Teruyuki Hirota

An immunoperoxidase study of S-100 protein distribution in normal and neoplastic tissues

ABSTRACTThe presence of S-100 protein was immunohistochemically studied in many types of formalin-fixed and paraffin-embedded tumors (260 cases). Peripheral nerve tumors, i.e., schwannomas, neurofibromas, granular cell tumors, and neurogenic sarcomas were demonstrated to contain variable amounts of S-100 protein in the tumor cell cytoplasm and nuclei. In ganglioneuromas and ganglioneuroblastomas, neoplastic Schwann cells or satellite cells were positive for S-100 protein. About one-half of the cases of carcinoid tumors stained weakly for S-100 protein. In addition to these nervous tissue and carcinoid tumors, chondrosarcoma, chordomas, pleomorphic adenomas of the salivary gland, and Langerhans cell granulomatosis were also shown to produce S-100 protein. In many types of breast tumors and other lesions, S-100 protein positive cells were likely to correspond to the distribution of myoepithelial cells. These results indicate that S-100 protein is not strictly specific to nervous tissue and its tumors; however, the immunohistochemical demonstration of S-100 protein can be a useful diagnostic tool in tumor diagnosis.

Clinicopathologic Characteristics and Prognosis of Breast Cancer Patients Associated with Pregnancy and Lactation: Analysis of Case-Control Study in Japan

Clinicopathologic characteristics and prognosis of breast cancer patients associated with pregnancy and lactation were clarified by means of a case‐control study of matched non‐pregnant and non‐lactating patients with breast cancer. From 18 institutions in Japan, a total of 192 subjects with breast cancer diagnosed during pregnancy (72 cases) and lactation (120 cases) were collected between 1970 and 1988, accounting for 0.76% of all breast cancer patients. The duration of symptoms was longer and tumor size was larger in the study subjects. Although the disease‐free interval was longer than that in the control patients, the survival time was shorter. There was no characteristic difference in histologic type. Vascular invasion and lymph node metastasis were found more frequently in the subjects. The positive rates of estrogen receptor and progesterone receptor were lower in the subjects. The 5‐ and 10‐year survival rates of the study patients were 65% and 55%, respectively, and these survivals were significantly lower than those of the control (P < 0.001). The survival rates were poorer in the subjects, in accordance with stage and lymph node metastasis. The results suggest that most of the patients with breast cancer diagnosed during pregnancy and lactation are in a more advanced stage because of a delay in detection and diagnosis, and hence have unfavorable prognosis. Therefore, it is important to diagnose and treat early for improvement of prognosis in patients with breast cancer during pregnancy and lactation.

Carcinogenicity in rats of the mutagenic compounds 1-nitropyrene and 3-nitrofluoranthene.

1-Nitropyrene and 3-nitrofluoranthene are present in diesel exhaust, in pollutants in air, and were also present in certain xerographic toners and copies. Their carcinogenicities were studied in male F344/DuCrj rats by subcutaneous injection. Sarcomas, mainly malignant fibrous histiocytomas at the site of injection were induced in 8 to 17 (47%) rats by 1-nitropyrene and in 4 of 10 (40%) rats by 3-nitrofluoranthene. Some tumors were serially transplantable in the same strain of rats.

Correlation between histologic grade of malignancy and copy number of c-erbB-2 gene in breast carcinoma. A retrospective analysis of 176 cases.

A system of histologic grade of malignancy in human breast carcinoma was devised by significantly modifying the way of evaluating number of mitoses and architectural atypia in the histologic grading of Bloom and Richardson. The modified grading system was applicable to all histologic subtypes of adenocarcinoma and showed a good association with prognosis of breast carcinoma patients in retrospective analysis of 176 consecutive surgical cases (P < 0.0001). Of the three components of histologic grade, architectural atypia and number of mitotic figures independently had a significant effect on the prognosis. The copy number of c‐erbB‐2, a prognostic factor independent of tumor size and nodal status, was strongly correlated with the histologic grade, number of mitotic figures, and degree of nuclear atypia (P < 0.001, each). Coxs regression model analysis showed that nodal status and histologic grade were two determinants of prognosis, and the independent effect of c‐erbB‐2 amplification was absorbed within that of the histologic grade. Although the importance of c‐erbB‐2 gene copy number seemed to be inferior to that of the histologic grade, both were shown to be strongly associated with the aggressiveness of the tumor itself rather than the extent of tumor spread.

Production of alpha‐fetoprotein, normal serum proteins, and human chorionic gonadotropin in stomach cancer: Histologic and immunohistochemical analyses of 35 cases

By immunoperoxidase histochemical staining of formalin‐fixed paraffin‐embedded sections, the production of alpha‐fetoprotein(AFP), albumin(ALB), transferrin(TF), alpha‐1‐antitrypsin(AAT), and human chorionic gonadotropin(HCG) was examined in 35 operatively resected stomach cancers with elevated serum AFP levels (higher than 20 ng/ml as determined by radioimmunoassay). Cells positive for AFP were found in 19 cases (54%). In 29 cases (83%), some tumor cells contained normal serum proteins (ALB, TF, or AAT). All 19 tumors with AFP‐positive cells also stained positively for two or three kinds of normal serum proteins. In some cases, AFP and normal serum proteins were localized in the same cells. There were two cases in which metastatic tumors produced AFP, whereas the primary sites did not. In nine cases (26%), HCG was present in tumor cells and HCG‐ and AFP‐positive cells were coexistent in six tumors. Histologic examination of AFP‐producing stomach tumors revealed medullary or papillotubular arrangements with marked nuclear atypia and eosinophilic granular or clear cytoplasms containing no glycogen or mucin. Some tumors with medullary patterns resembled liver cell carcinomas. Concordant phenotypic expression of AFP and normal serum protein production appears to be a general feature of AFP‐producing tumors such as liver cell carcinoma, yolk sac tumor, and stomach cancer.

Immunohistochemical Study on Overexpression of c‐erbB‐2 Protein in Human Breast Cancer: Its Correlation with Gene Amplification and Long‐term Survival of Patients

Using a polyclonal antibody monospecific to the c‐erbB‐2 oncogene product, an immunohistochemical study on the expression of c‐erbB‐2 protein was performed in formalin‐fixed, paraffin‐embedded tissue sections from 176 primary breast carcinomas in which amplification of the c‐erbB‐2 gene had been detected in 28 cases. Expression of the c‐erbB‐2 protein was detected in 44 cases (25%), being strongly positive in 27 (15%) and weakly positive in 17 (10%). All cases with amplification of c‐erbB‐2 showed positive staining of its protein. There were only four cases in which c‐erbB‐2 was strongly expressed without amplification of the gene. In the group showing strongly positive staining, both overall and disease‐free survival were significantly poorer than in the remainder of the cases. Using Coxs regression model analysis, overexpression of c‐erbB‐2 protein was demonstrated to be an effective prognostic factor independent of nodal status or tumor size.

Point Mutation of c‐Ki‐ras Oncogene in Gastric Adenoma and Adenocarcinoma with Tubular Differentiation

The presence of point mutation at codons 12,13 and 61 of the c‐Ki‐ras oncogene was investigated in 7 cases of gastric adenoma and 35 cases of gastric adenocarcinoma using DNA samples from formalin‐fixed and paraffin‐embedded tissues. Oligonucleotides encompassing the three codons were amplified by using the polymerase chain reaction (PCR), and then examined for point mutation by the selective oligonucleotide hybridization technique. Point mutation was detected in three of the 7 adenomas (43%) and three of the 35 carcinomas (9%). All the gastric adenomas showed the histology of tubular adenoma, being very similar to that of colonic adenoma. The 35 cases of gastric adenocarcinoma were classified into 17 cases of differentiated type and 17 cases of undifferentiated type including signet‐ring cell carcinoma. The point mutation of c‐Ki‐ras oncogene was detected only in the differentiated type (3/17, 18%), and there was no case with point mutation in the undifferentiated type. These results suggest that the genetic mechanism of carcinogenesis differs between the differentiated type and the undifferentiated type of gastric adenocarcinoma, and also that c‐Ki‐ros activation is possibly involved in a relatively early step of the “adenoma‐carcinoma sequence,” which leads to the development of a portion of differentiated adenocarcinomas in the stomach.

Bacteria closely resembling Helicobacter pylori detected immunohistologically and genetically in resected gallbladder mucosa.

A microorganism with close immunohistological and genetic resemblance toHelicobacter pylori was found in the resected gallbladder mucosa of a 41-year-old woman. The woman was admitted to hospital complaining of fever and right hypochondrial pain. Cholecystectomy was carried out under the diagnosis of gallstones and cholecystitis. A microorganism resemblingH. pylori (stained with H&E, Giemsa, and Wartin-Starry) was detected incidentally on pathological examination. The microorganism was also positive for immunohistochemical staining. An amplification reaction was seen on genetic examination by the polymerase chain reaction (PCR) method (urease β-genes). Our findings suggest thatH. pylori may be present in tissues other than gastric mucosa.

A pathologic study of benign breast diseases in Tokyo and New York

Two hundred thirty‐two biopsies of benign breast conditions from the National Cancer Center Hospital in Tokyo and 263 comparable biopsies from Memorial Hospital in New York City were reviewed. The component lesions of benign breast disease were identified and evaluated according to their relative frequency for different ages. Apocrine cysts, apocrine hyperplasia, intraductal hyperplasia, sclerosing adenosis, blunt duct hyperplasia, and atypical lobular hyperplasia were at least twice as common in biopsies from American women. Solitary papillomas were twice as common among biopsies from Japanese patients and tended to show more epithelial proliferation and sclerosing papillomatosis than did Americans. No major differences were found in the frequency of cysts, duct stasis, periductal mastitis, sclerosing intraductal papillomatosis, fibroadenomatoid mastopathy or fibroadenomas. Assuming intraductal hyperplasia and atypical lobular hyperplasia may represent premalignant epithelial changes, the high frequency of these lesions in New York biopsies when compared to Tokyo biopsies correlates well with the higher rate of breast cancer in the United States as compared to Japan. The greater frequency of lobular proliferative lesions and apocrine disease in New York suggests that these lesions may be produced by factors which also predispose American women toward breast cancer. Cancer 50:1899‐1903, 1982.

A comparative study of some pathologic features of mammary carcinoma in Tokyo, Japan and New York, USA.

Epidemiologic and clinical studies conducted in the past 15 years have demonstrated striking differences in the biology of mammary carcinoma among Japanese and American women living in their native countries. These variations have, in part, been related to some differences in the characteristics of the primary tumors between the two groups. As part of a collaborative study we have had an opportunity to compare the stage of disease and to examine and compare histological sections of patients with breast carcinoma treated in 1973–74 at the National Cancer Center Hospital (NCH) in Tokyo and in 1974 at the Memorial Hospital (MH) in New York. The former group consisted of 216 and the latter of 555 carcinomas. Fewer patients in each group had axillary metastases than reported in a prior study of patients treated at MSKCC and in Tokyo 20 to 30 years earlier. Negative axillary nodes were now found in 58% of the MH patients and in 63% of women treated at the NCH. The magnitude of improvement in stage relative to the prior report was similar in both groups. However, it would appear that the change occurred mainly from the mid‐1950s to the 1960s in New York and approximately 10 years later in Tokyo. Results of this study confirming prior reports were: (1) higher frequency of colloid and of medullary carcinoma with lymphoid stroma and lesser frequency of lobular carcinoma in the Japanese patients; (2) more intense lymphoid infiltrate in and around primary tumors in Japanese women; (3) higher frequency of rounded or circumscribed tumors in Japanese women; and (4) the more frequent occurrence of intralymphatic tumor emboli within the breast in American women. The difference in the frequency of lobular carcinoma was less striking when comparison was limited to patients with unilateral carcinoma.