Molecular genetics of dysplasia in ulcerative colitis.

Numerous molecular genetic events occurring in the development of sporadic colorectal neoplasia have been previously defined. The most frequent genetic alterations are mutations of the APC, KRAS, and TP53 genes, as well as loss of the DCC gene and of the second TP53 allele. The data from several groups indicate that these genes play an important role in ulcerative colitis-associated dysplasias and cancer, as they do in sporadic colorectal adenomas and carcinomas. KRAS and TP53 mutations were detected in dysplasia, but also in villous regeneration and active colitis, and affect a subpopulation of the cells composing these lesions. We conclude that in histologically defined dysplasia, clones can be found that genetically represent precancerous lesions in ulcerative colitis. Seen in this way, part of the active colitis and villous regeneration lesions might be considered as preneoplastic. When present, KRAS mutation is an excellent genetic marker to map populations of preneoplastic cells.

p53 and Ki-ras as prognostic factors for Dukes' stage B colorectal cancer.

Mutations of the TP53 and Ki-ras genes have been reported to be of prognostic importance in colorectal carcinomas. An increased intracellular concentration of the p53 protein, although not identical to, is sometimes seen in tumours with TP53 mutation and has been correlated with poor prognosis in some tumour types. Previous colorectal cancer studies, addressing the prognostic importance of Ki-ras mutation and TP53 aberrations, yielded contradictory results. The aim of this study was to determine in a clinically and therapeutically homogeneous group of 122 sporadic Dukes' B colorectal carcinomas with a median follow-up of 67 months (3-144 months) whether or not p53 protein expression, TP53 mutation and K-ras mutation correlated with prognosis. p53 staining was performed by immunohistochemistry, using the monoclonal antibody DO7 on paraffin-embedded tissue. Mutations in exons 5-8 of the TP53 gene and in codons 12 and 13 of the K-ras gene were assayed in paraffin-embedded tissue by the single-strand conformation polymorphism (SSCP) assay. Nuclear p53 staining was found in 57 (47%) tumours. Aberrant migration patterns indicating mutation of the TP53 gene were found in 39 (32%) tumours. Forty-six carcinomas (38%) showed a mutation of the Ki-ras codons 12 or 13. In a univariate analysis, patients with wild-type TP53 status showed a trend towards better survival, compared with those with mutated TP53 (log-rank test, P = 0.051). Likewise, tumours immunohistochemically positive for p53 showed a worse prognosis than p53-negative tumours (P = 0.010). The presence or absence of mutations in Ki-ras did not correlate with prognosis (P = 0.703). In multivariate analysis, only p53 immunoreactivity emerged as an independent marker for prognosis hazard ratio (HR) = 2.16, 95% confidence interval (CI) 1.12-4.11, P = 0.02). Assessment of p53 protein expression is more discriminative than TP53 mutation to predict the outcome of Dukes' stage B tumours and could be a useful tool to identify patients who might benefit from adjuvant therapy.

Enterocolic (lymphocytic) phlebitis: a rare cause of intestinal ischemic necrosis: a series of six patients and review of the literature.

Vasculitis of the gastrointestinal tract is known to occur as part of a systemic process but also may be present in a localized form involving only the digestive tract. We report the clinical and pathologic findings of six patients with intestinal ischemia and necrosis resulting from localized phlebitis associated with fresh and/or organized thrombosis of intramural mesenteric veins. None of the patients showed clinical or laboratory evidence of systemic vasculitis. In all cases the arteries were not involved in the inflammatory process. Follow up ranged between 2 and 15 years without recurrence necessitating reoperation. This form of intestinal phlebitis is described in the literature under different terms but lymphocytic phlebitis, granulomatous phlebitis, necrotizing phlebitis, and myointimal venous hyperplasia are probably morphologic variants of the same entity. We propose to unify the nomenclature and to use for this unusual clinicopathologic entity only the generic term of enterocolic (lymphocytic) phlebitis.

Idiopathic entero-colic lymphocytic phlebitis. A cause of ischemic intestinal necrosis.

Histological examination of the surgical specimens of three patients presenting with intestinal ischemic necrosis disclosed extensive lesions of lymphocytic phlebitis associated with thrombosis of different ages. Arterioles and arteries were not affected. The lymphocytic infiltrate was composed of a mixture of T- and B-lymphocytes. None of the patients showed clinical or laboratory evidence of systemic vasculitis. Follow-up ranged between 4 months and 5 years. There has been no recurrence necessitating reoperation. The etiology of this clinicopathological entity has not been elucidated.

Expression of p53 protein in gastric carcinomas. Association with histologic type and prognosis.

We searched for p53 protein accumulation in 72 gastric carcinomas. Of the 38 cases of the diffuse type, only four were positive for p53. Of the 34 cases of intestinal type, 24 had p53 protein accumulation. This difference (p < 0.0001) between histological types was present regardless of whether the carcinoma was superficial or infiltrative. Normal epithelial cells and intestinal metaplasia were never positive. No correlation was found between p53 protein accumulation and tumor size, lymph node metastases, age or sex of the patients. Although tumor size, lymph node metastases, and infiltrative character all have prognostic value, p53, either alone or in association with these parameters, does not; p53 mutations seem to play a role in oncogenesis only in the intestinal type of gastric carcinomas; however, p53 protein accumulation has no prognostic value in gastric tumors.

Gastric dysplasia. A histological follow-up study.

To evaluate the clinical and biological significance of gastric dysplasia, we reviewed the histology of all available specimens of gastric mucosa in 85 patients in whom dysplasia had been previously diagnosed. The initial diagnosis of dysplasia was mild (Dy I) in 23 cases, moderate (Dy II) in 41 cases, and severe (Dy III) in 21 cases. The length of follow-up varied from 3 months to 11 years, with an average of 42 months. The follow-up of cases with Dy I and Dy II suggests that both lesions progress slowly and in most instances will remain stable or regress. In 18 cases, a carcinoma was found--17 in the group of Dy III and one in the group of Dy II. Of the 18 carcinomas, nine were at an early stage. Our data suggest that severe dysplasia is a reliable marker of high risk of gastric cancer and represents a strong indication for a gastrectomy.

Effects of misoprostol on healing and prevention of biopsy-induced gastroduodenal lesions occurring during the administration of diclofenac to volunteers.

AIM: To determine whether misoprostol promotes the healing of non-steroidal anti-inflammatory drug-induced gastroduodenal lesions in a human experimental model. METHODS: Mucosal damage and healing of mucosal biopsy sites were assessed endoscopically in 10 healthy, Helicobacter pylori-negative volunteers with a normal initial endoscopy: they were enrolled in a double-blind, double-dummy, placebo-controlled cross-over study. They received 2-week courses of misoprostol (200 micrograms b.d.) or placebo; a water-soluble non-steroidal antiinflammatory drug diclofenac 50 mg t.d.s., was given during the second week of each dosage regimen after three endoscopic biopsies had been taken from each of the duodenum, antrum and corpus. RESULTS: The number of unhealed biopsy sites was not different after misoprostol or placebo, although the number of healed biopsy sites was greater in the corpus and duodenum than in the antrum. Misoprostol did not prevent the appearance of diclofenac-induced erosions and petechiae. Epigastric discomfort was related to the intake of diclofenac and was reduced by misoprostol. Bloating and flatulence occurred more frequently with misoprostol alone and with misoprostol plus diclofenac, than with placebo alone or placebo plus diclofenac. CONCLUSION: Misoprostol does not prevent new mucosal lesions induced by diclofenac in healthy volunteers and it does not accelerate the healing of the biopsy sites. Misoprostol decreases the frequency of diclofenac-induced epigastric discomfort, but it increases gas bloating and flatulence.

The effects of omeprazole on healing and appearance of small gastric and duodenal lesions during dosing with diclofenac in healthy subjects.

BACKGROUND: Non-steroidal anti-inflammatory drugs (NSAIDs) are associated with gastrointestinal mucosal damage. Omeprazole prevents the formation, and accelerates the healing, of NSAID-induced ulcers. AIM: To test whether omeprazole accelerates healing of standardized gastroduodenal lesions in the presence of diclofenac. METHODS: In a double-blind, double-dummy, placebo-controlled, crossover study, 12 healthy volunteers received consecutive, 2-week courses of omeprazole (40 mg o.d.) and placebo, in random order, with an intervening, 4-week washout period; diclofenac (50 mg t.d.s.), was given for the second week of each course. Five endoscopies were performed, one at the outset and the others before and after each course of diclofenac. Biopsies were taken from the endoscopically normal mucosa of the corpus, antrum and duodenum and also from any new mucosal lesion that developed after diclofenac. The sites of biopsies taken before each course of diclofenac were evaluated endoscopically after each course to assess the extent of healing according to a predetermined healing score scale. RESULTS: The healing scores observed after administration of placebo/diclofenac (median=0; range 0-6) and after omeprazole/diclofenac (median=0; range 0-6; P=0.17) did not differ. Small gastroduodenal lesions developed de novo in six subjects during placebo/diclofenac and in seven during omeprazole/diclofenac. Focal chemical gastropathy was observed only in close proximity to macroscopic lesions. CONCLUSIONS: In healthy subjects, omeprazole does not accelerate the healing of pre-existing mucosal lesions or prevent the development of small diclofenac-induced mucosal lesions.

Early gastric carcinoma with focal advanced cancer: a particular subtype of gastric carcinoma.

Early gastric cancer (EGC) is defined as a carcinoma limited to the mucosa or mucosa and submucosa, irrespective of whether metastasis to lymph nodes has occurred. EGC presents a much more favorable prognosis than advanced gastric carcinoma (AGC), with a 5-year survival rate between 88% and 96% for EGC versus 45% to 50% for AGC. Moreover, some gastric cancers appear as a more or less extended EGC with focal AGC (fAGC). The purpose of this study was to analyze prognostic factors in this intermediate group of tumors. From 1981 to 1992, among the 615 gastrectomy specimens with carcinoma examined at the Institute of Pathology of the University of Lausanne, only 19 tumors corresponded to the criteria of EGC with fAGC. Clinicopathologic features were studied, and a cytophotometric DNA analysis was performed. Our results show a 5-year survival rate for EGC with fAGC of 61% (11 of 18 patients alive), intermediate between that of EGC and AGC. No significant correlations were found between the most known predictive factors and prognosis. Most tumors analyzed (16 of 19) showed a diploid DNA content in the superficial as well as in the invasive areas. Contrary to the findings in the literature, which show a high-ploidy DNA pattern in most AGC, our cases show low-ploidy DNA even in the invasive portion of the tumors. In conclusion, we show that EGC with focal AGC represents a gastric cancer with an intermediate prognosis and, therefore, must be considered as a specific subtype of gastric carcinoma.

Aberrant crypt foci in patients with neoplastic and nonneoplastic colonic disease.

Aberrant crypt foci (ACF) are putative preneoplastic lesions that might represent the earliest morphological lesion visible in colonic carcinogenesis. However, findings concerning the growth and morphological features of these lesions in human studies suggest that ACF are highly heterogeneous in nature. In this study, we evaluated the morphological features of a large number of ACF in colon mucosa of 26 patients with colorectal carcinoma (CRC), four patients with adenoma as well as seven patients with nonneoplastic colonic diseases. By dissecting microscope, 508 ACF were identified, and of these, 378 were sampled for histological examination. The median ACF density (number of ACF/cm2) was significantly higher in the left colon than in the right colon (0.047 v 0.014 ACF/cm2). Unexpectedly, in our series, the overall ACF density was higher in the nonneoplastic colonic diseases than in CRC (0.13 v 0.032 ACF/cm2, P=.0087), cases of nonneoplastic diseases, however, being limited to 7 patients. ACF were significantly larger in colons with CRC or adenoma than in colons with nonneoplastic disease (P < .03). On histological examination, we observed 133 ACF with normal epithelium, 189 ACF with hyperplasia, 27 ACF with atypical hyperplasia, and 29 ACF with dysplasia. We noted a progressive increase of median ACF size from normal mucosa to hyperplasia, atypical hyperplasia, and dysplasia. Dysplastic ACF were more frequently observed in patients with CRC or adenoma and showed predominantly elongated crypt orifices (P < .0001). We conclude that ACF are histologically heterogeneous, encompass a spectrum of lesions of which only a subset are associated with dysplasia and then represent an early step in colorectal carcinogenesis. ACF with dysplasia are characterized by larger size, elongated crypt orifices, and an association with CRC.

The type of K-ras mutation determines prognosis in colorectal cancer.

BACKGROUND: Mutations involving the oncogene K-ras in colorectal cancer may be related to tumor aggressiveness. However, the value of K-ras gene determination as a prognostic marker has not been clearly established. PATIENTS AND METHODS: The results from 98 patients recruited in a prospective study analyzing the effect of a K-ras mutation as a prognostic factor in colorectal cancer are reported. RESULTS: Disease-free (P = 0.02) and overall survival (P = 0.03) were significantly reduced for patients harboring a K-ras mutation. Two specific mutations demonstrated a significantly increased risk of disease recurrence, namely, 12-TGT (P = 0.04) and 13-GAC substitutions (P = 0.002). Patients with either of these substitutions had a 2-year disease-free survival rate of 37% compared with that of 67% for the group of patients harboring any other mutation type or a wild-type status (P = 0.01). CONCLUSIONS: The results herein presented suggest that K-ras acts as a prognostic factor in colorectal cancer and that this effect is probably related to a limited number of defined mutations.

Estrogen and progesterone receptors and pS2 and ERD5 antigens in gastric carcinomas from the European population.

We examined immunohistochemically 50 gastric carcinomas from European patients for estrogen receptors, progesterone receptors, and hormone-receptor-related proteins pS2 and ERD5. Unlike gastric carcinomas from non-Europeans reported previously, the carcinomas of the present series were all negative for estrogen and progesterone receptors. One-half of them, however, expressed pS2, and three-fourths were positive for ERD5. pS2 expression was significantly more frequent in carcinomas of the diffuse type than in those of the intestinal type and in advanced carcinomas compared with early ones. Our results indicate that pS2 and ERD5 are estrogen independent in the stomach. The possibility that estrogen and progesterone receptor status could be different in gastric carcinomas from Occidental and non-Occidental patients is discussed.

[Histologic diagnosis of lymphoproliferative diseases of the digestive tract]. / Le diagnostic histologique des lésions lymphoprolifératives du système digestif.

The pathologic diagnosis of lymphoproliferative diseases of the gastrointestinal tract is sometimes very difficult or even impossible. In the majority of cases the gross appearance of the lesion is not helpful. Three histological criteria, when present, justify a definite diagnosis: cellular anaplasia and nodal involvement in malignant lymphomas, and the presence of germinal centers in pseudolymphomas. All other histological criteria, including transmural extension of the lesions, are of only relative diagnostic value. The definite diagnosis of these diseases is based on histological examination of the entire lesion. Only a diagnosis of probability is generally possible on endoscopic biopsies. The demonstration of different chains of immunoglobulins by means of immunohistochemistry may help in revealing malignant lymphomas with secretory activity and a polyclonal pattern in reactive lesions.

Murine autoimmune gastritis and the gastric H,K-ATPase: insights from a new model and autoantibody detection system.

Human type A chronic gastritis or autoimmune gastritis (AIG) is associated with gastric H,K-ATPase-specific autoantibodies (HKAb). The pathogenic role of the HKAb and the triggering autoantigen(s) are unknown. In a mouse model, neonatal thymectomy (nTx) induces AIG, which is likely T cell mediated, although HKAb are always present. Our aim is to study the role of the H,K-ATPase in the initiation of AIG. The direct involvement of the H,K-ATPase in the onset of AIG is suggested by the following findings. AIG appears at the age of 1 month in susceptible BALB.D2 mice, i.e. the time at which H,K-ATPase expression reaches adult levels. A new HKAb assay system based on immunoprecipitation of native H,K-ATPase expressed in Xenopus oocytes has revealed that the early lesion is already associated with low titers of HKAb. Injection of gastric membranes, rich in H,K-ATPase, into neonatal BALB.D2 mice without adjuvant induces a persisting AIG. This new model for AIG will provide the means to identify which H,K-ATPase subunit triggers AIG.

Improved method for mapping gastric intestinal metaplasia using selective histochemical morphometry.

A gastrectomy specimen containing two tubular adenomas from a 67-year-old woman was mapped by an improved method using selective histochemical staining. The specimen was divided into 83 blocks measuring 4.0 cm x 0.5 cm. Sections from the blocks were stained with alcian blue (pH 2.5) to detect mucin. Alcian blue-stained fields were easily identified and measured with the aid of a MOP 30 interactive digital image analyzer. The total area of gastric mucosa analyzed in the 83 sections measured 3,270.9 sq mm while the area occupied by alcian blue-stained goblet cells measured 755.9 sq mm (23.1% of the total area). Intestinal metaplasia was present in 46 of 83 blocks. Both the mean size of alcian blue-positive fields per section as well as the number of alcian blue-positive fields per section were significantly larger in the antral zone I and the intermediate zone II than in the fundal zones III, IV and V. The highest proportion of gastric mucosa with intestinal metaplasia was not found around the two gastric adenomas, but elsewhere. There was no significant difference in the proportion of intestinal metaplasia between the greater and lesser curvatures, further challenging the belief that intestinal metaplasia is always greatest along the lesser curvature. The method described will permit future studies of the possible association between intestinal metaplasia and dysplasias and adenocarcinomas of the stomach.

K-ras mutations and p53 alterations in neoplastic and nonneoplastic lesions associated with longstanding ulcerative colitis.

We have analyzed K-ras mutations and p53 alterations in 39 tumor and nontumor samples taken from nine patients with longstanding ulcerative colitis and colorectal carcinoma. Two of nine invasive carcinomas contained a K-ras mutation. By a combination of immunohistochemistry and single-strand conformation polymorphism analysis, p53 alterations were found in three of nine carcinomas. Five of 13 dysplastic lesions harbored a mutated K-ras gene, even in the absence of detectable changes in associated invasive tumors. One single focus of dysplastic mucosa harbored concomitant K-ras and p53 gene alterations. In two patients, a K-ras mutation was detected in epithelial lesions considered to be devoid of malignant potential (villous regeneration, active colitis). Our results indicate that: 1) the prevalence of K-ras and p53 genetic alterations found in ulcerative colitis-associated colonic carcinomas appears to be lower than in sporadic carcinomas; 2) K-ras mutations can be detected in dysplasia, villous regeneration, and active colitis and affect a subpopulation of the cells composing the lesions; 3) diverse genetic alterations can be detected in the same patient and the dysplastic lesions can exhibit a different genotype than the carcinomas; and 4) at least part of active colitis and villous regeneration lesions should be considered as preneoplastic in ulcerative colitis.

Budesonide in the treatment of collagenous colitis.

Collagenous colitis is characterized by watery diarrhea and inflammatory infiltration associated with a subepithelial collagen deposit on colonic biopsies despite a normal or subnormal endoscopic appearance. We here describe 5 patients treated with the locally active steroid budesonide. Complete and partial response was observed in 3 and 2 patients, respectively. Budesonide thus seems to be of therapeutic benefit in collagenous colitis. Prospective randomized long-term studies are needed to support this hypothesis.

The role of Helicobacter pylori in primary gastric MALT lymphoma.

AIMS: Helicobacter pylori has been claimed to be an important aetiological factor which raises the risk of mucosa-associated tissue lymphoid (MALT) lymphoma. However, some studies on gastric MALT lymphoma revealed a low rate of H. pylori infection suggesting that not all gastric lymphomas are related to H. pylori infection. The aim of this study was to verify the H. pylori infection frequency in a series of patients with primary gastric MALT lymphomas and to examine the relationship between H. pylori and the pathological features of those lymphomas. METHODS AND RESULTS: Thirty-one cases of resected gastric lymphoma were analysed: 10 cases (32%) were low-grade MALT lymphomas and 21 cases (68%) were high-grade MALT lymphomas. Helicobacter pylori was found in only 18 of 31 (58%) cases. Helicobacter pylori infection was significantly correlated with the grade and depth of invasion of MALT lymphoma since 63% of superficial low-grade MALT lymphomas were positive for H. pylori compared with 38% of advanced high-grade MALT lymphomas (P = 0.02). CONCLUSION: We confirmed the relationship between H. pylori infection and a subset of gastric MALT lymphoma. Our results also showed that not all low- and high-grade gastric MALT lymphomas are H. pylori-dependent. This suggests that H. pylori infection may play a promoter role in the development of MALT lymphoma, but its presence is not mandatory for the progression of the lymphoma in view of its low frequency in advanced high-grade MALT lymphoma.

[Eosinophilic gastroenteritis: two case reports]. / Gastro-entérite à éosinophiles: à propos de deux cas.

Eosinophilic gastroenteritis is a rare lesion that may present a diagnostic problem to the surgeon. It may be confused with a malignant tumor because it often presents with intestinal obstruction. We treated two cases at the Hôpital de zone de Morges. In one case the lesion was in the gastric antrum and in the other the ascending colon. Only 27 cases of colonic eosinophilic gastritis are described in the medical literature.