Fasting blood gastrin levels in colon adenomas and colorectal carcinomas]

The trophic effect of gastrin in the intestine has been shown. Fasting gastrin levels of patients with adenomatous polyps or adenocarcinoma and in control subjects were determined (n = 141). The mean value of fasting gastrin of control subjects (n = 75) was 47.1 pg/ml +/- 17.8, of patients with adenomatous polyps (n = 49) 49.8 pg/ml +/- 20.7, of patients with carcinoma (n = 17) 50.1 pg/ml +/- 23.3. Neither in the group of patients with adenomatous polyps nor in the group of patients with carcinoma, fasting gastrin levels were elevated compared to control subjects. Our study indicates that there is no significant difference in fasting gastrin between either group (control subjects, colon polyps and carcinoma).     

Expression of gastrin,gastrin/CCK-B and gastrin/CCK-C receptors in human colorectal carcinomas

To investigate further the presence of an autocrine proliferative loop involving gastrin in colorectal carcinomas and to clarify the receptor responsible, 102 human colorectal carcinomas and 10 hepatic metastases were investigated for the expression of the genes encoding gastrin, the gastrin/CCK-B receptor and the gastrin/CCK-C receptor. Levels of RNA expression were assayed by RNase protection assay. In addition, gastrin/CCK receptors on crude membranes of tumour tissue were assayed by radioligand binding. High-affinity gastrin/CCK-B receptors were not detected in any of the carcinomas investigated, whereas in 36% low-affinity binding was observed, consistent with the expression of the gastrin/CCK-C receptor. RNase protection assay detected the RNA for the gastrin/CCK-B receptor in 11% of the carcinomas investigated, whereas the RNA for the gastrin/CCK-C receptor was demonstrated in 75% and the RNA for gastrin in 86% of the carcinomas investigated. These results confirm the recent demonstration of progastrin fragments in colorectal carcinomas. One possible explanation for progastrin expression is that such progastrin fragments may participate in an autocrine proliferative loop. The receptor involved in this loop is more likely to be the low-affinity gastrin/CCK-C receptor rather than the gastrin/CCK-B receptor, which is rarely expressed in colorectal carcinomas.     

Histopathology of colorectal carcinomas and adenomas in cancer family syndrome

Seventy-five colorectal carcinoma patients (100 separate cancers) with verified cancer family syndrome were re-examined for the evaluation of histologic characteristics in carcinomas and adenomatous polyps in this inherited syndrome in a comparison with control patients with colorectal carcinoma but no hereditary background. In the cancer family syndrome group there were significantly more mucinous carcinomas (35 to 39 percent vs. 20 percent;P<0.05–0.01), and also more poorly differentiated tumors (24 vs. 12 percent) than in the control group. The differences could not be explained by the site or stage of the tumors or by the age or sex of the patients. Additional adenomas occurred quite often both in cancer family syndrome patients (19 percent) and in the controls (16 percent). In the cancer family syndrome group, however, there were more adenomas with moderate or severe dysplasia (P<0.01) and more adenomas with villous features (P<0.05) than in the control group. Mucinous histologic features in colorectal carcinoma, although not fully specific, might be characteristic of cancer family syndrome, and thus serve as one sign in the indentification of the syndrome. The presence of the adenoma-carcinoma sequence in cancer family syndrome also was supported, and the histologic aggressivity of the associated adenomas might signify an accelerated advancement of this phenomenon in cancer family syndrome. Supported by the Finnish Cancer Foundation.     

The spectrum of p53 mutations in colorectal adenomas differs from that in colorectal carcinomas

BACKGROUND: p53 mutations are frequently observed in colorectal carcinomas but they have also been found in colorectal adenomas, although considerably less frequently. AIMS: To explore p53 mutations in benign tumours, we have screened 70 colorectal adenomas for allelic loss at, and point mutations in, TP53 by analysis of selected microdissected cell populations. RESULTS: Sixteen (22.8%) adenomas were found to have allelic loss, of which 11 (15.7%) had p53 mutations. In adenomas with mild, moderate, or severe dysplasia, mutation or allelic loss occurred in 4.8%, 16.7%, and 52.6%, respectively (p<0.001). Seven different mutations were found, all missense changes or inframe deletions: one (Thr150Arg) has not been found before while three (Gln144His, Gly245Arg, and Glu285Gln) have not been described previously in colorectal tumours. The other three mutations (Arg175Gly, DeltaPro190, and Gly245Ser) have been found in colorectal carcinomas, the last commonly. Adenomas harboured a spectrum of p53 mutations which was significantly different from cancers as regards the position in the gene and a higher frequency of G-->C/C-->G changes. CONCLUSIONS: Combining our data on adenomas with data already published and in comparison with the spectrum of mutations in colorectal carcinomas, it is suggested that some p53 mutations have a weaker effect than others and are therefore more likely to be found in adenomas which have not progressed to carcinomas.     

Enzyme activities in biopsy specimens from large-bowel mucosa in colorectal adenomas and carcinomas

Biopsy specimens from 29 adenomas, 17 adenocarcinomas, and 6 synchronous adenomas in cancer patients and from uninvolved mucosa of all main segments of the large bowel were examined histologically and assayed for a series of organelle marker enzymes. Six enzymes--lactase, sucrase, alkaline phosphatase, 5'-nucleotidase, acid phosphatase, and N-acetyl-beta-D-glucosaminidase--showed less activity in adenomas than in adjacent uninvolved mucosa and in specimens from controls. Cancer tissue had higher gamma-glutamyltransferase and lower lactase, alkaline and acid phosphatases, and N-acetyl-beta-D-glucosaminidase activities than specimens from uninvolved mucosa in cancer patients and control patients. Enhanced alkaline phosphatase and N-acetyl-beta-D-glucosaminidase activities were seen in uninvolved mucosa of cancer patients as compared with those of adenoma and control patients. Evidence has been found for multienzyme analysis to identify adenomas with signs of malignant transformation and carcinomas with poor prognosis.     

Lymphocyte subset infiltration patterns and HLA antigen status in colorectal carcinomas and adenomas.

Fifty eight large bowel adenocarcinomas and 20 adenomas were studied immunohistochemically, using fresh frozen tissue sections, with regard to lymphocyte subpopulations (CD3, CD4, CD8, CD19, and CD20) in the inflammatory infiltrate and to expression of human leucocyte antigens (HLA-ABC, HLA-A2, and HLA-DR). The findings were related to differentiation and Duke's stage of carcinoma. The inflammatory infiltrate was found to have a phenotype that remained constant irrespective of the intensity of the inflammation. CD4 and CD3 positive cells predominated with fewer CD8 positive cells and a scanty diffuse CD19/20 positive cell population. CD19/20 follicular aggregates were common at the advancing margin of the carcinomas. There was no significant association with Duke's stage, differentiation or HLA status. HLA changes (ABC loss, A2 loss, and DR gain) were associated with differentiation, being more common and more extensive in poorly differentiated carcinomas. HLA-A2 loss was also associated with stage of progression of carcinoma. Inflammation associated with adenomas was found to have a similar phenotype to that associated with carcinomas. HLA changes in adenomas were uncommon, being seen in only one of our 20 cases.     

Flow cytometry of biopsy specimens from ulcerative colitis, colorectal adenomas, and carcinomas

The cellular DNA distribution pattern in biopsy specimens from all main segments and neoplastic lesions of the large bowel, obtained from 16 patients with ulcerative colitis, 22 with adenomas, 17 with carcinoma, and 20 controls, has been studied by the flow cytometry technique. Aneuploid cell populations were demonstrated in three patients with ulcerative colitis (19%), in six with tubular adenomas (27%), and in nine with carcinoma (53%). Aneuploid cells were found in all cases of poorly differentiated adenocarcinomas. The fractional number of cells with a DNA content corresponding to the DNA synthetic and G2M phases of the cell cycle was defined as the 'proliferative index' (PI). In controls PI and its complementary G1 cell fraction varied significantly (p less than 0.005) between the segments, on the basis of analysis of variance. When compared two by two, PI was significantly higher in the sigmoid colon (p less than 0.01) and rectum (p less than 0.05) than in the ascending part. The PI of uninvolved mucosa from adenoma patients with diploid histograms was significantly higher than that in controls (p less than 0.01), ulcerative colitis (p less than 0.05), and cancer patients (p less than 0.05), when dependence on segment was taken into account.     

Detection of proliferative cells in colorectal carcinomas and adenomas by monoclonal antibody to DNA polymerase alpha

DNA polymerase alpha is an endogenous DNA replication enzyme expressed in all cells in a proliferation cycle. An immunoperoxidase method and the monoclonal antibody to DNA polymerase alpha were used to identify proliferating cells in colorectal carcinomas (n = 35) and adenomas (n = 43). The labeling index (L.I.) in colorectal carcinomas was 51.6%, being significantly higher than 28.6% in adenomas. The L.I. in colorectal carcinomas correlated with clinical staging (stage I: 33.1%, stage II and III: 49.5%, stage IV and V: 66.9%). Furthermore, the L.I. had a tendency to elevate as carcinoma deeply invaded (pm: 25.8%, ss-s or a1-a2: 52.2%, si or ai: 67.5%). The L.I. in adenoma was related to the degree of atypia. The L.I. in adenomas with mild atypia, with moderate atypia, and cancer in adenoma were 18.3%, 31.5%, and 47.0%, respectively. And the L.I. of cancer in adenoma had no significant difference in advanced carcinomas (47.0% vs 51.6%). These results suggest that the L.I. is useful as a marker for evaluating the degree of biological malignancy of human colorectal carcinomas and the degree of histopathological atypia of adenomas.     

DNA aneuploidy in colorectal adenomas. Role in the adenoma-carcinoma sequence.

INTRODUCTION: Aneuploidy has been observed in 6-27% of lesions known to be precursors of colorectal cancer, such as adenomas or ulcerative colitis. It has been suggested that aneuploidy may predispose to malignancy in these cases. However, its role in the adenoma-carcinoma sequence has not been definitely established. The objective of this study was to assess the incidence of aneuploidy in colon adenomas, as well as to study its possible role in the adenoma-carcinoma sequence. MATERIAL AND METHODS: The study was performed on a series of 57 large bowel adenomas measuring 10 mm or more, collected from 54 consecutive patients. All specimens were obtained either by endoscopic or by surgical resection. There were 49 adenomas with low-grade dysplasia, two with high-grade dysplasia, two intramucous carcinomas, and four microinvasive carcinomas. A flow cytometric DNA analysis was performed in fresh specimens following Vindelov's method. RESULTS: Aneuploid DNA was detected in five out of 49 low-grade dysplasia adenomas (10%), in all four high-grade dysplasia adenomas or intramucous carcinomas (100%), and in three out of four microinvasive carcinomas (75%). The association between aneuploidy and high-grade dysplasia adenomas, intramucous, or microinvasive carcinoma was statistically significant (p < 0.001). No association was found between aneuploidy and any of the following features: age, gender, clinical symptoms of patients, and size or location of adenomas. CONCLUSIONS: The incidence of aneuploidy in this series was 10% in low-grade dysplasia adenomas, and 87% in high-grade dysplasia adenomas or carcinomas, and this difference was statistically significant. These findings suggest that aneuploidy may play a role in the adenoma-carcinoma sequence.     

Prognostic factors in colorectal carcinomas arising in adenomas: implications for lesions removed by endoscopic polypectomy

Endoscopic polypectomy has become the preferred technique for the removal of most colorectal adenomas. Whether polypectomy alone or segmental colectomy is the appropriate management of the patient whose adenoma contains carcinoma is a controversial issue. We studied 129 colorectal carcinomas that arose in adenomas and in which invasion was no deeper than the submucosa of the underlying colonic wall. The following factors were evaluated: location; gross appearance (sessile versus pedunculated); histologic type of adenoma (tubular, villous, mixed); grade of carcinoma; level of invasion (0--carcinoma confined to the mucosa, 1--head, 2--neck, 3--stalk, 4--submucosa of underlying colonic wall); vascular invasion; and adequacy of excisional margins. Patients were divided into two groups with respect to outcome: adverse (dead from colorectal carcinoma, alive with colorectal carcinoma or positive nodes on colectomy), and favorable (absence of above). Sixty-three patients were treated by polypectomy alone and 66 by colectomy (21 preceded by polypectomy); there were no operative deaths. Mean follow-up was 81 mo. None of 65 patients with carcinoma confined to the mucosa had an adverse outcome, but 8 of 64 patients with invasive carcinoma did. Level 4 invasion (p less than 0.001) and rectal location (p = 0.025) were the only statistically significant adverse prognostic factors. Seven of 28 level 4 lesions and six of 42 rectal lesions had an adverse outcome; level 4 lesions were overrepresented in the rectum (14 of 42; p = 0.032). We conclude that the level of invasion should be the major factor in determining prognosis for the management of carcinoma arising in an adenoma.     

Androgen receptors in colorectal adenomas

Summary To evaluate the potential effect of androgens on the development and growth of human colorectal adenomas, the prevalence and concentration of cytosolic androgen receptors (AR) were analysed in 26 adenomas and 19 samples of normal colonic mucosa by a hybrid ligand receptor-binding assay. AR were detected in 7 of the adenomas (26.9%), and in 6 of the normal mucosa samples (31.6%). In the adenomas, AR levels demonstrated were low, ranging from 6 to 31 fmol/mg cytosol protein, and dissociation constants (Kds) ranged from 0.17–2.7x10^-9 M. Of 13 adenomas excised from men, 6 (46%) had positive receptor activity, whereas only 1 of 13 (7.7%) from women was positive (P=0.03, Fisher's exact test). There was no correlation between AR titre and patient age, or between adenoma size and histological type or degree of dysplasia. In normal mucosa, AR levels ranged from 7 to 33 fmol/mg and Kds ranges from 0.24–3.1x10^-9 M. There was no significant difference between either AR prevalence or levels in the adenomas and normal mucosa. The sex difference was exclusive to the adenoma. Endogenous androgen may play a role in adenoma development early in the promotional process.     

Squamous differentiation in colorectal adenomas

Patterns of stratified squamous epithelium have been recognized recently in colorectal adenomas. Light microscopic and keratin immunohistochemical analysis of four cases in the present report suggested origin from large intestinal reserve cells, with impaired and disorderly maturation in the squamous foci. One case had an invasive adenocarcinoma separately in the same polyp, bringing the reported incidence of malignant transformation in these adenomas to seven of 48 (15 percent). Evidence is presented to support the notion that squamous differentiation may be an inherently neoplastic phenomenon in colorectal adenomas, which may be added to the list of markers for colorectal polyps at higher risk for malignant transformation.     

Mandibular osteomas in colorectal adenomas

Orthopantomography of the mandible was carried out on 50 patients with colorectal adenoma(s) without carcinoma or any known familial disposition. Four patients (8%) had osteomas, and we advance the hypothesis that individuals with both osteomas and adenomas represent a separate type of adenoma patient. Further studies are needed to evaluate the prognostic value of the association of adenomas and mandibular osteomas.     

Serum gastrin levels and colorectal neoplasia

PURPOSE: Confirmation of an association between elevated serum gastrin concentrations and presence of colorectal tumors would have important implications with regard to screening procedures and therapeutic strategies. METHODS: We compared fasting serum gastrin concentrations of patients with colorectal cancer (n=91; mean age, 66 (range, 35–87) years), colorectal polyps (n=89; mean age, 61 (range, 38–86) years), or a normal colonoscopy (n = 101; mean age, 62 (range, 34–82) years) in the period between 1983 and 1992. RESULTS: Median serum gastrin concentrations were, respectively, 20, 20, and 21 pmol/liter (not significant). We were unable to find a relation with histology of the polyp, presence or severity of dysplasia, and extent of cancer. CONCLUSIONS: This large study fails to show any difference in serum gastrin concentrations among the three studied groups.Read at the American Gastroenterological Association meeting of the Digestive Disease Week, New Orleans, Louisiana, May, 1994.     

Cyclo-oxygenase inhibition in colorectal adenomas and cancer

Increasing evidence indicates that Non-steroidal anti-inflammatory drugs (NSAIDs), compounds that inhibit the enzymatic activity of cyclooxygenase (COX), can reduce the number and size of adenomas in patients with familial adenomatous polyposis as well as the incidence of colorectal cancer. The COX enzyme family consists of the classic COX-1 and a second enzyme, COX-2, which is induced by various stimuli, such as mitogens and cytokines. While it is well proven that COX-2 overexpression is a central event in colorectal carcinogenesis, that prostaglandins (PGs) can contribute to tumorigenesis, and that COX-2 selective inhibitors are active chemopreventive agents, the molecular mechanisms by which NSAIDs exert their chemopreventive effect is not fully understood. However, significant advances have been made in understanding the interference of NSAIDs with the pathways that control cell growth and survival even independently from their COX-inhibiting properties, making their use attractive both alone and in combination with standard therapies in the treatment of advanced colorectal cancer. In addition, the recently recognized anti-angiogenic and radiosensitizer properties of COX-2 inhibitors support, further suggest their use in the adjuvant setting.