[Breast carcinoma with features of osteosarcoma--a light and electron microscopic and immunohistochemical study].

Reported is the case history of a 58-year-old woman with a lump in the left breast. The tumor was composed of two nodules, sharing a common portion. Grossly, one was an irregular hard tumor that was grayish in color, and the other was a well circumscribed cystic tumor that showed necrosis and a hemorrhage that had filled it with a reddish soft mass. Light microscopically, combined features of a scirrhous carcinoma and of an osteosarcoma were observed in each nodule, but the common portion was consistent with a metaplastic carcinoma, with cancer cells and sarcoma-like cells closely mingled. An ultrastructural study showed that the sarcoma-like cells were composed of polymorphic cells that resembled osteoblasts, myofibroblasts, osteoclasts, histiocytes, and undifferentiated tumor cells. Immunohistochemically, vimentin and alpha 1-antitrypsin in the sarcoma-like cells were positive, suggesting these cells were of a mesenchymal rather than of an epithelial origin.

[Oncogenes in human gastric carcinoma].

Alteration of oncogene and loss of chromosomal heterozygosity are infrequent in human gastric carcinoma compared with those in other gastrointestinal carcinomas. Amplification of c-erbB-2 gene is observed in well differentiated adenocarcinoma, while sam gene is found in poorly differentiated adenocarcinoma or scirrhous carcinoma. sam gene, which was isolated from a gastric cancer cell line KATO-III by a DNA renaturation method, encodes tyrosine-specific protein kinase domain. A good correlation evidently exists between the synchronous expression of TGF alpha and ras p21 and biological malignancy of gastric carcinoma. c-myc and c-fos proteins are found not only in tumor cells but also in stromal cells including macrophages and fibroblast around the tumors. The prognosis of patients with c-myc p 62-positive stromal cells is significantly better than that of patient with p 62-negative stromal cells. Coamplification of the hst-1 gene and int-2 is observed in 50% of primary tumors and all metastatic tumors of esophageal carcinoma. PCR (polymerase chain reaction) technique seems to be useful for the detection of oncogene point mutation in human gastric carcinoma.

[Hydroxyproline in breast cancer].

The content of hydroxyproline was determined in cancerous and noncancerous tissues obtained from 40 patients with primary breast cancer, and investigated from a clinicopathologic viewpoint. The level of hydroxyproline in cancerous tissue was higher than that in normal mammary gland, but was lower than that of the tissue of mastopathy. In relation to the histologic type, the level was the highest in scirrhous carcinoma, followed by papillotubular and solid tubular carcinoma. With regard to lymph node metastasis, the hydroxyproline level was significantly higher in positive than in negative metastatic cases. The corresponding level tended to be higher in patients at stages II-IV than in those at stage I. There was no obvious relationship to tumor size. However, a significant, negative correlation was found between the hydroxyproline level and patient age. Thus, the content of hydroxyproline was found to be closely related to age and clinicopathologic factors such as the histologic type and degree of lymph node metastasis.

Gastric carcinoma metastatic to the breast diagnosed by mucosubstance histochemistry and electron microscopy.

Bilateral breast tumors with a histologically scirrhous pattern were conclusively diagnosed as gastric carcinoma metastatic to the breast using mucosubstance histochemistry and electron microscopy. The majority of the carcinoma cells gave histochemically positive reactions for galactose oxidase-Schiff, stable class III con A, and high-iron diamine-alcian blue (HID-AB). Also electron microscopically, numerous HID-positive mucus droplets (sulfomucin) were seen in the carcinoma cells. These findings invalidated the possibility that the carcinomas were primary breast cancer. The practical applications of distinctive patterns of mucus secretion are discussed.

[Correlation of epidermal growth factor receptor status and clinical outcome in gastric carcinoma].

Analysis of epidermal growth factor receptor (EGFR) was performed on 242 primary gastric carcinomas and the results correlated with histologic findings and S-phase fractions measured by bromodeoxyuridine (BrdU) labeling. They were stained for EGFR by means of an indirect immunoperoxidase technique using a monoclonal antibody against the receptor. Seventy-six of these cancer tissues exhibited EGFR reactivities. All the cancer cell membranes were stained and sometimes the stroma were stained. These EGFR status were then compared on the basis of pathologic findings including macroscopic type, depth of invasion, differentiation type, vascular invasion and lymph node metastasis. Staining for EGFR in Borrmann's 3 or 4 type was significantly stronger than those in other macroscopic types. The staining for EGFR was closely related to the poorly differentiated type and frequent serosal involvement. BrdU labeling index was studied in 25 cases. These values were from 2.3% to 18.6%, with a mean of 10.4%. The mean BrdU labeling index of EGFR positive cases was 12.2%, of negative cases 7.6%, respectively. There was a good correlation between BrdU labeling index and EGFR status. In addition, There was a signifiCANT 8P less than 0.05) correlation between the presence of the EGFR and poor prognosis. However, EGFR status was not significantly correlated with the lymph node metastasis, vessel invasion and size of the tumors. These results indicate that demonstration of EGFR status may be useful in prognosis and this receptor may be a suitable target for therapy.

[Factors influencing on the prognosis in breast cancer].

TNM classification, tumor size, lymph node metastasis, histological type of primary tumor, ER status and biological tumor markers have been recognized as prognostic factors in breast cancer. The 673 breast cancer patients undergoing radical mastectomy at this department were analyzed for TNM classification influencing on the postoperative prognosis. Five-and ten- year survival rates were 93% and 89% in stage I, 83.9% and 75.5% in stage II, 67.3% and 60% in stage III. The most common histological type, namely, invasive ductal carcinoma, of primary breast cancer was classified into three types by Japan Mammary Cancer Society. The first type was papillotubular carcinoma, the second solid-tubular carcinoma, and the third scirrhous carcinoma. The prognosis of papillotubular carcinoma was best. Many investigators reported that the prognosis of ER positive breast cancer was good. But in the latest report, the opposite result is obtained. More study is necessary to evaluate the prognostic value of ER. The most common biological tumor markers were CEA, LDH and ALP. The CEA was the best prognosis-factor in biological tumor markers.

[Gastric scirrhous carcinoma and growth factors].

Recent in vivo and in vitro evidence suggests that EGF-related growth factors and TGF beta derived from tumor cells mutually act not only on tumor cells themselves but also on fibroblasts surrounding the tumor, resulting in extensive progression and fibrosis of gastric scirrhous carcinoma. There are two mechanisms involved in such extensive fibrosis. One is collagen production by fibroblasts upon stimulation by tumor-derived growth factors, and the other is collagen synthesis by the tumor cells themselves. However, the expressions of the EGF-related growth factors, TGF beta and procollagen, in tumor cells are not specific for gastric scirrhous carcinoma. Future elucidation of the function and structure of the sam gene may shed light on the developmental mechanism of gastric scirrhous carcinoma.

Immunohistochemical localization of myoepithelial cells and basement membrane in normal, benign and malignant human breast lesions.

Distributions of actin and type IV collagen were investigated immunohistochemically as markers for myoepithelial cells and basement membranes. Carnoy's and Methacarn-fixed, paraffin-embedded tissues from 103 human breast lesions from 103 patients were examined; 65 with carcinomas, 27 with mastopathies, 9 with fibroadenomas and 2 with phyllodes tumours. Fifty-five samples of the normal mammary gland tissue adjacent to tumours were also included for comparison. In normal breast and benign breast diseases, type IV collagen was identified around the mammary glandular cells and actin-positive cells were demonstrated to attach to basement membranes. In noninvasive carcinomas, type IV collagen was found as a continuous lining around a cell nest, while actin-positive cells were usually absent in ductal but quite numerous in lobular carcinomas. In invasive carcinomas, type IV collagen was fragmented or absent and actin-positive cells were very uncommon around the fragmentary basement membranes. These results suggest that the different distributions of myoepithelial cells and basement membrane material is useful in the differential diagnosis of surgical pathology of the breast.

Estrogen receptors in gastric adenocarcinoma: a retrospective immunohistochemical analysis.

Estrogen receptors (ER) in human gastric carcinomas were examined immunohistochemically using a specific monoclonal antibody to human ER. ER-immunoreactivity (ER-IR) was positive in 30 (27.8%) of the 108 gastric carcinomas examined. ER-IR was located in the nucleus of cancer cells. The incidence of ER-IR positive gastric carcinoma was not significantly different between male and female cases. However, the positive tumour cells were observed in 28 (39.4%) out of the 71 poorly differentiated adenocarcinoma, the incidence being significantly higher than that in well differentiated adenocarcinoma (p less than 0.01). There was no significant difference in the incidence of ER-IR between scirrhous carcinoma and non-scirrhous poorly differentiated adenocarcinoma. Synchronous expression of ER and epidermal growth factor receptor was found in 8 of the 26 scirrhous carcinomas (30.8%). Patients with ER-IR positive scirrhous gastric carcinomas showed a much worse prognosis than those with ER-IR negative scirrhous carcinomas.

Tamoxifen binding sites in human mammary cancers.

Tamoxifen binding sites (TBS) were measured using 3H-tamoxifen, the objective being to evaluate the relationships among TBS and hormone receptors and/or clinical and pathological characteristics in malignant tissues from 60 patients with mammary cancer. TBS were detected in most (96.7 per cent) cancers in the breast tissues, and the mean content and affinity were 569 fmol/mg X protein with Kd: 1.98 nM. There was no significant correlation between TBS and the estrogen receptor and/or progesterone receptor, with respect to positivity or content. However, there was a significant correlation between TBS and histological grading, thereby indicating the differentiation and the proliferative activity in this tissue. The content of TBS was significantly higher in the group with a high grade of malignancy. The TBS content significantly increased in parallel with the degree of malignancy, as related to tubule formation, nuclear pleomorphism and mitotic activity. On the other hand, there was no significant correlation between TBS and age, tumor size, lymph node status or clinical stage. These results suggest the possibility that TBS may be associated with differentiation and cell-proliferation in breast cancer tissues.

[Endocrine therapy of scirrhous carcinoma of the stomach].

Tissue localization of endogenous estrogens (estrone; E1, estradiol; E2, estriol; E3) progesterone was examined in scirrhous type of gastric cancer by the peroxidase-antiperoxidase (PAP) immunoperoxidase method. Twelve of 47 specimens showed positive estrogen staining, and 4 of 47 showed positive progesterone staining. The incidence of positive staining for these 4 substances was higher in male patients than in female patients. The number of specimens with positive E2 staining was the highest among E1, E2 and E3 staining. Prognosis of patients who had undergone curative surgery with positive estrogen staining were better than that of patients with negative estrogen staining. The existence of estrogen receptor (ER) and progesterone receptor (PgR) was also shown in 3 specimens and one specimen, respectively, from another 15 specimens with scirrhous type of gastric cancer by the dextran-coated charcoal assay. In a clinical test, Tamoxifen administered patients with scirrhous carcinoma following curative or noncurative gastrectomy showed better prognosis than non-Tamoxifen administered those.

Human epidermal growth factor in gastric carcinoma as a biologic marker of high malignancy.

The presence of human epidermal growth factor (hEGF) was studied in a total of 210 gastric carcinomas comprising 52 early carcinomas, 113 advanced carcinomas and 45 scirrhous carcinomas. An immunohistochemical study revealed no hEGF-immunoreactivity in early gastric carcinomas, while hEGF-positive tumor cells were detected in 24 (21.2%) of the 113 advanced carcinomas and in 15 (33.3%) of the 45 scirrhous carcinomas. The incidence of hEGF-immunoreactivity in well-differentiated adenocarcinomas was significantly higher than that in poorly differentiated adenocarcinomas (P less than 0.05). Moreover, hEGF-immunoreactive tumor cells were observed in 13 (30.4%) of the 42 scirrhous poorly differentiated adenocarcinomas, the incidence being significantly higher than that in non-scirrhous poorly differentiated adenocarcinomas (P less than 0.05). The average hEGF content in the tumor tissue estimated by radioimmunoassay was 3.77 +/- 0.61 (mean +/- SE) ng/g wet weight in immunohistochemical hEGF-positive tumors and 2.19 +/- 0.18 ng/g wet weight in hEGF-negative tumors, the difference being significant (P less than 0.05). Patients with hEGF-positive carcinomas (excluding scirrhous carcinomas) had much worse prognosis than those with hEGF-negative carcinomas. These results suggest that EGF produced by tumor cells plays an important role in the invasive growth and productive fibrosis of gastric carcinoma and also serves as a biologic marker of high malignancy in patients with gastric cancers.

Calcitonin in human gastric mucosa and carcinoma.

The localization of immunoreactive calcitonin (IR-CT) in the human gastric mucosa and tumor tissues was studied using an immunohistochemical peroxidase-antiperoxidase method. A small number of IR-CT-containing cells were observed in both infant and adult gastric antral mucosa and the ratio of IR-CT-containing cells to G cells was about 1:50-100. Moreover, tissue content of IR-CT in normal antral mucosa was 2.37 +/- 0.35 ng/g wet weight. IR-CT-containing cells and G cells decreased with the progress of chronic atrophic gastritis and were totally absent in intestinal metaplastic glands. IR-CT was detected in G cells, suggesting a paracrine relation between gastrin and CT. IR-CT was not found in tumor cells of 35 gastric adenomas and 40 well differentiated adenocarcinomas. On the other hand, it was demonstrated in a very small number of tumor cells in 4 of 46 poorly differentiated adenocarcinomas, and in a good number in 3 of 7 scirrhous argyrophil cell carcinomas. IR-CT in plasma could serve, therefore, as a tumor marker of scirrhous endocrine cell carcinoma, and its production in cancer cells was considered to be eutopic rather than ectopic.

[Laser flow cytofluorometry as a supplementary method of determining the degree of tumor differentiation in breast cancer patients]. / Lazernaia protochnaia tsitofliuorimetriia kak dopolnitel'nyi metod opredeleniia stepeni differentsirovki opukholi u bol'nykh rakom molochnoi zhelezy.

Content of cell DNA and RNA was studied by method of laser flowing cytophotometry in 21 cases of pretumorous conditions and 64 tumours of mammary gland. A clear-cut difference in DNA and RNA histograms is shown in non-proliferative and proliferative forms of mastopathy, in mastopathy and infiltrating mammary gland carcinoma. Likewise, a clear-cut correlation between the degree of malignancy and a nucleic acid content in the carcinoma cells is established.

Biochemical and immunohistochemical studies on the scirrhous carcinoma of human stomach.

Tumor mass of the stomach from patients with scirrhous carcinoma was analyzed biochemically and immunohistochemically to elucidate whether or not infiltrating carcinoma cells are directly responsible for overproductions of collagen in the lesion. Collagen content per unit transverse section of the tumor was two to four times higher than the normal. Of particular interest was that the contents of hyaluronic acid and chondroitin sulfate were five to ten times higher than the normal, suggesting that cells in the lesion of the tumor are in an actively proliferating stage. Immunohistochemical observations using type-specific anti-collagen antibodies and anti-carcinoembryonic antigen antibody revealed that type IV collagen was diffusely distributed through the tumor stroma of submucosa and fragmented regions of muscle layer, along with dense fibrous components composed of type I and type III collagens. Stroma cells in the lesion were often stained with antibody to type IV collagen. In contrast, carcinoma cells were with antibody to type I collagen, but not with antibodies to type III and type IV collagen. Quantitative analysis of the collagen production by isolated stroma cells and undifferentiated (KATO-III) and highly differentiated (MKN-28) carcinoma cells in culture in the presence and absence of a combination of the conditioned medium of these cells has shown that the scirrhous carcinoma of stomach results from the "stroma reaction" of stroma cells induced by infiltrating malignant epithelium.

[Sex hormone dependency in diffuse carcinoma of the stomach and results of chemo-endocrine therapy].

Based on experimental study that the growth of diffuse carcinoma of the stomach depended on sex hormone, chemo-endocrine therapy using an anti-estrogen after gastrectomy for female patients are carrying out in National Cancer Center Hospital since 1980. The results are as follows. The cumulative 3 year survival rate in 21 patients with chemo-endocrine therapy (TAM+) revealed significant higher (45.8%) than those (7.4%) in 23 patients with chemotherapy alone (TAM-). The results of TAM(+) in curatively resected cases (8 cases) were both 100% of 2 and 3 year survival rate with 2 recurrent cases. In TAM(-) 10 cases, 2 and 3 year survival rate showed 56.0% and 20.0% respectively (P less than 0.01). This study suggests that the chemo-endocrine therapy may be a new adjuvant therapy in female patients with diffuse carcinoma of the stomach.

Collagen composition in the ductal infiltrating carcinoma of human breast.

Ductal infiltrating carcinoma of the breast is characterized by a remarkable amount of collagen fibrils surrounding nests and cords of neoplastic cells. Sequential extractions with pepsin release three classes of intact collagen chains, which have been identified as alpha 1 (I), alpha 2 (I) and alpha 1 (III) types. Alpha 1 (I) is prominent among these classes.