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DNA distribution pattern of the so-called severe dysplasias and small carcinomas of the colon and rectum and its possible significance in the tumor progression.

The DNA distribution pattern was determined by cytofluorometry in 25 cases of colorectal small carcinoma and the so-called severe dysplasia. The colorectal carcinoma and "severe dysplasia" consisted of four principal stemlines as to DNA ploidy: diploidy, aneuploidy, and their respective polyploidies. These patterns appeared in various combinations in individual neoplasms. DNA distribution of the severe dysplasia was diploid-predominant (11 cases) or aneuploid-predominant (three cases), usually showing mosaicism in various degrees with respective first order polyploidy. Similar DNA distribution patterns also were found in submucosally invasive small carcinomas. The neoplastic cell populations of a higher polyploidy (second or third order), however, occurred only in the submucosally invasive carcinomas (three cases) regardless of their basic ploidy. The mitotic index tended to be higher in the aneuploid-predominant tumors than in the diploid-predominant tumors. In the current observation, there was no significant correlation between the DNA distribution pattern and histologic type of the "dysplasia" or carcinoma. We found that most of the so-called severe dysplasias of the colon and rectum already gained definitive characteristic of carcinoma in the DNA pattern, i.e., ploidy heterogeneity. Therefore, they can be identified as intramucosal carcinomas, distinct from the normal epithelia and adenomas of the colon and rectum.

Aneuploidy↗

Interphase cytogenetics of renal cortical neoplasms. Correlation with DNA ploidy by flow cytometry.

The genotypic changes in 22 renal cortical neoplasms and 16 of the corresponding normal kidney tissues by fluorescence in situ hybridization (FISH) were studied using directly labelled probes for chromosomes 7, 8, 10, 11, 12, 17, 18, X, and Y, and by flow cytometry (FCM). DNA ploidy analysis revealed 8 DNA aneuploid and 14 DNA diploid neoplasms. The mean single spot hybridization in normal kidney was 5 +/- 0.9% for chromosomes 7, 8, 10, 11, 12, and the X in females. The mean single spot hybridization for chromosomes 17 and 18 was 14.9% and 18.5%, respectively. The mean number of more than two (> 2) hybridization signals in normal kidney cells for all autosomes and the X-chromosome in females was 3 +/- 1.2%. Significant chromosomal loss was restricted to chromosomes 8, 18, X, and Y. The net chromosomal gain and loss correlated with the DIs in aneuploid tumors. All DNA diploid neoplasms showed both chromosomal loss and gain with a tendency to a net loss. No apparent correlation between the chromosomal aberrations and the clinicopathologic factors was found in this cohort. Our study demonstrates that: (1) tissue specific controls may provide better information for definable performance criteria for this technique; (2) monosomy can more reliably be assessed on fresh samples; (3) chromosomal loss is confined to certain chromosomes; (4) DNA diploid tumors manifest heterogeneous gain and loss of various chromosomes with a tendency to a net loss; and (5) integrated FISH and FCM analysis provide more information on the chromosomal abnormalities of these neoplasms.

Adult↗

Frequent genetic instability in small intestinal carcinomas.

To determine whether genetic instability plays a part in the development of digestive tract carcinomas, we analyzed 3 microsatellite loci isolated from tumors and surrounding normal tissue samples obtained during surgery. The polymerase chain reaction (PCR) technique was used to assess differences between tumor and matched normal DNAs. Replication errors (RERs) were observed in 3 of the 29 cases (10%) of gastric carcinoma and in 11 of the 72 cases (15%) of colorectal carcinoma. None of the 13 (0%) esophageal carcinoma cases showed any RER, but 5 of the 11 cases of small intestinal carcinoma (45%) had RERs, a significantly frequent finding. These results suggest that genetic instability plays an important role in the pathogenesis of small intestinal carcinomas.

Colorectal Neoplasms↗

Mouse mammary tumor virus and mammary tumorigenesis in wild mice.

The current knowledge of the distribution of the mouse mammary tumor virus (MMTV) proviral genomes and the mechanism of mammary tumorigenesis by MMTV in mice, with the main emphasis on Asian feral mice, is reviewed. The relevant earlier discoveries on the mode of MMTV transmission are summarized to provide an outline of the biology of MMTV. Finally, the viral etiology of human breast cancer will be discussed.

Animals↗

DNA ploidy of oncocytic-granular renal cell carcinomas and renal oncocytomas by image analysis.

DNA ploidy analysis of five renal oncocytomas, six pure oncocytic-granular renal cell carcinomas, 15 pure clear cell renal carcinomas, and two cases of mixed oncocytic-granular and clear cell heterogenous renal cell carcinomas were determined on Feulgen-stained paraffin sections using the (CAS-200 image Analyzer). All five renal oncocytomas were diploid, as were six oncocytic-granular renal cell carcinomas. Three of the 15 clear renal cell carcinomas were aneuploid. In one heterogeneous renal cell carcinoma, the oncocytic-granular foci were diploid and the clear cell focus was aneuploid. The other heterogeneous renal cell carcinoma was uniformly diploid. In 21 renal cell carcinomas, one of 14 stage I tumors was aneuploid, all four stages II and III tumors were diploid, and two of three stage IV cases were aneuploid. All stages I, II, and III patients were free of disease 3 to 48 months after surgery. All three stage IV cases were dead of their disease within 36 months of surgery. We conclude that DNA analysis by image cytometry best identifies the heterogeneity of ploidy patterns in mixed cell type carcinomas, generally correlates with the stage of disease, and may be of value in predicting overall prognosis of renal epithelial neoplasms. DNA analysis by image cytometry, however, did not reveal significant differences between oncocytic granular cell carcinoma and oncocytoma, since both lesions were generally diploid. The distinction between the two tumors is best made on morphologic grounds.

Adenoma↗

Gastrointestinal T cell lymphoma: predominant cytotoxic phenotypes, including alpha/beta, gamma/delta T cell and natural killer cells.

Gastrointestinal T cell lymphoma (TCL) is a rare subset of peripheral TCL, presenting with or without cytotoxic phenotype, a history of coeliac disease (CD) and enteropathy. However, CD is rare in Japan. Here, we describe the clinicopathological features of 18 Japanese cases. Lesions were found in the small intestine (n=13), stomach (n=3) and colon (n=2). Seven patients presented with enteropathy but none had a history of CD. Lymphomas appeared as ulceration (n=11), tumour formation (n=6), or polypoid growth (n=1). Histologically (REAL classification), neoplastic lesions were composed of intestinal type T cell lymphoma (ITCL, n=13, including one case with NK type), anaplastic large cell (ALCL, n=2), adult T cell leukaemia/lymphoma (ATLL, n=2), and lymphoblastic type (n=1). Epstein Barr virus infection was detected by EBER-1 in situ hybridization in 6 of 11 cases with ITCL but not in the other types. ALCL expressed CD30. CD56 was expressed in 3 of 11 cases of ITCL but not in other types. Among the 10 examined cases, 8 were alphabeta T cell type [CD2+, CD3+, T cell receptor (TCR)delta-1-, betaF1+], one was gammadelta T cell type [CD2+, CD3+, TCRdelta-1+, betaF1-], and the remaining case expressed natural killer (NK) cell type [CD2+, CD3-, CD56+, TCRdelta-1-, betaF1-]. Among the 8 examined cases, 3 expressed CD103 molecule, which was associated with extrathymic T cells of intraepithelial lymphocytes. All cases except ATLL expressed the cytotoxicity-associated molecule of TIA-1, and 11 of 14 TIA-1 positive cases expressed activated cytotoxic molecules of perforin, granzyme B, and/or Fas ligand. Despite the morphological, genetic and phenotypic heterogeneity, prognosis was poor, and 11 of 13 patients with small intestinal lesions died albeit appropriate treatment, but 3 of 4 patients with gastric or colonic lesions were still alive. The main cause of death was intestinal perforation. The latter might be due to the site specificity of small intestine and tumour cytotoxicity.

Adult↗

Genetic instability in pancreatic cancer and poorly differentiated type of gastric cancer.

To examine genetic instability during carcinogenesis, we screened 171 carcinomas of the breast, liver, proximal colon, stomach, pancreas, uterine cervix, and ovary for replication error at four microsatellite marker loci on chromosome 2, 3, and 17. A significantly high incidence of genetic instability was observed in pancreatic (6 of 9 tumors) and gastric cancers (22 of 57 cases). In other types of carcinoma, the incidence of replication error-positive cases was relatively low (3-16%). Among gastric carcinomas, significantly more replication error-positive cases were observed in the poorly differentiated types (16 of 25 cases) than in well differentiated types (3 of 18) (P = 0.0023 by Fisher's exact test). Our results suggested that genetic instability is likely to play an important role in development of pancreatic and gastric cancers, particularly poorly differentiated adenocarcinomas.

Adenocarcinoma↗

[Nucleolus organizer regions and ploidy pattern of DNA in stomach neoplasms].

We studied 20 gastric adenocarcinoma to determine DNA ploidy pattern by flow cytometry and nucleolar organizer regions by the colloidal silver method. There were 12 diffuse and 8 intestinal type lesions. 11 tumors were classified as diploid and 9 as aneuploid. No correlation was observed between DNA ploidy pattern and mean number of nucleolar organizer regions. The histologic type was significantly related to the number of nucleolar organizer regions (p < 0.01). Poorly differentiated lesions had significantly less nucleolar organizer regions than intestinal type lesions. Lesions with ring cells (n = 6) had similar number of nucleolar organizer regions than poorly differentiated lesions.

Adenocarcinoma↗

Flow cytometric analysis of nuclear DNA from adrenocortical neoplasms. A retrospective study using paraffin-embedded tissue.

Nuclear DNA content of paraffin-embedded tissue from 48 adrenocortical neoplasms, 18 histologically normal control adrenal glands, and five hyperplastic adrenal glands was analyzed retrospectively using flow cytometry. Aneuploidy was compared with morphologic criteria as a predictor of recurrence. All 18 controls, five hyperplastic glands, and 39 neoplasms were diploid. Nine neoplasms were aneuploid. Compared with their diploid counterparts, aneuploid neoplasms were more likely to weigh more than 50 g (P less than 0.0001) and to have three or more histologic features of carcinoma (P less than 0.0001). Thirty-six neoplasms were followed clinically for at least 2 years (range 24 to 120 months, mean = 64.6 months) or until local recurrence, metastasis, or death. Five were clinically malignant. Neoplasms which recurred or metastasized were more apt to be aneuploid (P less than 0.005) than those showing no evidence of further disease during the follow-up period. They were also more likely to weigh more than 50 g (P less than 0.005) and to have three or more histologic features of carcinoma (P less than 0.0025). However, neither aneuploidy, large size, nor unfavorable histology result was a consistent feature in every malignant neoplasm. Flow cytometric DNA content analysis appears to be as effective a predictor of clinical outcome as size and histology and may be of particular value when the morphologic features are ambiguous.

Adenoma↗