Yoshiro Kubota

Small “flat adenoma” of the large bowel with special reference to its clinicopathologic features

Thirty-three small “flat adenomas,” not more than 1 cm in diameter, were collected from surgically and colonoscopically removed specimens, and their colonoscopic and histologic characteristics were described. There were 14 adenomas with mild atypia, five with moderate atypia, 14 with severe atypia (or focal carcinoma limited to the mucosa). The grade of atypia seems to increase with the size of lesions, and these lesions were assumed to play an important role in the adenoma-carcinoma sequence. The importance of recognizing the presence of these small “flat adenomas” in everyday practice is stressed.

Procyanidin B1 is detected in human serum after intake of proanthocyanidin-rich grape seed extract.

To confirm the absorption of proanthocyanidin (PA) into the human body, four healthy adults were administered 2.0 g of PA-rich grape seed extract (GSE). Blood were drawn before intake and 2 h after intake. Through the enzymatic treatment of sulfatase and β-glucuronidase, blood samples were analyzed by HPLC coupled with mass-spectrometry (LC/MS). Procyanidin B1 [epicatechin-(4β→8)-catechin] was detected in human serum 2 h after intake. Its concentration was 10.6±2.5 nmol/l.

Distribution and quantification of somatostatin in inflammatory disease.

To study the possible alteration of mucosal-submucosal somatostatin-containing cells in inflammatory bowel diseases (IBD), the total numbers of somatostatin-containing endocrine cells (SCEC) and submucosal ganglion cells (SGC) were counted in Crohns disease (CD) and ulcerative colitis (UC). Tissue specimens from 25 CD and 25 UC patients were fixed in Hollandes fixative immediately after resection and were investigated by immunohistochemical staining. A single specimen was collected from 25 colorectal cancer patients, the control group. There was a significant difference in the number of SCEC between the tissues taken from the proximal colon (ascending and transverse colon) and the distal colon (descending and sigmoid colon). The distal colon tended to contain more somatostatin-immunoreactive cells than did the proximal colon. In IBD, SCEC were decreased in number compared with the controls. This decrease was related to the degree of inflammation in CD; the higher the grade of inflammation, the lower the number of SCEC. The number of SGC was decreased in IBD: however, a significant decrease was noticed only in CD. The anatomic origin and the degree of inflammation did not affect the number of SGC. In the present study, the decrease of somatostatin-containing cells was noticed in both CD and UC, but there was no significant difference between CD and UC. Therefore, it was assumed that this decrease was secondary to inflammation. However, the decrease of somatostatin, which works as an inhibitory peptide for inflammation, might have some role in the pathogenesis of IBD.

Malignant potential in flat elevations

Ninety-nine colonoscopically removed flat elevations were examined. They were divided into two groups: Group 1—flat elevations 1 to 5 mm in diameter (55 cases)- and Group 2—flat elevations 6 to 10 mm in diameter (44 cases). Group 2 had a higher percentage of adenomas (86.4 percent) than Group 1 (67.3 percent). In adenoma cases (flat adenomas), Group 2 tended to show a higher degree of dysplasia. The rates of mild and moderate dysplasia were 83.8 percent and 16.2 percent in Group 1vs.1.70 percent and 13.2 percent in Group 2, respectively. Group 2 contained six cases (15.8 percent) of intramucosal carcinoma (severe dysplasia), while there were no cancer cases in Group 1. Both malignancy rate and degree of dysplasia were size dependent; the larger the lesion the more severe the dysplasia. Our study also revealed that small flat elevations tend to contain higher numbers of nonneoplastic lesions than do larger lesions. Increased detection of nonneoplastic lesions seems to have contributed to an overall decline in the malignancy rate of flat elevations in recent reports.

Substance P containing nerve fibers in rectal mucosa of ulcerative colitis

BACKGROUND AND PURPOSE: The intestine is rich in peptidergic innervation, which modulates mucosal immune responses. Among neuropeptides, substance P (SubP) has received considerable attention for stimulatory effects on various immunocytes in inflammatory diseases. In our prior study, we demonstrated increased innervation of SubP containing nerve fibers (SubP fibers) in ulcerative colitis (UC) surgically resected colonic specimens. In the present study, we examined the alterations of SubP fibers among various subgroups of UC, divided according to clinicopathologic features. METHODS: Distribution of SubP fibers were examined immunohistochemically in the rectal biopsy specimens of UC. The UC group was further divided into subgroups according to six clinicopathologic parameters. The linear density of SubP fibers was measured by digitalized morphometry for quantitative analysis. RESULTS: Multivariate analysis revealed significant correlations between linear density of SubP fibersvs.activity of diseases and total dose of prednisolone. Linear density was significantly increased in active cases of UC (active UC, 22.6±1.6 μm/1,000 μm2;vs.inactive UC, 12.2±0.8 μm/1,000 μm2;P<0.01). Furthermore, the increase was pronounced in cases that showed persistent inflammation and, accordingly, needed a high dose or continuous administration of prednisolone. CONCLUSION: Alterations in SubP fibers appear to play an important role in the pathogenesis of UC.

Local immunity and metastasis of colorectal carcinoma.

The subsets of tumor-infiltrating lymphocytes (TIL) and prostaglandin (PG) E2were measured in the resected tissues of 32 colorectal cancers without metastasis and 14 with metastasis in order to investigate the local immunity in metastasis of colorectal carcinoma. Subsets of TIL (Leu 1, Leu 2a, Leu 3a, Leu 10, Leu 1 1b, IL-2 receptor) were detected by immunohistochemical staining of frozen tissues. The number of positive cells was counted and expressed as number positive per 250 × 250μm2.The numbers of T cells (Leu 1) and natural killer cells (Leu 11b) were larger in early cancers and decreased in parallel with the presence of metastasis (control [n=9]: 89±28, 6±4; early cancers [n=9]: 269±112*,76±56*;advanced cancers without metastasis [n=11]: 182±80*,56±59*;advanced cancers with metastasis [n=11]: 76±42*,26±21; values are mean ± SD;*P< 0.05, ANOVA). The level of PG E2from the draining vein (V) measured by radioimmunoassay was higher than that from the feeding artery (A) (119.1±14.3vs.15.4±1.9 pg/ml;P<0.001). The PG E2V/A ratio of cancers with metastasis was significantly higher than that of those without metastasis (132±2.4vs.5.6 ±0.8;P<0.001). TIL was decreased in parallel with the increase of PG E2V/A ratio. We conclude that TIL and PG E2may play an important role in metastasis of colorectal carcinoma and that PG E2has an adverse effect in suppressing local immunity and enhancing metastasis.

Impact of a Clinical Pathway and Standardization of Treatment for Acute Appendicitis

Abstract.Purpose: Acute appendicitis is one of the most common surgical diseases. Simple and precise guidelines for treating acute appendicitis are necessary for improving the treatment outcome of this disease. The purpose of this study was to determine the impact of a clinical pathway and standardization of treatment for acute appendicitis at our hospital. Methods: The clinical pathway and standardization of treatment for acute appendicitis were introduced to our hospital in January 2000. We compared the length of hospitalization, postoperative stay, hospital costs, and operation time during the years before and the years after their introduction. Results: There was no significant difference in the clinical characteristics of the 73 patients in the control group and the 112 patients in the pathway group. There were 6 (8.2%) and 24 (21.4%) cases of perforated appendicitis in the respective groups. The mean length of hospitalization (P < 0.001), postoperative stay (P < 0.001), and hospital costs (P < 0.01) were significantly less in the patients in the pathway group who underwent surgery. Conclusion: Our clinical pathway and standardization of treatment for acute appendicitis proved effective for treating patients with acute appendicitis and minimizing costs without compromising patient care.

High proliferative activity is associated with dysplasia in ulcerative colitis

PURPOSE: Ulcerative colitis is associated with an increased risk of colorectal neoplasia. Markers of proliferation are reported to be valuable in the diagnosis of dysplasia in ulcerative colitis. However, it is not known whether dysplastic change or proliferative change occurs first. Whether abnormal proliferation is present in normal-seeming mucosa in ulcerative colitis was investigated. METHODS: Eighteen cancer or high-grade dysplasia specimens and 9 low-grade dysplasia specimens from 5 patients and 51 specimens from 31 patients without neoplasia were studied. Immunostaining with anti-Ki 67 antibody was used to evaluate proliferative activity. Labeling index (in the superficial one-half of crypt) was calculated. Crypts with labeling index more than 0.3 were determined to have abnormal proliferation. RESULTS: The mean ± standard error of the mean labeling index in specimens negative for dysplasia (0.056±0.004) was significantly lower than that in low-grade dysplasia specimens (0.418±0.024) and that in high-grade dysplasia specimens (0.503±0.027;P<0.0001). In specimens negative for dysplasia, only 4 (4 cases) of 339 (1.2 percent) crypts had abnormal proliferation, whereas the ratio of crypts with abnormal proliferation was 76 percent (54/71) in low-grade dysplasia and 92.1 percent (35/38) in high-grade dysplasia. The labeling index in background mucosa was 0.139±0.009, which was significantly higher than that in specimens negative for dysplasia (P<0.001). In background mucosa 15.7 percent of crypts showed abnormal proliferation. A follow-up study revealed that two of four cases developed cancer or high-grade dysplasia one and seven years after proliferative abnormality was detected in nondysplastic specimens. CONCLUSION: Ki-67 immunostaining can be an aid in the diagnosis of dysplasia. High proliferating activity in background mucosa suggests that proliferating activity change precedes dysplasia detected with hematoxylin-and-eosin staining.

DNA ploidy pattern in rectal carcinoid tumors.

The nuclear DNA pattern of 22 rectal carcinoids was determined by cytophotometry of paraffin embedded tissues. The results were compared with clinical as well as histopathologic features of the tumor. Three of the carcinoids with synchronous or metachronous metastasis had aneuploid DNA pattern, whereas 19 tumors with no metastasis showed diploid DNA pattern. No other single clinical or pathologic feature of the tumor could predict more accurately the malignant potential and the subsequent course of the rectal carcinoid. It is concluded that DNA aneuploidy in rectal carcinoid tumors is not so rare as indicated by earlier studies and that it is a factor of significant prognostic value.

Overexpression of p53 protein and histologic grades of dysplasia in colorectal adenomas.

PURPOSE: To clarify the relation between tumor-suppressor gene p53 expression and histologic grades of dysplasia in colorectal adenomas, we performed immunohistochemical analysis in a series of 59 colorectal polyps and 40 advanced carcinomas. METHODS: Adenomatous polyps were stained by hematoxylin and eosin and classified into mild, moderate, and severe dysplasia (intramucosal carcinoma), according to the World Health Organizations classification. RESULTS: p53 was positive in 7.1 percent (2/28) of mild, 29.4 percent (5/17) of moderate, and 62.5 percent (5/8) of severe dysplasia. In submucosal and advanced carcinomas, positivity rates were 75 percent (3/4) and 47.5 percent (19/40), respectively. Different staining patterns were found, according to grades of dysplasia. In the adenomas with mild or moderate dysplasia, a few focal crypts showed localized p53-positive staining. Adenomas with severe dysplasia had two different staining types. One was a focal staining type as shown in mild or moderate dysplasia; the other was a diffuse staining type, in which glands with mild or moderate dysplasia, surrounding severe dysplasia area, were also stained. Submucosal and advanced carcinomas showed a strong positive staining in cancer cells only. CONCLUSIONS: Overexpression of p53 protein in adenomas with mild or moderate dysplasia and existence of two types of expression in adenomas with severe dysplasia were observed. These facts suggested the possible existence of different pathways in the adenoma to carcinoma progression.