The topographic distribution of lymphocytic gastritis in gastrectomy specimens.

Forty-eight entire gastrectomy specimens received consecutively at this Department were cut into blocks for histologic examination. Focal or more extended areas of chronic gastritis (i.e. superficial or atrophic with or without intestinal metaplasia) were present in all 48 specimens. In addition, two of the 48 specimens had a large number of lymphocytes in the surface and foveolar epithelium of the mucosa. In the literature the latter is regarded as "lymphocytic gastritis". Lymphocytic gastritis was found in all 156 sections obtained from the two specimens. This lympho-epithelial phenomenon was present even in areas lacking chronic inflammation in the subjacent lamina propria mucosae. From our results it would appear that while chronic gastritis has a focal or a regional topographic distribution, lymphocytic gastritis includes the entire surface-foveolar epithelium of the gastric mucosa.

Tumor-associated antigens common to humans and chemically induced colonic tumors of the rat.

The expression of human tumor-associated antigens CO17-1A, GA73-3, BR55-2, GICA 19-9, and CA50 and of carcinoembryonic antigen was immunohistochemically studied in the colonic mucosa of 70 Sprague-Dawley rats. Fifty were treated with 1,2-dimethylhydrazine (DMH) (with EDTA as a vehicle), ten were treated with EDTA only, and ten were untreated normal rats. The tumors were histogenetically divided as: (a) adenocarcinomas arising from villous adenomas; (b) adenocarcinomas arising from lymphoid-associated mucosa (LAM); and (c) adenocarcinomas arising in flat mucosa. Of 44 colonic adenocarcinomas, BR55-2 was expressed in 41 tumors, CO17-1A in 40 tumors, GA73-3 in 38 tumors, and GICA 19-9 in 38 tumors. CA50 and carcinoembryonic antigen were not expressed in the tumors. The highest antigenic expression (number of cells) was observed in adenocarcinomas arising in villous adenomas and the lowest in those arising in flat mucosa. Adenocarcinomas arising in LAM had an intermediate expression. The expression of these antigens had no correlation to the localization of the tumor and to the differentiation. The expression of these antigens was similar in the non-lymphoid-associated normal colonic mucosa of the untreated, EDTA-treated, and DMH-treated rats. In DMH-treated rats, LAM demonstrated increased expression (number of cells) and increased staining intensity of these tumor-associated antigens. In six of the 50 DMH-treated rats, only LAM expressed carcinoembryonic antigen. CA50 was not expressed in the normal colon of untreated, of EDTA-treated, and of DMH-treated rats, nor was it in DMH-induced tumors. None of the tumor-associated antigens (GICA 19-9 and CA50 and carcinoembryonic antigen) was detected in serum. It is concluded that this animal model would be of value in the preclinical evaluations of monoclonal antibodies for therapy in humans.

Effect of indomethacin in autotransplanted colonic tumors.

Seventy-five male Sprague-Dawley rats received weekly injections of dimethylhydrazine (DMH) for six months. Indomethacin was given orally to 40 of the rats. At the end of the allotted period, colonic tumors were autotransplanted into the subcapsular space of the left kidney. The autopsy demonstrated colonic tumors in 32 of 34 rats treated with DMH (94.1 percent), but only in 15 of 40 rats (37.5 percent) treated with DMH-indomethacin. Successful kidney autotransplantation was accomplished in 20 of 32 DMH-treated rats (63 percent) and in 5 of 15 DMH-indomethacin-treated rats (33.3 percent). Thus, the induction of colonic tumors by DMH and successful kidney autotransplants can be substantially abrogated by synchronous treatment with indomethacin.

A method of quantitating Paneth cell metaplasia of the stomach by image analysis.

Paneth cells are one of the histologic components of intestinal metaplasia of the stomach, as are mucin-producing goblet cells. With the aid of an image quantifier, the distribution of Paneth cells histochemically labeled with acid fuchsin was analyzed for a gastrectomy specimen containing an adenocarcinoma of the intestinal type; the topographic distribution of goblet cells histochemically labeled with Alcian blue (pH 2.5) was also analyzed. The specimen was cut into 63 blocks (0.5 X 4.0 cm) in four zones; antrum (zone I), intermediate region (zone II) and fundus (zones III and IV). Paneth cells were found only in sections containing mucin-producing goblet cells. Paneth cells were found in 12.5% of the 16 sections from the antral zone I containing Alcian blue-positive goblet cells. The rates were 44.4% for the intermediate zone II and 55.5% for the distal fundic zone III. The total area occupied by Paneth cells was significantly lower in the gastric mucosa as compared to the duodenal mucosa. The "Paneth cell index" (total Paneth cell area/total goblet cell area) was highest in the duodenum, followed by the distal fundic zone III. This method of quantitating Paneth cell metaplasia of the stomach will be used to investigate the topographic distribution of those cells in populations with low and high incidences of intestinal metaplasia.

A model to evaluate acute and chronic stress in the colonic mucosa of rats.

The effect of acute and chronic stress on the colonic mucosa of the rat was investigated at various time intervals, ranging from one day to eight weeks. The amount of DNA synthesized by the mucosa was used as a marker of time-related events. A total of 75 Sprague-Dawley rats were investigated. Acute stress was considered for rats briefly plunged (psychic stimulus) or swimming for two hours (physical stimulus). Chronic stress was determined when rats were briefly plunged or swam for two hours for periods ranging from one to eight weeks. "Sham-transported" rats were used as controls. DNA in the descending colon decreased significantly in rats swimming for two weeks, but increased (even for plunged rats) at four and eight weeks. In the ascending colon, a substantial increase in DNA content was found in rats plunged or swimming for eight weeks. The descending colon appears to be quantitatively more affected by various stressors than the ascending colon. It is apparent that, in control rats, the mucosa of the descending colon differs from the ascending colon. Fluctuations in the colonic DNA synthesis throughout the experiment suggest that this phenomenon may be connected to compensatory mechanisms toward cell adaptation to stress conditions. The model may prove of value in studies of the therapeutic abrogation of the fluctuations of the DNA replication of the colonic mucosa during the acute and chronic phases of a given stress.

Autotransplantation of colonic tumors into the colonic wall of the rat.

Colonic tumors were induced in Sprague-Dawley rats by weekly subcutaneous injections of 1,2 Dimethylhydrazine (DMH) for 4 months. The animals were thereafter laparotomized and a palpable tumor was transplanted into the same animal in a tumor-free area of the transverse colon. Autotransplanted tumors were considered those tumors growing in the wall of the transverse colon, covered by intact colonic mucosa. The frequency of autotransplanted tumors was 34%. The possibility that autotransplantation may also occur in humans by accident, during procedures to remove a colorectal adenocarcinoma, is discussed.

A model for the study of metastases from colonic tumors by autotransplantation.

Thirty male Sprague-Dawley rats received weekly injections of dimethylhydrazine for three months. They were subsequently laparotomized and tumors were palpated in 21 rats. The colonic tumor was removed and a fraction was autotransplanted into the wall of the transverse colon and a second fraction into the subcapsular space of the left kidney. The results demonstrated successful autotransplantation of colonic tumors in 13 of 21 rats (i.e., 62 percent). In 11 of the 21 rats (52 percent) the tumor grew in the left kidney. Of the various experimental methods proposed for the study of tumor metastases, the one described herein appears to be the first in which primary and secondary tumors were studied in the same individual, since dimethylhydrazine-treated rats usually develop more than one colonic tumor per individual. The model may be useful to monitor the effect of various drugs known to affect tumor growth, not only at the primary site, but also at the site of metastasis.

Minimal invasive carcinoma of the colon in rats.

The careful histologic examination of the macroscopically normal colon in rats treated 8 months previously with a single dose of the colonotropic carcinogen dimethylhydrazine (DMH) demonstrated atypical colonic glands in normally occurring lymphoid mucosal patches. The atypical glands were characterized by the absence of cytoplasmic mucus, hyperchromatic cell nuclei, cell stratification, and increased number of mitotic figures. In 61.7% of the experimental animals, atypical colonic glands were found beyond the boundary of the muscularis mucosae, but in none of the controls. Thus, microinvasive adenocarcinoma of the colon seems to be a common finding in rats treated with a single dose of DMH. These adenocarcinomas remain, however, undetected at macroscopic examination. Measurements performed in consecutive lymphoid aggregates demonstrated that 50% of rats receiving DMH had thicker lymphoid aggregates than control animals. In spite of this, no tumor was recorded at naked eye examination in these areas. The macroscopic examination appears to be an unreliable method of ruling out malignancy in experimental rats treated with a single dose of the above-mentioned carcinogen.

Monitoring the histogenesis of colonic tumors in the Sprague-Dawley rat.

A total of 306 male Sprague-Dawley rats, injected with dimethylhydrazine (DMH), dose 21 mg/kg body weight s.c., were investigated. Of the 109 rats receiving the dose once only, seven colonic adenocarcinomas developed; all seven (100%) were seen to originate in discrete lymphoid patches. Of the 97 rats treated with one dose/week for 3 months, only 6% of the 50 adenocarcinomas developed in discrete lymphoid patches, while 46% were seen to originate in a pre-existing adenoma. Of the remaining 100 rats, receiving one dose/week for 6 months, only 3.5% of the 57 adenocarcinomas arose from discrete lymphoid patches; 43.9% arose from a pre-existing adenoma. Thus, the histogenesis of adenocarcinomas at our laboratory appears to be dose-dependent. Experiments are therefore being designed to monitor in detail the events of these two histogenetically different adenocarcinomas in the colonic mucosa in our animal model.

Partial colon resection as a promotor of cancer growth in the rat.

Sprague-Dawley rats were treated with dimethylhydrazine (DMH) once a week for three months. After a treatment-free period of five months, they were subjected to minimal colon resection with an end-to-end anastomosis. Autopsy (one year after the discontinuation of DMH treatment, and seven months after surgery) demonstrated anastomotic tumors in 50% of the animals. Conclusions were that the carcinogen had induced genetic changes in the nonmigrating stem cells in the colonic crypts and that the chronic reparative process resulting from surgical trauma may have promoted colonic cells to induce tumors at the suture line.

Carcinogenesis at colonic anastomotic sites. An animal study.

For three months 65 male Sprague-Dawley rats received subcutaneous 1,2-dimethylhydrazine (DMH) weekly. Of the 65 animals, 45 were subjected to resection of the transverse colon, which subsequently was stitched to the abdominal wall. The remaining 20 animals were sham-operated controls. Fifty-four per cent of the tumors occurred either at the anastomotic site in the functioning colon (31 per cent) or at the anastomotic site of the isolated and defunctionalized colonic loop (23 per cent). On the other hand, only 10 per cent of the tumors occurred in the transverse colon of sham-operated controls. The difference was significant (P less than 0.001).