliferating cell nuclear antigen (PCNA) immunolabelling, did not differ significantly between the MSC in each patient. Ras immunostaining was detected in 53 out of 61 patients, but also in metaplasia and regenerative hyperplasia in the specimens. In survival analysis, no difference was observed between patients with solitary or multiple early or advanced carcinomas. Our results suggest that in at least a high proportion of patients with gastric cancer multiple primary tumours arise from precancerous conditions leading to similar genetic alterations.     

Gastric acid secretion and cellular immunity in patients with gastric cancer

Three hundred and one gastric cancer patients have been examined preoperatively to investigate their gastric acid secretions after stimulation by tetragastrin, and serum gastrin stimulation by a test meal, as well as for skin reactions and an evaluation of their serum glycoproteins. The results have indicated that their gastric secretions and serum gastrin response were found to be reduced, according to the advancement of their cancer, and that the gastric acid secretion of patients with signet ring cell carcinoma was higher than that of patients with other histological carcinomas. Gastric acid secretions of patients with an ulcerated type of cancer, that is, type IIc and type III in an early cancer stage and type IIc of an advanced Borrmann V type, was higher than in patients with other types, and there were significant correlationships between gastric secretions and PHA skin test and gastric secretions and the IAP and the sialic acid.     

Diagnosis of the infiltrating depth of gastric cancer by endoscopic ultrasonography

In the diagnosis of the infiltrating depth of thirty four cases with gastric cancer, in which twenty two cases were early cancer and fourteen cases advanced cancer, the rate of the diagnostic accuracy by EUS was eighty eight % in the differentiation between early cancer and advanced cancer. While, in distinction of cancer spreading into the mucosa, the submucosa, the muscularis propria and over the subserosa, diagnostic accuracy was sixty four % in early cancer and seventy five % in advanced cancer. There were two reasons mainly in the wrong diagnosis of EUS. One was the existence of fibrosis in cases of the depressed type of early cancer and the other was the dissemination of the cancer cells extending into the deeper tissues, which could be detected only by histological examinations.     

A comparative morphological study of gastric and colorectal cancer--differences in early type IIc and advanced type 4 cancer

Five hundred and nineteen gastric and 883 colorectal cancers have been compared macroscopically according to their Japanese classification. Most early cancers were found to be of a protruded (I and IIa) type in the intestine and a depressed (IIc) type in the stomach, and it is felt that their histogenesis in the mucosa may play an important role in causing this difference. Type 4 advanced cancer is common in the stomach, but rare in the intestine. Histologically, most type 4 gastric cancers present scirrhous findings. Type 4 colorectal cancers can be classified into 4 groups based on their pathological characteristics, such as lymphangiosis, muconodular, mixed, and scirrhous types.     

A micrometric classification of intramucosal carcinomas of the stomach

Background. The aim of this study was to assess whether the results of micrometric measurements could be correlated with the macroscopic-endoscopic classification of intramucosal carcinomas of the stomach. Methods. The thickness of 86 consecutive intramucosal gastric carcinomas (IMGCs) was micrometrically assessed. IMGCs having more than twice the thickness of the non-involved gastric mucosa (NIGM) were regarded as protruding (type I) and those having twice or less of the thickness of the NNGM, as non-protruding (type II). Non-protruding IMGCs were subclassified as elevated (thicker than NNGM, or type IIa), flat (the same thickness as NNGM, or type IIb), and depressed (thinner than NNGM, or type IIc). Results. Only 9.3% ( n = 8) of the 86 IMGCs were protruding and 90.7% ( n = 78) were non-protruding. Of the 78 non-protruding IMGCs, 46.2% ( n = 36) were elevated (type IIa), 38.5% ( n = 30) were flat (type IIb), and the remaining 15.4% ( n = 12) were depressed (type IIc). A low correlation was found when the micrometric and a similar gross classification were compared. Protruding and elevated IMGCs were often histologically of intestinal type (60.3%), whereas flat and depressed IMGCs were often of diffuse type (73.9%). Conclusion. Tumor differentiation may be related to the micrometric profile of the tumor. Non-protruding IMGCs (type II) may expand laterally, without “becoming” protruding and without invading the submucosal layer. Received: April 3, 2000 / Accepted: June 9, 2000     

Five cases of rectal cancer showing remarkable response to suppository administration of tegafur

Five cases of rectal cancer, one male and 4 females, were preoperatively treated with Tegafur suppositories at 1,500 mg per day, for 8 to 21 days (mean, 14 days). These tumors were 2 early cancers and 3 advanced cancers, the configuration of which were one IIa type, one IIa + IIc type and 3 Borrmann 2 types. Their size ranged from 1.3 to 4.2 cm in diameter. Curative resections were performed in all cases, and the examination of the resected specimen revealed marked effects of Tegafur as follows: 1) Reduction of tumor size, 2) disappearance of cancer wall, 3) degeneration of cancer cells and destruction of cancer glands accompanied by fibrous stroma with infiltration of lymphocytes and plasma cells, 4) formation of xanthogranulomatous tissue with foamy histiocytes, which were characteristic findings showing that cancer tissue had been present there. As a result, rectal cancer clearly showed remarkable response to suppository administration of Tegafur for only about two weeks, if the tumor cells were sensitive to the drug.