Takaaki Nakamura

Microsatellite instability in sporadic human breast cancers

Human breast‐cancer specimens from 100 patients were analyzed for microsatellite instability (referred to as replication error; RER) at 12 genomic loci on 7 chromosomes, and results were correlated with clinicopathologic characteristics. In 42 of 100 breast‐cancer patients, we investigated whether RER was associated with the amplification of oncogenes and/or suppression of tumor‐suppressor genes. Of the 100 patients, 8 (8%) were RER‐positive at one or more chromosomal loci. The majority of RER‐positive patients had early‐stage disease with ER‐positive tumors, suggesting that RER occurs early in breast tumorigenesis. However, no significant correlation was observed between RER and oncogenes or tumor‐suppressor genes. Thus, the mechanism of RER in sporadic human breast cancer may be independent of the multi‐step carcinogenesis caused by the alterations of oncogenes and tumor‐suppressor genes.

Clinical significance of bcl-2 gene expression in human breast cancer tissues

The expression of estrogen receptor (ER) and bcl-2(Bcl-2), an apoptosis protective oncogene, in normal andcancerous breast duct epithelia was immunohistochemically examined infresh frozen tumor tissues from 142 Japanese breastcancer patients. The clinico-pathological characteristics and the diseasefree survival of the patients were analyzed. Theexpression of both the proteins was also observedin intraductal components of breast cancer. Although lessthan 1% of normal duct epithelia expressed ER,Bcl-2 was diffusely expressed. The expression of boththese proteins in breast cancer significantly correlated witheach other. Their expression significantly correlated negatively withtumor size but not with lymph node status.The papillo-tubular sub-type of invasive ductal carcinoma expressedBcl-2 significantly more frequently than the solid-tubular sub-type.Patients with Bcl-2 expressing tumors survived without recurrencesignificantly more than those with tumors exhibiting reducedexpression. Papillary-cribriform type intraductal componentsexpressed both those proteins more often than the solid-comedo type.

Pancreatic Fibrosis Correlates With Delayed Gastric Emptying After Pylorus-Preserving Pancreaticoduodenectomy With Pancreaticogastrostomy

ObjectiveTo show that residual pancreatitis delays gastric emptying, the authors used surgical specimens and studied gastric stasis after pylorus-preserving pancreaticoduodenectomy (PPPD). Summary Background DataDelayed gastric emptying is a leading cause of complications after PPPD, occurring in 30% of patients. The pathogenesis of delayed gastric emptying remains unclear. MethodsSurgical specimens of the pancreas from 25 patients undergoing PPPD and pancreaticogastrostomy were collected and examined by microscopy according to progressive pancreatic fibrosis and divided into three groups: no fibrosis, periductal fibrosis, and intralobular fibrosis. The authors then measured gastric output from the nasogastric tube, pancreatic output from the pancreatic tube, and the time until patients tolerated a solid diet. ResultsPancreatic juice output was significantly related to the degree of pathologic findings, and gastric output was inversely related to them. A significant prolongation of postoperative solid diet tolerance correlated with increased pancreatic fibrosis and gastric fluid production. ConclusionsPancreatic fibrosis and increased gastric fluid production correlate with delayed gastric emptying after PPPD with pancreaticogastrostomy.

Loss of heterozygosity and microsatellite instability in ductal carcinoma in situ of the breast

To investigate the alterations of genetic instabilities in carcinogenesis of the breast, we analyzed the allelotypic profile of 65 ductal carcinomas in situ (DCIS), compared with that of 207 invasive ductal carcinomas (IDC) of the breast. These studies were performed by means of examining microsatellite-length polymorphisms at seven loci (AluVpa, ESR, D11S988, D13S267, D16S398, D17S1159, and D17S855) from microdissected paraffin sections. Allelic loss or imbalance, considered a loss of heterozygosity (LOH), tended to be more frequently seen in IDC than in DCIS. In particular, the frequency of LOH at the 17p locus was significantly higher in IDC than in DCIS (42 vs. 23%, P=0.022). LOH in DCIS was most frequently seen at D16S398 (26%). LOH frequency at D16S398 in low- and intermediate-grade DCIS was higher than that in high-grade DCIS, while LOH frequencies at D11S988 and D17S1159 in low- and intermediate-grade DCIS was lower than those in high-grade DCIS. LOH frequency at D11S988 in non-comedo type DCIS was lower than that in comedo type DCIS. Furthermore, the frequency of microsatellite instability (MSI) at only one locus in DCIS (28%) was statistically higher than that in IDC (6%) (P<0.001), while there was no difference between the frequency of MSI at multiple loci in DCIS (6%) and that in IDC (3%). Together, these observations indicate that chromosomal losses of 16q may occur in low- and intermediate-grade DCIS and those of 11p and 17p may occur high-grade DCIS, and that MSI occurring at only one locus is not yet clear and MSI at multiple loci is uncommon in not only IDC but also DCIS of the breast.

SOLITARY RECTAL ULCER SYNDROME ACCOMPANIED BY SUBMUCOSAL INVASIVE CARCINOMA

We report a case of carcinoma in solitary rectal ulcer syndrome. The diagnosis was made by colonoscopic appearance and biopsy. A tumor measuring 0.9 × 0.6 cm was found in a resected solitary rectal ulcer. The lesion exhibited typical histological features of solitary rectal ulcer syndrome, with a well differentiated adenocarcinoma invading submucosal layers and some dysplastic glands. We believe that the adenocarcinoma represents a malignant transformation from solitary rectal ulcer syndrome, because similar to longstanding chronic idiopathic colitis, colorectal dysplasia and carcinoma may develop.

Microsatellite instability in in situ and invasive sporadic breast cancers of Japanese women.

We studied the timing of microsatellite instability (referred to as replication error; RER) presentation during human breast carcinogenesis using tissue microdissected from both in situ and invasive breast cancers of Japanese women. We analyzed 100 breast cancer specimens for RER at nine genomic loci on seven chromosomes. Eight of the 100 cases (8%) were RER-positive at one or more chromosomal loci. Additionally; we obtained genomic DNA from two of four RER-positive patients with an intraductal component, both of which showed microsatellite instability in in situ foci. This finding indicates that microsatellite instability may be an early event during human breast carcinogenesis.

Immature teratoma producing alpha-fetoprotein without components of yolk sac tumor in the pineal region

Abstract A case of pineal region tumor in a 9-year-old boy with a high serum alpha fetoprotein (AFP) level is reported. The serum levels of beta-human chorionic gonadotropin (HCG) and placental alkaline phosphatase (PLAP) were not elevated. The tumor was composed of radiologically different components and was removed surgically. Postoperative radiation therapy was performed and the serum level of AFP gradually declined to the normal range. The pathological diagnosis was immature teratoma, and no elements of yolk sac tumor or embryonal carcinoma were found. In the immunohistochemical study, AFP was detected in the cytoplasm of gastrointestinal-type epithelium and primitive neuroepithelial element. This is considered a rare case of intracranial immature teratoma in which AFP was detected immunohistochemically in the columnar epithelium and immature neural tissue.

p53 protein and proliferating cell nuclear antigen in eccrine poroma and porocarcinoma. an immunohistochemical study.

The expression of p53 protein and proliferating cell nuclear antigen (PCNA) in 18 eccrine poromas and four po-rocarcinomas was examined by immunohistochemistry. Immunoreactivity for p53 in eccrine poromas was negative in five tumors, <10% of tumor cells in one (low ex-presser), 10–50% in seven (moderate expressers), and <50% in five (high expressers). The duration of the presence before excision of p53-negative poromas was shorter, and the size of these tumors was smaller in comparison with those of p53-positive poromas. Moreover, all high expressers showed some atypical cells in limited areas. Of the four porocarcinomas, three were high expressers and one a low expresser of p53 protein. The low-expresser tumor showed clinically more rapid growth and histologically no poromatous foci in contrast to the high expressers. No significant correlation was found between p53 protein expression and PCNA positive staining in either eccrine poromas or porocarcinomas. However, the percentages of PCNA-positive cells in porocarcinomas were significantly higher than those in poromas, with no overlapping values. These results suggest that the PCNA index is useful in differentiating between poroma and porocarcinoma and that p53 gene mutation may occur in long-standing eccrine poromas and correlate with atypical changes in histology as well as subsequent progression to porocarcinoma.

BREAST CANCER WITH OSTEOCLAST‐LIKE MULTINUCLEATED GIANT CELLS

A case of breast cancer containing osteoclast‐like multinucleated giant cells was examined cytologically, light and electron microscopically to find morphological evidences suggesting the origin of the giant cells. There were multiple evidences showing the same carcinomatous origin of each cell including osteoclast‐like multinucleated giant cells. ACTA PATHOL. JPN. 34: 1475–1484. 1984.

Detection of DNA Fragmentation in Human Breast Cancer Tissue by an Antibody Specific to Single-stranded DNA.

While there have been many reports concerning the clinical significance of bcl-2 expression in human breast cancer, little is known about apoptosis in primary breast cancers. We immunohistochemically examined DNA fragmentation in 107 primary human breast cancers from Japanese women using an antibody specific to single-stranded DNA. The apoptosis index, calculated as the product of the positive cell number and the cellularity coefficient, ranged from 0 to 48. The average incidence of apoptosis was calculated as 0.1% of tumor cells. No relationships were observed among the apoptosis index, expression of bcl-2, and the histological grade of the tumors. Almost all apoptotic cells were phagocytosed by surrounding tumor cells immediately after DNA fragmentation. Apoptotic body formation was rare. The apoptotic cells seemed to be degraded within phagocytes, leaving no trace of apoptosis except the tiny shells of nuclei. The intensive phagocytic reaction might be one of the main reasons for the low incidence of apoptosis in human breast cancers.