Seishi Orii

Analysis of genetic alterations, classified according to their DNA ploidy pattern, in the progression of colorectal adenomas and early colorectal carcinomas.

DNA aneuploidy is a biological marker of the oncogenic potential of colorectal adenomas. The accumulation of genetic alterations of cancer‐related genes is also essential for colorectal carcinogenesis. However, it is unclear whether there is any relationship between these genetic alterations and the DNA ploidy of colon tumour cells in the progression of colorectal adenomas and early colorectal carcinomas. Here we have studied the DNA ploidy state and genetic alterations occurring in colorectal tumours using the crypt isolation technique. Crypts isolated from a total of 106 colorectal tumors (adenoma, 93; early carcinoma, 13) were examined using a combination of flow cytometric analysis of DNA content, polymerase chain reaction–microsatellite assay, and single‐strand conformation polymorphism assay for evidence of chromosomal allelic imbalance (AI; 17p; 5q; 18q) or p53 gene mutation. In addition, we examined microsatellite instability (MSI) with BAT 26 primer sets. DNA multiploidy was infrequently detected in colorectal adenomas (15.1%), in contrast to early carcinomas (46.2%). There was a significant difference in the incidence of AI of chromosome 18q between diploid adenomas and aneuploid populations of multiploid adenomas (18.1% vs 57.1%, p = 0.0043). Mutation of p53 was also found more frequently in aneuploid populations of early multiploid colorectal carcinomas than in early diploid colorectal carcinomas (66.7% vs 0%, p = 0.021). MSI was found in only 2 of 93 adenomas, with no MSI detected in early colorectal cancers. The two MSI‐positive adenomas were diploid. We subdivided multiploid adenomas into two groups: those with a low or a high DNA index (DI). The incidence of genetic alterations of high‐DI adenomas did not differ from those of low‐DI adenomas. Allelic imbalance involving loci on chromosome 18q and mutations of p53 seems to be associated with the progression of diploidy to multiploidy in colorectal tumours. On the other hand, MSI may be associated with the development of some diploid tumours. In addition, the incidence of genetic alterations in the colorectal adenomas that we examined appears to be independent of the tumours DNA index. Copyright

Hyperplastic (metaplastic) polyposis of the colorectum associated with adenomas and an adenocarcinoma

Hyperplastic (metaplastic) polyposis associated with adenoma and adenocarcinoma of the colorectum is rare. We describe a 55-year-old man with hyperplastic polyposis associated with multiple adenomas and an adenocarcinoma who underwent total colectomy. We found at least 200 polyps in the surgical specimen. Nearly all of the polyps were hyperplastic, and some were adenomas. Furthermore, some hyperplastic polyps had adenomatous areas. This indicates the transformational sequence of a hyperplastic polyp to adenoma to adenocarcinoma.

NEW ENDOSCOPIC TECHNIQUE TO CLOSE LARGE MUCOSAL DEFECTS AFTER ENDOSCOPIC MUCOSAL RESECTION IN PATIENTS WITH GASTRIC MUCOSAL TUMORS

Endoscopic mucosal resection has been recognized as a standard method for treating mucosal tumors of the stomach in Japan. In our department, we have treated mucosal defects after this procedure by using metallic clips to prevent and manage complications related to endoscopic mucosal resection. In the present study, we explain the new technique, the ‘loop‐and‐clips’ method, which uses clips and a detachable snare to close large mucosal defects after endoscopic mucosal resection.

Pleuropericarditis and Disseminated Intravascular Coagulation in Ulcerative Colitis

We report a 30-year-old woman with pleuropericarditis, cardiac tamponade, and disseminated intravascular coagulation complicating active ulcerative colitis (UC). Other autoimmune diseases were not present. She responded to pulsed steroid therapy and anticoagulant with resolution of the complication and UC. We reviewed the literature and found 27 cases of pleuropericarditis associated with idiopathic inflammatory bowel disease (IBD). It has been reported that pleuropericarditis associated with IBD responds well to nonsteroidal antiinflammatory drugs, as well as steroids. The causes of cardiac involvement in IBD remain unclear, but the pleuropericarditis must be recognized as a potential extraintestinal manifestation of IBD.

DNA ploidy heterogeneity in early and advanced gastric cancers.

To evaluate the clinical utility of flow cytometric DNA analysis in gastric cancers, four or more fresh tissue specimens were systematically taken from gastric cancers in 127 consecutive patients including 68 early cancers. DNA ploidy and its variation in individual tumors were determined, and the data were related to clinicopathologic findings. DNA aneuploidy was detected frequently (84.3%) irrespective of tumor progression and correlated significantly with histologic grade (G1-2 [89.6%] vs. G3-4 [76.0%], P < 0.05). DNA ploidy heterogeneity was found in 67.7% of tumors and correlated with invasion depth (mucosa [40.5%] vs. submucosa-serosa [81.2%], P < 0.001), regional lymph node metastases (negative [58.4%] vs. positive [82.0%], P < 0.01), and stage grouping (I [58.8%] vs. II-IV [86.0%], P < 0.01). The maximum DNA index of a tumor correlated significantly with invasion depth (mucosa [1.16, median] vs. submucosa [1.82], P < 0.01) and lymph node metastases (negative [1.22] vs. positive [1.86], P < 0.001). The DNA index of the subpopulation that was the most widely distributed within the tumor was significantly associated with lymph node metastases (negative [1.14, median] vs. positive [1.44], P < 0.001) and histologic grade (G1-2 [1.37] vs. G3-4 [1.12], P < 0.001). More than 80% of the diploid and/or single aneuploid stemline tumors were stage I, whereas more than half of diploid and multiple aneuploid stemline tumors were stage IV. Variation in DNA ploidy rather than presence of DNA aneuploidy correlates best with progression of gastric cancer.

Analysis of mucin, p53 protein and Ki-67 expressions in gastric differentiated-type intramucosal neoplastic lesions obtained from endoscopic mucosal resection samples : A proposal for a new classification of intramucosal neoplastic lesions based on nuclear atypia

There are differing views between Western and Japanese pathologists on the use of histological criteria to classify gastrointestinal tumors. It is therefore a priority to create a new histological classification of the stomach in order to resolve the confusion. Expression patterns were examined of mucin (MUC2, CD10, MUC5AC, pyloric gland‐type mucin), p53 protein, and Ki‐67 in tumor cells according to the following new classification system for differentiated‐type intramucosal neoplastic lesions of the stomach, based on nuclear atypia: borderline neoplasia (adenoma (including dysplasia), indefinite tumor of adenoma or low‐grade cancer, and low‐grade cancer) and definite carcinoma (intermediate cancer, and high‐grade cancer). The resulting grades were: adenoma, 23; indefinite tumor for adenoma or low‐grade cancer, 6; low‐grade cancer, 28; intermediate cancer, 48; high‐grade cancer, 20. While the frequency of intestinal‐type borderline neoplasias was higher than that of definite carcinomas, the mixed‐type of definite carcinomas occurred with higher frequency than borderline neoplasias. The p53 protein overexpression and the Ki‐67‐positive rate increased with an increase in the grade assigned according to the new classification. The correlated expression levels of p53 protein, Ki‐67, and various mucins, support the conclusion that this classification of intramucosal neoplastic lesions is useful for obtaining a consensus diagnosis of gastric intramucosal neoplasia between pathologists and gastrointestinal clinicians.

A case of a lipoma in the colon complicated by intussusception.

A 61-year-old man was admitted for investigation of weight loss and abdominal swelling. Abdominal ultrasonography showed a rounded, 3–4 cm hyperechoic colonic mass. Computed tomography scanning revealed a low-density colonic tumour, while a barium enema examination demonstrated a 4 cm tumour in the ascending colon. At colonoscopy, a large, smooth, yellow tumour with a large stalk was evident in the ascending colon together with a submucosal mass that was too large for endoscopic resection (Fig. 1). On MRI examination, the tumour exhibited a high-intensity signal on T1and T2-weighted images. A clinical diagnosis of a lipoma in the ascending colon was therefore made.

ROLE OF DNA ANEUPLOIDY, OVEREXPRESSION OF P53 GENE PRODUCT, AND CELLULAR PROLIFERATION IN THE PROGRESSION OF GASTRIC CANCER

DNA aneuploidy, p53 overexpression, and high cell proliferation frequently occur in gastric cancer. However, little is known about the time of their appearance throughout cancer progression. Therefore, the objective of the present study was to determine when such abnormalities occur during gastric cancer progression. We classified the gastric cancers examined into intestinal (n = 65) and diffuse (n = 34) types. DNA ploidy was examined using flow cytometry and expression of MIB-1 and p53 immunoreactivity were studied using the avidin-biotin complex method in three stages of gastric cancer (mucosal, submucosal, deeply invasive cancer, i.e., advanced cancer). The incidence of DNA aneuploidy in intestinal-type mucosal cancers (15/27, 55.6%) was lower than that of submucosal invasive cancers (14/16, 87.5%) or advanced cancers (19/22, 86.4%), while a low incidence of DNA aneuploidy was observed in each diffuse-type cancer group (mucosal, 1/12, 8.3%; submucosal invasive, 3/9, 33.3%; advanced, 8/14, 57.1%). Although overexpression of the p53 gene in intestinal-type cancer was found in early stage, that in diffuse-type cancer was observed in advanced stage. Among the intestinal-type mucosal cancers, the MIB-1 percent positive was higher in aneuploid tumors than diploid ones. DNA aneuploidy and overexpression of the p53 gene may play an important role in the early tumorigenesis of intestinal-type gastric cancer and in the late event of tumorigenesis of diffuse-type gastric cancer.

ACUTE PROMYELOCYTIC LEUKEMIA IN CROHN'S DISEASE : CASE REPORT AND REVIEW OF THE LITERATURE

A 19-year-old man with a documented 2-year history of Crohns disease abruptly developed leukopenia and thrombocytopenia. A diagnosis of acute promyelocytic leukemia was established by bone marrow cytology. Chromosomal analysis of bone marrow aspirate revealed aberrations of no. 8 trisomy and translocation between no. 15 and no. 17 [46,XY,t(15q+,17q-)/47,XY,+8,t(15q+,17q-)]. Nine cases of Crohns disease complicated by leukemia have been reported, including the present one; once again, a relationship between Crohns disease and leukemia is suggested.

Analysis of subclonal expansion of colorectal carcinomas by flow cytometry

Abstract DNA heterogeneity of colorectal carcinomas has been investigated by flow cytometry; most studies have focused on the clinical usefulness of DNA ploidy analysis. Since cancers consist of predominant subclones with proliferative advantage due to clonal expansion, we attempted to analyse the clonal expansion of colorectal carcinomas within a tumour by measuring DNA ploidy. The DNA ploidy and heterogeneity of multiple fresh samples obtained from 164 colorectal adenocarcinomas were analysed by flow cytometry. Each tumour was divided into an average of six specimens, which were analysed separately. For 146 of the tumours (89%) at least one DNA aneuploid population was found within the cancer tissue examined. DNA multiploidy was detected in 26 cases (17.8%) among the cancers with aneuploidy. Based on the DNA index (DI), hypertriploid aneuploidy (1.7<DI<1.8) was found most frequently in the aneuploid colorectal cancers examined. DNA ploidy heterogeneity was seen in 75 (51.4%) of the DNA aneuploid tumours. There were only 3 cases with more than three subclones including a diploid line. The present results indicate that colorectal carcinomas consist of a few dominant subclones and have a DNA content (hypertriploid aneuploid) that confers a proliferative advantage.