Rossella Fante

Familial occurrence of gastric cancer in the 2-year experience of a population-based registry

The authors studied the familial occurrence of tumors in 154 individuals with gastric cancer by reviewing the clinical data and the genealogical tree of all patients registered in 1986 through 1987 in the Local Health Care District of Modena, Italy, for cancer of the stomach. Crude and age‐adjusted (world population) incidence rates of gastric cancer were 34.0 and 21.4 new cases/100,000/year, respectively, in men, and 24.5 and 10.9 in women, respectively. Among first‐degree relatives of the registered patients there were 30 cases of gastric carcinoma versus 15 cases in a control group matched for age and sex (Mantel‐Haenszel odds ratio [M‐H OR] 3.14, P < 0.01). This excess of gastric neoplasms was observed in siblings (17 versus 7, MH OR 4.33, P < 0.02) but not in parents (13 versus 8, not significant). Besides gastric cancer, there was no significant excess of other type of tumors in case families. The familial occurrence of gastric cancer tended to be more frequent in patients with “diffuse” carcinoma (52%) than in subjects with “intestinal” cancer (33%), although the difference was not statistically significant. In conclusion, the current investigation suggests that a “family history” for gastric neoplasms is usually observed in approximately 10% to 15% of the registered cases. As already described for other common malignancies, therefore, the familial occurrence of gastric carcinoma suggests the existence of a genetic susceptibility to cancer of the stomach, at least in a fraction of these patients.

Synchronous occurrence of epithelial and stromal tumors in the stomach: a report of 6 cases.

OBJECTIVE The synchronous development of epithelial and stromal tumors in the stomach has been reported rarely in the literature. A series of 6 such cases is described in this article. METHODS Clinical and pathologic data were recorded and the literature was reviewed. RESULTS Five cases featured the simultaneous occurrence of stromal tumors (1 benign, 3 borderline, 1 malignant) and adenocarcinomas, whereas the stromal tumor in the sixth case was found in association with a carcinoid. No collision tumors were observed. In 2 cases, tumors arose from the same site and were closely juxtaposed, but in 4 patients they developed from different areas of the stomach. A preoperative histologic diagnosis of both tumors was not achieved in any case. Two patients harbored occult infiltrative epithelial lesions (1 diffuse-type adenocarcinoma, 1 carcinoid), which were detected only at pathologic examination of the gastric mucosa adjacent to the stromal tumor. CONCLUSIONS The simultaneous occurrence of epithelial and stromal tumors in the stomach can be less rare than usually expected. Coincidence alone could account for such an association, particularly in areas with high incidence rates of gastric cancer. The hypothesis that a single carcinogenic agent might interact with two neighboring tissues in the stomach inducing the development of tumors of different histotype cannot be theoretically discarded.

Microsatellite instability in multiple colorectal tumors.

Tumor multiplicity is a hallmark of hereditary cancers: in the colon‐rectum multiple tumors represent 5–10% of all colorectal cancer cases. A portion of these cases belongs to hereditary non‐polyposis colorectal cancer (HNPCC), a genetic cancer syndrome due to mismatch repair (MMR) gene mutations, phenotypically expressed as microsatellite instability (MSI); the majority of multiple tumors, however, is apparently without any family history. We analyzed 78 (38 synchronous and 40 metachronous) neoplasms from 37 patients with multiple tumors of the large bowel, both HNPCC and sporadic, with the aim of identifying a common genetic basis in multiple tumors. DNA was extracted from normal and cancerous formalin‐fixed tissue and was analyzed for MSI using 6 markers. Tumors showing MSI in at least 2 of 6 microsatellite loci were defined as MSI(+). The overall number of MSI(+) tumors was 22 (28.2% of the total). A significant difference in the rate of MSI(+) between HNPCC and sporadic tumors was observed (85% vs. 17%). In the same patients, the MSI phenotype of synchronous tumors (both HNPCC and sporadic) tended to be more concordant than that of the metachronous ones. The higher frequency of MSI in HNPCC than in sporadic tumors, even when multiple, suggests that the involvement of MMR genes in the pathogenesis of the sporadic cases may be uncommon, thus confirming that screening for MSI in multiple colorectal tumors could be a useful tool in the identification of HNPCC in the general population. Int. J. Cancer 81:1–5, 1999.

Histology of aberrant crypt foci in the human colon

Aberrant crypt foci (ACF) have been identified in the methylene‐blue stained mucosa of the human colon. Some lines of evidence suggest that ACF may be precursors of colon cancer. The objective of the present study was to establish morphological criteria able to define and classify ACF in histological sections. Twenty‐four colectomy specimens were collected after operation for colorectal cancer and fixed in 10% formalin. Strips of grossly normal mucosa were stained in a 0.2% solution of methylene blue in saline for 5–10 min. The strips were measured, put on a glass slide and observed under a light microscope at ×25. One hundred and fourteen ACF identified by topology were sectioned parallel to the muscularis mucosae. Eighty‐four ACF were evident at histological examination and could be classified into three main groups: group A (61 ACF, 72.6%) including foci whose epithelial cells had regular nuclei, with only mild or focal crowding but no stratification, no mucin depletion and no dysplasia; group B (16 ACF, 19.1%), in which features of hyperplasia were evident; and group C (seven ACF, 8.3%) including foci with enlarged, crowded and stratified nuclei, mucin depletion, frequent mitoses, and evident dysplasia, diffuse or focal (mild in five cases, moderate in two) representing microadenomas. Finally, hyperplastic foci were significantly larger than foci of group A and C. Group B ACF were also more frequent in the rectum than in the colon. In conclusion, selected histological features allow the definition of groups of ACF, which may represent sequential steps in the development of human colorectal tumours.

Survival analysis in families affected by hereditary non‐polyposis colorectal cancer

Previous survival studies suggested a better prognosis of hereditary nonpolyposis colorectal cancer (HNPCC) patients compared with the sporadic counterpart. In the present study we evaluated the clinical outcome of HNPCC patients with respect to that of patients with colorectal cancer recorded in a population‐based cancer registry. We assessed survival of 85 colorectal cancer patients from 24 unrelated families defined as having HNPCC according to the criteria of the International Collaborative Group, for whom adequate information on subject‐ and tumor‐related parameters and a 5‐year follow‐up (cancer diagnosis from 1980‐1989) were available. Three hundred and seventy‐seven colorectal cancer patients, registered from 1984‐1986, with a 5‐year follow‐up, were used for comparison. Colorectal cancer‐specific 5‐year survival rates were 55.2% and 42.5% for HNPCC and non‐HNPCC, respectively. Using Cox regression analysis, tumor staging and location were independently associated with survival, whereas HNPCC diagnosis was not. Stage II HNPCC cases exhibited a better prognosis than non‐HNPCC patients. By Cox regression analysis, none of the variables were significantly related to survival. Both overall and stage II HNPCC cases showed a survival advantage in comparison with non‐HNPCC patients. However, the difference disappeared when clinical and pathological variables were controlled for with a Cox regression analysis. Int. J. Cancer 71:373‐376, 1997.

Aberrant crypt foci in patients with colorectal cancer

Aberrant crypt foci (ACF) are clusters of abnormally large colonic crypts identified on the mucosal surface of the human colon. They are thought to be preneoplastic lesions. The aim of the present study was to compare density (number of ACF per square cm of mucosal surface), crypt multiplicity (number of crypts per ACF) and histology of ACF in colonic resections of colorectal cancer patients resident in two Italian provinces with a twofold difference in colorectal cancer incidence rates. Thirty-two and 26 colonic resections were collected after operation in Ragusa (Southern Italy) and Modena (Northern Italy), respectively, and fixed in 10% formalin. Mucosal layers were observed under a light microscope at 25x after staining with methylene blue. Density of ACF was significantly higher in Modena (median 0.101 ACF cm(-2)) than in Ragusa (0.049, P = 0.001), whereas there was no difference in crypt multiplicity. ACF were classified into three groups according to histological features: ACF with mild alterations (hypertrophic ACF, 73%), ACF with hyperplasia (hyperplastic ACF, 17%) and ACF with dysplasia (microadenomas, 10%). The proportions of ACF in the three groups were similar in the two provinces. Density of ACF was higher and crypt multiplicity lower proceeding from proximal to distal large bowel. Microadenomas were observed only in the colon, whereas hyperplastic ACF were more frequent in the rectum. In conclusion, density of ACF correlates with colorectal cancer rates in two Italian provinces, and shows a positive gradient from proximal to distal large bowel. Histology of ACF suggests that they may be precursors of both hyperplastic and adenomatous polyps. These data provide further evidence of the role of ACF in human colorectal carcinogenesis.

Small bowel carcinoma in hereditary nonpolyposis colorectal cancer

A 53-yr-old man, a member of a hereditary nonpolyposis colorectal cancer (HNPCC) family, with previous colonoscopic polypectomies, presented for persisting vomiting and marked signs of dehydration. Previous radiological and endoscopic examinations of the upper digestive tract were negative, with the exception of the presence of a duodenal adenomatous polyp. Enteroclysis led to a diagnosis of obstruction at the Treitz angle due to a moderately differentiated adenocarcinoma. Microsatellite instability was demonstrated in the DNA extracted from the tumor. The patient was the carrier of a mutation in the intron 13 of the hMLH1 gene, one of the four mismatch repair genes known to be responsible for HNPCC.

K-ras andp53 mutations in hereditary non-polyposis colorectal cancers

Genetic instability related to defective DNA mismatch repair genes may be involved in the pathogenesis of carcinoma in Hereditary Non‐Polyposis Colorectal Cancer (HNPCC). To test that the targets of genetic instability could include critical transforming genes involved in colon tumor progression, we examined 23 colorectal carcinomas in patients with HNPCC in order to detect somatic mutations in K‐ras and p53 genes. Using single strand conformation polymorphism followed by direct DNA sequencing, we detected 4 mutations in K‐ras gene (17%) and 3 in p53 gene (13%) which change the aminoacid sequence of the protein p53. This is significantly lower than in sporadic cancer. Our data suggest that colon cancer in HNPCC might partly involve a distinct pathogenetic mechanism that involves other genes than those altered in sporadic tumors. Int. J. Cancer 74:94–96.

Expression of p53 Protein in Prostate Cancers of Different Histologic Types

Mutations and overexpression of p53 gene in prostate carcinoma have been found but their significance in the development and progression of cancer is so far unknown. We investigated the prevalence of abnormalities of p53 protein in a heterogeneous group of prostate carcinoma to verify whether acinar and non acinar carcinomas have a different expression of p53 protein. Paraffin sections of 45 prostate carcinomas (39 acinar, 3 ductal papillary, 1 transitional cell, 1 mucinous and 1 pure small cell) were examined for the expression of p53 protein using a panel of antibodies (monoclonal antibodies Pab 1801, D07 and polyclonal antibody CM1). No p53 expression was observed in any acinar carcinomas independent of grade and stage. For non acinar carcinomas only small cell and transitional cell carcinomas exhibited detectable amounts of p53 protein in tumour cell nuclei. The prevalence of p53 overexpression in prostate carcinoma is relatively low compared with that found in many other tumours. In the present study, the overexpression of p53 in a small cell carcinoma and in a transitional cell carcinoma suggest that the loss of suppressing role of p53 gene may be an important mechanism in the genesis and in the development of these uncommon tumours.

Metastatic capacity and differentiation in murine melanoma cell lines: A Morphometric Study

A morphometric analysis was carried out on electron micrographs of cells of the F1 (low metastatic capacity) and F10 (high metastatic capacity) variant sublines of the murine B16 melanoma, both in in-vitro cultures and in lung-metastatic nodules developed after the intravenous injection of neoplastic cells in syngeneic C57 black male mice. A group of 28 morphometric parameters was derived to describe quantitatively each neoplastic cell profile. No qualitative difference was observed between the two cell lines. The quantitative expression of subcellular organelles was dissimilar in the two sublines, being consistently characterized, both in in-vitro cultured cells and in lung-metastatic colonies, by a significant decrease in the mean values of parameters related to melanosomes in the high metastatic capacity cell line (B16-F10). Moreover, in in-vitro cultured cells, indices describing heterochromatin masses and cytoplasmic membranous compartments displayed statistically significant differences between the two sublines. In this experimental system, an inverse relationship between metastatic capacity and differentiation is detected, since cells with a more aggressive metastatic behavior exhibit a decreased degree of differentiation.