Bowel Carcinoma Research Articles

Expression of plasminogen activator inhibitor type 1 (PAI-1) by HT-29di human large bowel carcinoma cells is modulated as a function of epithelial differentiation

Highly differentiated epithelial populations (36% mucin-producing cells; sixfold increase in alkaline phosphatase activity; development of flat, substrate-adherent, entero-cytic foci) were induced upon in vitro exposure of HT-29di human colon carcinoma cells to sodium butyrate (NaB). 1,25-dihydroxyvitamin D 3 [1,25-(OH) 2D 3] (10 −7 M) and the ionophore A23187 (0.5 μM) significantly augmented (two to threefold) NaB-induced HT-29di differentiation, whereas 1,25-(OH) 2D 3 or A23187 alone were not effective. Induction reflected specific changes in protein abundance, involving, most notably, a differentiation-associated increase in the expression and substrate-deposition of a 47-kDa protein with pI/mw two-dimensional map coordinates and immunochemical properties identical to that of plasminogen activator inhibitor type 1 (PAI-1), a major regulator of the pericellular proteolytic cascade. Culture of HT-29di cells in medium of either high (2.5 mM) or low (0.25 mM) Ca 2+ concentration did not affect the incidence of ‘spontaneous’ differentiation, although NaB-induced goblet cell and enterocytic maturation was Ca 2+-dependent. The inability of 1,25-(OH) 2D 3, A23187 or modulated Ca 2+ levels alone (i.e., in the absence of NaB) to effect differentiation of HT-29di cells and the Ca 2+-dependence of the NaB response indicate that NaB and Ca 2+ act co-operatively to induce colonic epithelial maturation in vitro.

Occult Celiac Disease in an Octogenarian Presenting with a Small Intestinal Adenocarcinoma

An 85-year-old male initially presented with an obstructed upper gastrointestinal tract associated with a duodenal adenocarcinoma. Subsequent histological studies revealed occult celiac disease, an associated condition that otherwise would not have been recognized in this elderly patient. The celiac disease responded to a gluten-free diet, even in the presence of an intestinal adenocarcinoma. This report suggests that celiac disease and small bowel carcinoma may coexist more frequently than is appreciated.

CCK-8 and gastrin plasma levels in cholecystectomized and colorectal cancer patients.

The elevated incidence of large bowel carcinoma after cholecystectomy has long been controversial. The pathomechanism of this entity, however, is still unclear. Many authors have demonstrated a correlation between cholecystokinin (CCK) and gastrin levels and the occurrence of colorectal cancer. As yet, no clear data are available on the potential impact of cholecystectomy on CCK level alterations. Moreover, no reports have yet been published on CCK receptors. We have investigated the role of CCK-8 and gastrin plasma levels in patients with prior cholecystectomy and CCK receptor levels in patients with colorectal cancer. 125 patients entered a prospective study. Of these, 45 served as controls. 40 patients had prior cholecystectomy, 5 patients underwent cholecystectomy during the ongoing trial. 35 patients had a colorectal cancer, 5 of these had prior cholecystectomy. No patient had elevated CCK-8 plasma levels. Gastrin levels were slightly elevated in 2 patients. There was no correlation between large bowel carcinoma and CCK-8 and gastrin levels. Elevated CCK-8 levels following cholecystectomy occur neither immediately after surgery nor on a long-term basis. Immunohistochemical studies in patients with colorectal cancer showed no CCK receptors in the normal colonic or tumor tissue. These findings are contrary to gastrin receptor data.

Strong HLA-DR expression in large bowel carcinomas is associated with good prognosis

One hundred large bowel carcinomas operated on between 1978 and 1982 were studied immunohistochemically with regard to expression of HLA-DR antigens. Three sections from each tumour were investigated by a semiquantitative scoring system, and a mean score for each patient established. Based on this scoring system, the tumours were divided into three groups: 0; 0.1-1.0; and > 1.0. All patients were followed until death (n = 68) or until June 1, 1992, and all cancer-specific deaths (n = 56) have been recorded. Analysis of survival in the whole patient group showed significant difference between the three levels of tumour HLA-DR expression (P = 0.006); patients who had tumours with strong HLA-DR expression showing the best survival. In a stratified analysis after Dukes' stages there was still a significant difference (P > 0.001) between the three levels of HLA-DR staining intensity. After a multiple regression analysis (Cox) with correction for different variables, the HLA-DR expression maintained its significance as a risk factor. To our knowledge this is the first time a relationship between intensity of tumour DR expression and survival has been shown in large bowel carcinoma.

Adenocarcinoma of the proximal small intestine. A marker for familial and multicentric cancer?

Adenocarcinoma of the small intestine is uncommon. The Hawaii Tumor Registry (HTR) has identified 49 of these tumors since 1960, and the Japan-Hawaii Cancer Study (JHCS) has identified only four of these tumors among a cohort of 8006 Hawaiian-Japanese men followed up for a period of 22 years. Each of the four men reported by the JHCS had multicentric gastrointestinal cancers. Newly diagnosed cancers are recorded separately by the HTR and JHCS, and linkage is maintained between the two files. Family histories are available from the JHCS, and these are supplemented by a state population file maintained by the Department of Genetics, University of Hawaii. Five men, all Japanese, were found to have carcinoma of the proximal small intestine. Each had multicentric carcinomas of the gastrointestinal tract. Carcinoma of the stomach and colon was found in the primary relatives of each of four men whose families lived in Hawaii. The familial clustering of uncommon neoplasms (small bowel carcinoma and multicentric large bowel carcinoma), and the concurrence of gastric and colonic carcinoma suggests that these subjects have a genetic trait that increases susceptibility to a broad range of carcinogens.

Metastatic ovarian carcinoma of large intestinal origin simulating primary ovarian carcinoma. A clinicopathologic study of 25 cases.

The distinction of metastatic ovarian carcinoma from a primary malignant ovarian neoplasm is crucial to its subsequent management. The most common metastatic carcinoma that mimics primary ovarian carcinoma is that of large bowel origin. The clinical and pathologic features of 25 cases of intestinal adenocarcinoma metastatic to the ovaries were analyzed. The patients ranged in age from 47 to 80 years (average age, 60 years). Most patients had abdominal pain and a pelvic mass. In 56%, the ovarian tumors and the large bowel carcinomas were discovered synchronously; 44% were metachronous. Seventy-five percent of the tumors were unilateral. Gross examination revealed that all the ovarian tumors were solid and cystic with smooth outer surfaces. Most of the tumors showed hemorrhage and necrosis. Histologic examination showed that 13 cases had a predominantly endometrioid-like pattern, four cases were predominantly mucinous, and the rest demonstrated a mixed pattern. The presence of a garland pattern with cribriform areas and "dirty" necrosis were the most distinctive features that were helpful in correctly differentiating these tumors from primary endometrioid ovarian carcinoma, with which they are often confused. Immunohistochemical stains for carcinoembryonic antigen showed strong intracytoplasmic positive staining in all the cases of intestinal adenocarcinoma metastatic to the ovaries, in contrast to primary ovarian endometrioid carcinoma, which stain negatively for carcinoembryonic antigen or show only intraluminal or apical positivity. As expected, intestinal adenocarcinoma metastatic to the ovaries had a very poor prognosis. Seventy percent of the patients died within a period of 1 to 19 months (average, 8.2 months). Its distinction from primary ovarian carcinoma is crucial because the management and prognosis of metastatic ovarian carcinoma of large intestine origin is different.

Congenital genitourinary anomalies. Is there a predilection for multiple primary malignant neoplasms?

A case of simultaneous uterine and renal cell carcinoma in an elderly woman who had a septate vagina, double cervix, uterus didelphys, and a single kidney secondary to contralateral renal agenesis is reported. She was treated for a period of 8 months, first with pelvic irradiation followed by total abdominal hysterectomy and bilateral salpingo-oophorectomy and subsequently with heminephrectomy. Her renal function was normal postoperatively. The patient died of congestive heart failure in June 1990 after being free of carcinoma for approximately 18 years. The authors believe that this is the only case of its kind currently reported in the literature. Four of her family members died of either gastric (n = 3) or lung (n = 1) cancer, and one sister is alive with colon cancer. Only 19 proven cases of this constellation of congenital anomalies have been reported in the literature, and none have been associated with genitourinary (GU) carcinomas. There is a 50% to 70% incidence rate of genital tract anomalies in female patients with unilateral renal agenesis, secondary to the intimate association of the mesonephric and müllerian ducts. It has been suggested that the GU tract is prone to multiple primary malignant neoplasms, and there are families genetically predisposed to the development of large bowel and GU carcinomas. No conclusions can be drawn concerning the development of carcinoma in patients with congenital GU anomalies because of the small number of patients and the lack of follow-up in the literature.

The CD56 adhesion molecule is the major determinant for detecting non-major histocompatibility complex-restricted cytotoxic mononuclear cells from the intestinal lamina propria.

In this study, specific antibodies against natural killer (NK) cell surface markers identify these cells to be commonly present in normal intestinal mucosa of inflammatory bowel disease (IBD) and carcinoma patients. Cells expressing the CD56 adhesion molecule were found to be far more abundant than CD16+ cells. Functional studies revealed that cells mediating non-major histocompatibility complex-restricted cytotoxicity (NK activity) in the lamina propria express the CD56 surface antigen, whereas only a minority of this activity resides in the population with CD16 expression. This is in contrast with peripheral blood NK cells, which were found to be almost exclusively both CD16+ and CD56+. Moreover, in the lamina propria of the intestine we found CD3+ T lymphocytes not to be involved in spontaneous cell-mediated killing of tumor cells. Considerably higher numbers of cells with the CD16 or CD56 surface markers were found to be present in normal mucosa of IBD patients compared with normal mucosa of carcinoma patients, which was also reflected in higher levels of cytotoxicity detected in lamina propria mononuclear cell preparations from normal IBD mucosa. Because of the disease-related localization of the mucosa studied from both patient groups, i.e. ileum vs. colon, the observed differences may be related to tissue characteristics. Within the IBD group, relatively high levels of cytotoxicity were found in cell preparations from normal mucosa of Crohn's disease patients compared with ulcerative colitis patients, which might support the current concept that Crohn's disease affects the whole of the gastrointestinal tract.

CHANGES IN THE FECAL MICROFLORA IN PATIENTS WITH CARCINOMA OF THE LARGE BOWEL

The changes in the intestinal microflora were examined in patients with advanced carcinoma of the large intestine, and healthy subjects were surved as control. Comparing to control, patients group revealed high fecal moisture and fecal pH, but showed low levels in various organic acids except succinic acid. Only succinic acid was detected in high level and frequency. No significant difference in the number and occupation rate of Gram-positive bacteria participating in the endogenous endotoxin production was noted between both groups. The pattern of fecal microflora in patients group was similar to that in control. However, the aerobic microorganisms including Staphylococcus were highly found in patients group. These results suggested that the colonic enviornment of the patients with large bowel carcinoma was in aerobic state in comparison with healthy subjects.

Colorectal carcinoma over 30 years at one hospital: no evidence for a shift to the right

Many recent reports in the North American literature have documented an increase in the ratio of proximal to distal colorectal cancers with an increase in right-sided lesions. In order to assess trends in the distribution of large bowel carcinoma at our hospital we reviewed the files of 1553 patients who presented with primary colorectal carcinoma over a 30-year period. Thirty-nine percent of patients were over 70 years old and 51% were in the 50-69 year age group. Seventy five percent of the carcinomas were left-sided, 22% right-sided and caecal carcinomas accounted for 18%. This distribution varied only slightly over the study period. Left-sided lesions were more common in males (55%: p less than 0.005), and right-sided lesions were more common in females (57%: p less than 0.005). Caecal carcinoma was more common in patients over 69 years old than in younger patients (p less than 0.001). In elderly females (greater than 69 years) 30% of colorectal carcinomas occurred in the caecum. These findings may have important implications for the investigation of patients with suspected colorectal disease or for screening programmes.

Near diploid large bowel carcinomas have better five-year survival than aneuploid ones

One hundred patients who underwent surgery for large bowel carcinoma between 1978 and 1982 were examined by flow cytometric DNA quantitation of fresh tumor specimens and divided into an aneuploid (AN) group of 63 and a near diploid (ND) one of 37. All patients were followed until death (n = 63) or until December 31, 1988. Forty-one patients (65%) with AN tumors died of cancer, as did 12 patients (32%) with ND carcinomas. Thus patients with ND tumors had a better survival rate (P = 0.04) than did those with AN ones. The difference was apparent in Dukes' Stages A, B, and C, but not in Stage D. All patients with tumors in this stage died from their carcinomas irrespective of ploidy group. Multiple regression analyses (Cox) of prognostic factors revealed that the most important prognostic variables were (in descending order) Dukes' Stage D, Dukes' Stage C, and DNA ploidy pattern. Histologic grade was not significant as an independent prognostic variable. These results indicate that the presence of a distinctly aneuploid DNA ploidy pattern in large bowel carcinoma is an important prognostic variable that worsens survival rates significantly.

A case of small bowel carcinoma in Crohn’s disease

A 46-year-old man had symptoms of ileus four years and five months after being diagnosed as Crohn's disease. Upon small bowel radiography, a short, spindle shaped stenosis on the distal site of the ileum was found. In the resected specimen, there was a constricted area with wall hypertrophy, and the mucosal surface of this region was rough and granular. At the site of this region, well differentiated adenocarcinoma was noted, which infiltrated the serosa in the form of mucous adenocarcinoma. Transmural disproportional inflammation and non-caseating granuloma were also around there. The X-ray findings in this case are considered to be useful for diagnosis of carcinoma during the long term observation period for Crohn's disease.

Investigation of colonic prostaglandins in carcinogenesis in the rat colon

Large bowel carcinoma was induced in rats by injecting MNNG intrarectally, and changes in the large bowel mucosa prostaglandin (PG) with time were determined. The PGE2 levels of the colonic mucosa in a control group were 20.9 +/- 9.7 (pg/mg total protein) at 5 weeks, 25.5 +/- 9.7 at 10 weeks, 26.5 +/- 18.1 at 20 weeks, and 34.8 +/- 12.7 at 40 weeks. The PGE2 levels in the MNNG-treated group were 44.7 +/- 6.2 at 5 weeks, 43.1 +/- 14.9 at 10 weeks, 70.1 +/- 23.4 at 20 weeks, and 79.7 +/- 54.1 at 40 weeks. The intrinsic PGE2 levels of the noncancerous mucosa were thus significantly higher for the MNNG group than for the control group at all weeks. At 40 weeks, the PGE2 levels of cancer lesions were significantly high compared with those of the noncancerous area. In the cancerous lesions, 6-keto-PGF1 alpha and PGF2 alpha decreased and TXB2 increased significantly at 40 weeks. The observations demonstrated that PGE2 was implicated as a promoter in the development and proliferation of carcinoma in MNNG-induced large bowel carcinogenesis in rats.

Nuclear shape as a prognostic discriminant in colorectal carcinoma

In search for a more reliable prognostic discriminant, a retrospective analysis of 100 cases of colorectal carcinoma having undergone curative resection and followed for at least 5 years were assessed by nuclear morphometry. Each case was staged according to the Dukes' classification as well as graded histologically. For all patients in this series, the perimeter, area, and nuclear shape factor of 50 interphase nuclei were determined for each carcinoma. The information was obtained through the use of an image analysis system by tracing the nuclear profiles (magnification 1000x) as digitized on a video screen. The nuclear shape factor was defined as the degree of circularity of the nucleus, a perfect circle recorded as 1.0. A nuclear shape factor greater than 0.84 was associated with poor outcome. Multiple regression models showed that the single nuclear parameter of the shape factor was the most highly significant predictor of survival (P less than 0.0001). This variable remained highly significant even when corrected for sex, age, histologic grade, and Dukes' classification. These findings indicate that a nuclear shape factor greater than or equal to 0.84 as determined by nuclear morphometry is an independent morphometric nuclear variable of great importance in the prognosis of large bowel carcinoma.

Surgical Treatment and Prognosis of Obstructed and Perforated Large Bowel Carcinoma

Surgical Treatment and Prognosis of Obstructed and Perforated Large Bowel Carcinoma

Stomal adenocarcinoma in Crohn's disease.

Malignant change occurring at the site of a stoma in two patients with proved Crohn's disease is described. Patients with ulcerative colitis have an increased risk of colonic malignancy and Crohn's disease is also associated with both small and large bowel carcinoma. Most previous reports of stomal carcinoma have been associated with ulcerative colitis although Crohn's disease seems to carry a greater risk of associated small bowel carcinomas. This is the first report of stomal carcinoma complicating Crohn's disease. Epithelial dysplasia is associated with gastrointestinal carcinomas in both ulcerative colitis and Crohn's disease and a dysplasia-carcinoma sequence has been suggested as the origin of these tumours. In both our patients with stomal adenocarcinoma, dysplasia was identified in adjacent tissues, which suggests a similar mechanism. Malignant change should be suspected if epithelial dysplasia is discovered in a biopsy specimen from the mucosa of an ileostomy in Crohn's disease, and this risk is increased if the dysplasia is of a high grade.

Tissue carcinoembryonic antigen and dna aneuploidy in precancerous and cancerous colorectal lesions

Chronic inflammatory bowel disease (CIBD) and colorectal adenoma are considered as precancerous conditions and lesions of large bowel carcinoma, respectively. They, therefore, may be used to study the behavior of such different factors as tumor-associated antigens and nuclear DNA content abnormalities in colorectal carcinogenesis. Tissue concentrations of carcinoembryonic antigen (CEA) were significantly higher in those precancerous lesions (CIBD: 61 +/- 11.2 ng/mg, adenoma: 70 +/- 6 ng/mg; mean +/- standard error of the mean) than in normal colonic mucosa (36 +/- 4.7 ng/mg). Colorectal carcinoma had still higher tissue levels (437 +/- 108.2 ng/mg). No correlation between tissue CEA and tumor differentiation could be found, but there was a significant difference between aneuploid (747 +/- 354 ng/mg) and diploid (139 +/- 43 ng/mg) tumors. Using flow cytometry DNA aneuploidy was present in 31.6%, 10.5%, and 51.6% of CIBD, colorectal adenoma, and carcinoma, respectively. These data suggest that the occurrence of aneuploidy is not strongly dependent on a malignant transformation, but it may also be present in premalignant colorectal lesions without cellular dysplasia.

大腸癌の発生母地と発育進展について

当科で経験した早期大腸癌と実験大腸腫瘍を病理組織学的に検討し, 大腸癌の発生母地, 発育進展について考察を加えた.早期大腸癌32病変, 実験大腸腫瘍34病変を対象とした.腺腫を有する早期大腸癌は21病変を占め肉眼形態はすべて隆起型であった.2.0cm未満のものはすべてm癌であった.径が大きくなるにつれ sm癌が多くなった.腺腫を伴わない早期大腸癌は11病変を占めた.陥凹型が3病変にみられ, 肉眼形態と壁深達度との間には特別な関係はみられなかった.腺腫を有する早期大腸癌とは逆に2.0cm未満のものがすべてsm 癌であった.実験大腸腫瘍では18病変が癌であった.肉眼形態はすべて隆起型で径の小さなものは腺腫, 大きなものは癌であった.腺腫と癌を合併したものはみられなかった.以上より腺腫を伴わない早期大腸癌や実験大腸癌の大部分が de novo 発生と考えられた.

Prognostic significance of DNA content in large bowel carcinoma: a retrospective flow cytometric study.

Flow cytometric (FCM) determination of DNA content was performed on surgical specimens from 44 patients with previously untreated colonic carcinoma. For each tumor, cell suspensions were prepared from 2-4 40-microns thick sections obtained from formalin-fixed and paraffin embedded tissue samples. Aneuploidy was found in 47.2% of all the tumors and the aneuploid clone had a median DNA index of 1.49 (range: 1.24-1.93). Aneuploidy was found in 26.7% of highly differentiated tumors (WHO histologic classification), in 53.8% of moderately differentiated tumors and in 100% of poorly differentiated tumors (P = 0.04). The 33.3% of stages 1 + 2 (TNM) and the 70.6% of stages 3 + 4 tumors were aneuploid (P = 0.002). Median survival from surgery was 46.4 months for all patients. It was 18.8 months for patients with aneuploid tumors and 85.7 months for those with diploid tumors (P = 0.0002). FCM determination of DNA in colon carcinomas can easily be performed on archival histological material and provides prognostic information.

Management of obstructed and perforated large bowel carcinoma

Obstructed large bowel carcinoma is a disease of the aged, often with concomitant disease and also advanced malignancy. The immediate mortality rate of operation is high and long-term prognosis is poor in comparison with elective surgery. It is important before operation that the diagnosis be established by sigmoidoscopy and emergency contrast studies. Staged procedures based on considerations of safety have given way to immediate resection. For right-sided colonic obstruction immediate resection and anastomosis is now almost universal and for left-sided tumours primary resection has overtaken staged resection in the UK. An anticipated survival advantage for primary resection has not, however, been confirmed. Obstruction complicated by perforation is an absolute indication for resection. After left-sided resection, making an anastomosis is associated with higher risk of leakage than after an elective operation. In the most adverse circumstances of associated sepsis, Hartmann's operation retains its place but immediate anastomosis is the most frequent option for many. Additional manoeuvres to make this safe include peroperative antegrade colonic irrigation and subtotal colectomy, although segmental resection with anastomosis and without bowel preparation is also practised and may be safe in selected patients. When major resectional surgery is undertaken in aged patients at high risk of mortality, the rule that the operator should be fully trained in elective large bowel surgery is incontrovertible. It is at least equally important that the anaesthetist is experienced and capable of instituting, interpreting and acting upon sophisticated cardiopulmonary monitoring.