Immunohistochemical analysis on biological markers in ductal carcinoma in situ of the breast.

BACKGROUND: The increasing use of mammographic screening has led to an increased detection of ductal carcinoma in situ (DCIS) of the breast. The detailed biological characteristics of DCIS and a new classification of DCIS based on these characteristics are needed. METHODS: Immunohistochemical studies were performed to assess the expression of c-erbB-2 (ErbB-2), estrogen receptor (ER), p53 and proliferative activity (Ki-67) in 65 patients with pure DCIS and 60 with invasive ductal carcinoma (IDC). We classified pure DCIS tumors using three classifications, the architectural, Nottingham, and Van Nuys classifications. RESULTS: ErbB-2, ER and p53 staining was positive in 34%, 66% and 21% of patients with DCIS, respectively, and 58%, 42% and 33% in patients with IDC, respectively. Ki-67 stained positively in 1.5% of patients with DCIS and 11.2% of patients with IDC. The comedo type showed a high rate of positive ErbB-2 and p53 staining. The cribriform and papillary types showed a high rate of positive ER staining. Under the Van Nuys classification, ErbB-2, p53 and Ki-67 expression were highest in the group with high nuclear grade and lowest in the group with non-high nuclear grade without necrosis. CONCLUSION: Although the biological markers of IDC tended to suggest aggressive behavior more so than those of DCIS, these differences were based on the histological sub-type, comedo or non-comedo. The Van Nuys classification best defined the subgroups of DCIS with a distinct expression pattern of biological markers, and the best candidates for breast-conserving surgery.

Readministration of tamoxifen after adjuvant therapy for recurrent breast cancer.

BACKGROUND: Previous series concerning tamoxifen (TAM) rechallenge did not obtain satisfactory results. Using stricter criteria, we now assess the usefulness of readministration of TAM as an initial therapy for patients with recurrent breast cancer. METHOD: The eligibility criteria were postmenopausal, estrogen receptor (ER) positive or unknown, at least 12 months of adjuvant TAM, a 6-month or longer drug-free period and no previous therapy after recurrence. A total of 10 patients were enrolled. TAM was administered in daily doses of 20 or 30 mg. RESULTS: The mean age of the patients at the time of recurrence was 64.8 years. The receptor status was positive in 8 patients and unknown in 2. The median disease-free interval (DFI) after mastectomy was 71.7 months. A complete response was observed in one patient, a partial response in 6, stable disease in 2, and progression in one. The response rate was thus 70%, with an additional two patients showing no progression over 6 months. Although only one patient with a DFI of less than 48 months showed a positive response, all patients with a DFI longer than 48 months showed a clinical response. The duration of response was less than 12 months in 3 patients and longer in 4. CONCLUSION: The post-adjuvant readministration of tamoxifen is a useful first choice therapy for postmenopausal recurrent breast cancer patients with positive ER and longer DFI.

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.

The clinical value of serum CA15-3 assay postoperatively in breast cancer patients.

Serum carbohydrate antigen (CA15-3) values were examined in 300 normal subjects in order to determine the standard value of this antigen. The clinical relevance of repeatedly assaying this marker in patients with or without recurrent breast cancer postoperatively was compared with assaying the serum carcinoembryonic antigen (CEA) values. The upper limit of CA15-3 was calculated as being 25.3 U/ml in the normal subjects and the distributions of CA15-3 values were not markedly different among the normal subjects, even if they had been selected according to sex or age. Moreover, no differences were observed among normal women who had been randomly selected according to the age distribution of the breast cancer patients. Thirty samples taken from the breast cancer patients postoperatively revealed values of higher than 25 U/ml and 73 samples showed lower levels. The serum CEA values were positive in 16 samples and negative in 85 samples. Although the accuracy of the CEA assay was about 10 per cent higher than that of the CA15-3 assay, its low positive rate was unsatisfactory for effective use in the breast clinic. The results of this study suggest that serum CA15-3 is not detectable unless there is a relatively large number of tumor cells. The higher false positive rate of the CA15-3 assay should therefore be considered as suggesting recurrence.

[A case of stromal sarcoma of the breast occurring after augmentation mammaplasty].

The first case of stromal sarcoma of breast occurring after augmentation mammaplasty is reported. The patient is 55-year-old Japanese woman who had received injection augmentation mammaplasty 19 years earlier. Both breasts indurated soon after mammaplasty and the patient felt a severe pain in her right breast for about 6 months before seeking treatment. Stromal sarcoma of the breast was proven by a subcutaneous mastectomy, and the determined histological subclassification was a malignant fibrous histiocytoma (MFH). The patient died with tumor recurrence 14 months after her first admission. The tumor cells were found to have invaded the surrounding tissue, such as the nerves, the muscle, the lymphatic vessels, and a severe reactive inflammation, caused by the injected material, was noticed.

[The localization of estrogen receptor (ER) in target tissues as visualized by immunoperoxidase method using anti-ER antibody].

It is very important to detect the intracellular distribution and dynamics of estrogen receptor (ER) in order to make the mechanisms of estrogen action clear. In a recent report, monoclonal antibodies localized ER only in the nucleus of target cells under both the presence and absence of estrogen. We purified cow and human uterine ER and induced specific polyclonal anti-ER antibodies. In this report, the specificity of immunological reactivity of anti-ER antibodies was examined, and the distribution of ER in the target tissues was detected by the indirect immunoperoxidase method. The specific staining was observed in the nucleus and cytoplasm of the endo- and myometrium of cow, rat and human uterus. In the nontarget organs, such as kidney and muscle, the specific staining was not detected. The cytoplasm of MCF-7 cells and immature rat uterine tissues were mainly stained without estrogen; however, the nuclear staining increased obviously after the estrogen priming. The cytoplasmic and/or nuclear staining was positive in 63% of 21 human breast cancer cases. This immunohistochemical assay (IHC) method of ER measurement was compared with the DCC assay method, a biochemical assay based on hormone binding ability. The concomitant positivity or negativity in DCC and IHC were observed as 61.9% (13 cases) or 19.0% (4 cases), respectively. Therefore, these two methods showed the same assay results in 81.0% of human breast cancer tissues.