Immunohistochemical demonstration of metallothionein in normal human breast tissue and benign and malignant breast lesions

Metallothioneins (MTs) are a set of low molecular weight proteins with a high binding affinity to metal ions. MT over-expression has been recently demonstrated in invasive ductal carcinoma of the breast with poor clinical prognosis. In the present study, MTs have been immunohistochemically investigated in normal human breast tissue and a variety of benign, pre-invasive, and malignant breast lesions. In normal breast tissue, MTs were present in myoepithelial cells whereas the vast majority of luminal cells were MT negative. In lesions without increased cancer risk (adenosis and scleradenosis), MT was only immunolocalized in myoepithelial cells. In papillomas, MT was also found exclusively in myoepithelial cells. In most cases of epitheliosis, both the luminal and myoepithelial cells expressed MT. Atypicallobular hyperplasia, lobular carcinomain situ, and 13/15 invasive lobular carcinomas showed no MT over-expression. The two invasive lobular carcinomas with MT over-expression were classified as pleomorphic lobular carcinomas with apocrine differentiation. In contrast to lobular cancerization, 12/24 ductalin situ carcinomas and 9/20 invasive ductal carcinomas showed MT over-expression.In situ components found within invasive ductal carcinomas usually reflected the MT status of their invasive counterpart. It is concluded from our immunohistochemical results that breast carcinoma cases with MT overexpression arise from lesions which also show MT overexpression. Thus MT expression in carcinomas may be regarded as a genuine feature of the tumour cells and seems not to be related to endogenous or exogenous factors known to induce MT synthesis.     

Breast cancer detection by dedicated breast positron emission tomography according to the World Health Organization classification of breast tumors

ObjectiveConsidering the difficulty in detecting primary breast cancers using whole-body positron emission tomography (WBPET) owing to its limited spatial resolution, we aimed to evaluate the detectability of breast cancer by ring-type dedicated breast PET (DbPET) on the World Health Organization (WHO) histological classification in comparison with WBPET.MethodsA total of 938 patients with breast cancer underwent WBPET and ring-type DbPET, and 1021 lesions were histologically assessed based on the WHO classification of tumors of the breast. The findings of WBPET and DbPET were retrospectively evaluated and compared.ResultsThe size-related sensitivity of DbPET was superior to that of WBPET for subcentimetric tumors (81.9% vs. 52.4%, P < 0.001). The histological distribution was as follows: 11 lobular carcinoma in situ, 158 ductal carcinoma in situ, 738 infiltrating duct carcinoma not otherwise specified (NOS), 12 lobular carcinoma NOS, 40 mucinous adenocarcinoma, 13 tubular carcinoma, 36 invasive breast carcinoma others, and 13 papillary neoplasms. WBPET had low sensitivity for lobular carcinoma in situ, ductal carcinoma in situ, lobular carcinoma NOS, mucinous adenocarcinoma, and tubular carcinoma. DbPET showed improved sensitivity for all the above except lobular and tubular carcinoma. The maximum standardized uptake values (SUVmax) of DbPET were significantly higher than those of WBPET for histological types, excluding lobular carcinoma in situ. The SUVmax of papillary neoplasms was high regardless of low-grade histology and Ki-67 labeling index.ConclusionsDBPET was found to have high sensitivity and SUVmax values for all histologic types that showed low sensitivity of detection on WBPET, except lobular carcinoma in situ.     

Correlation between karyotypic pattern and clinicopathologic features in 125 breast cancer cases

A correlation analysis was performed on 125 cytogenetically characterized breast cancer cases to assess the relationship between the tumor karyotype and clinicopathologic features. The carcinomas of young women had a higher modal chromosome number than those of older women. The number of chromosomal aberrations and modal chromosome number were also found to correlate with the histologic type, grade and mitotic activity of the tumor. Whereas all lobular carcinomas were karyotypically normal or near-diploid, more than 3 aberrations and sometimes near-triploid or near-tetraploid karyotypes were common findings in ductal carcinomas, especially in grade-III tumors and in tumors showing high mitotic activity in vivo. Karyotypes with cytogenetically unrelated clones and unbalanced structural chromosomal rearrangements were more frequent in infiltrating than in in situ carcinomas but, at least as far as the second of these 2 characteristics is concerned, especially in infiltrating carcinomas that also had an in situ component. The presence of cytogenetic polyclonality correlated with tumor grade. Although recurrent chromosome aberrations were significantly more common in ductal than in lobular carcinomas, none of these breast cancer-associated anomalies seemed to be specific for any particular clinicopathologic parameter. The associations between modal chromosome number and mitotic activity and between cytogenetic polyclonality and tumor grade were found to be statistically significant in multivariate models. No correlation was seen between the karyotypic findings and tumor size or the presence of axillary-lymph-node metastases. © 1996 Wiley-Liss, Inc.     

E-Cadherin Expression Correlates With Histologic Type But Not Tumour Grade in Invasive Breast Cancer

The traditional classification of infiltrating breast carcinomas into ductal and lobular can be diagnosticallychallenging in a small proportion of cases with equivocal histological features and in in-situ lesions withoverlapping features. Distinguishing between the infiltrating ductal (IDC) and lobular (ILC) carcinomas isclinically important because of the different pattern of systemic metastases and prognostic evaluation. E-cadherinis a potentially useful immunohistochemical marker which may serve to differentiate between the two tumourtypes. We therefore studied E-cadherin expression in 32 cases of breast carcinomas comprising 16 IDCs and 16ILCs. The correlation between E-cadherin expression and the histological grade of IDCs was also analysed. Ourresults showed complete loss of E-cadherin expression in all ILCs, while the IDCs consistently showed variableE-cadherin positivity. No significant correlation was found between E-cadherin expression and the histologicalgrade of IDCs. We conclude from this study that E-cadherin is a useful marker to differentiate between IDCand ILC of the breast. A larger study of IDCs is now needed to further evaluate the correlation between Ecadherinand tumour grade to estimate its prognostic potential.     

Immunohistochemical distribution of c-erbB-2 in infiltrating and in situ breast cancer

An immunohistochemical study of c-erbB-2 expression was performed on invasive and in situ breast cancer. Strong membrane staining was seen in 16% of the infiltrating ductal carcinomas and 44% of the in situ lesions. c-erbB-2 was overexpressed in ductal rather than lobular tumours. Our results indicate that a small sub-group of breast carcinomas are associated with over-expression of this oncogene which may define an important subgroup of in situ and infiltrating ductal carcinomas.     

The distribution of carcinoembryonic antigen in breast carcinoma. Diagnostic and prognostic implications

Carcinoembryonic antigen (CEA) has been shown to be a useful tumor marker in patients with breast carcinoma. The unlabeled antibody immunoperoxidase technique was used to localize CEA in 93 cases of primary breast carcinoma, 15 cases of atypical duct papillomatosis, and 4 cases of duct papilloma. Normal breast epithelium and breast epithelium in fibrocystic disease did not stain positively for CEA. Twenty-four of 27 (88%) intraductal carcinomas, and 47 of 69 (68%) infiltrating duct carcinomas were CEA positive. In contrast, only 5 of 21 (23%) in situ lobular carcinomas and 8 of 24 (33%) infiltrating lobular carcinomas were positive for CEA. All 15 cases of atypical epithelial papillomatosis were negative, whereas 1 of the 4 cases of duct papilloma exhibited microscopic foci of weak CEA positivity. There was a trend for infiltrating duct carcinomas, 3 cm in diameter or smaller, staining strongly positive for CEA, to be associated with synchronous axillary lymph node metastases (P = 0.09). Tumor heterogeneity was a constant feature of CEA staining with positivity varying from region to region and even from cell to cell. Positive immunohistochemical staining for CEA may play an adjunctive role in discriminating intraductal carcinoma from atypical papillary ductal proliferations.     

The influence of infiltrating lobular carcinoma on the outcome of patients treated with breast-conserving surgery and radiation therapy

Background: The role of conservative surgery and radiation therapy (CS and RT) in the treatment of patients with infiltrating ductal carcinoma is well established. However, the efficacy of CS and RT for patients with infiltrating lobular carcinoma is less well documented. The goal of this study was to examine treatment outcome after CS and RT for patients with infiltrating lobular carcinoma and to compare the results to those of patients with infiltrating ductal carcinoma and patients with mixed ductal–lobular histology. Methods: Between 1970 and 1986, 1624 patients with Stage I or II invasive breast cancer were treated with CS and RT consisting of a complete gross excision of the tumor and 6000cGy to the primary site. Slides were available for review for 1337 of these patients (82%). Of these, 93 had infiltrating lobular carcinoma, 1089 had infiltrating ductal carcinoma, and 59 had tumors with mixed ductal and lobular feature these patients constitute the study population. The median follow-up time for surviving patients was 133 months. A comprehensive list of clinical and pathologic features was evaluated for all patients. Additional histologic features assessed for patients with infiltrating lobular carcinoma included histologic subtype, multifocal invasion, stromal desmoplasia, and the presence of signet ring cells. Results: Five and 10-year crude results by site of first failure were similar for patients with infiltrating lobular, infiltrating ductal, and mixed histology. In particular, the 10-year crude local recurrence rates were 15%, 13%, and l3% for patients with infiltrating lobular, infiltrating ductal, and mixed histology, respectively. Ten-year distant/regional recurrence rates were 22%, 23%, and 20% for the three groups, respectively. In addition, the 10-year crude contralateral breast cancer rates were 4%, 13% and 6% for patients with infiltrating lobular, infiltrating ductal and mixed histology, respectively. In a multiple regression analysis which included established prognostic factors, histologic type was not significantly associated with either survival or time to recurrence. Conclusions: Patients with infiltrating lobular carcinoma have a similar outcome following CS and RT to patients with infiltrating ductal carcinoma and to patients with tumors that have mixed ductal and lobular features. We conclude that the presence of infiltrating lobular histology should not influence decisions regarding local therapy in patients with Stage I and II breast cancer.     

Expression of hyaluronan in benign and malignant breast lesions

Hyaluronan (HA) is one of the extracellular-matrix components involved in wound healing, tumour growth and metastasis. Due to the limited data on HA expression in benign and malignant breast lesions, we analyzed its presence in these lesions by using the biotinylated-hyaluronan-binding region and the link-protein complex (bHABC) of cartilage proteoglycan as a specific probe. In all benign breast lesions, the expression of HA was restricted to the stromal connective tissue, the ductal epithelial cells being completely devoid of HA. In malignant breast tumours, the intensity of stromal HA staining was significantly stronger than in benign lesions. In addition, HA was detected on cell membranes or in cytoplasms of adenocarcinoma cells, in some cases of ductal carcinoma in situ and in 31% of malignant tumours. The staining pattern was mostly similar in all breast-cancer types studied, i.e., ductal, lobular, tubular, mucinous and medullary. In ductal breast cancer, intense HA expression in stroma and carcinoma cells correlated statistically significantly to poor differentation of carcinoma, suggesting that altered HA expression may affect the mechanisms of breast-cancer progression. Int. J. Cancer 74:477–481, 1997. © 1997 Wiley-Liss, Inc.     

Nuclear morphometry of benign and malignant breast lesions

The mean nuclear area (MNA) of mammary gland epithelium was measured in 403 breast specimens, comprising 239 invasive carcinomas, 49 carcinomas in situ, 45 cases of fibrocystic disease (f.c.d.) with intraductal epithelial hyperplasia, and 60 cases of f.c.d. without intraductal hyperplasia. Normal breast tissue adjacent to other benign or malignant lesions was measured in 170 specimens. Statistical analysis revealed no difference between the MNA of invasive ductal carcinoma and ductal carcinoma in situ. The MNA of lobular and ductal carcinomas were significantly different. Significant differences were also found between ductal carcinoma and the two classes of f.c.d. The MNA of f.c.d. with and without intraductal hyperplasia were also significantly different, the former having the highest MNA. All breast lesions showed MNA significantly higher than that of normal breast epithelium. These findings show that there is a gradual increase in MNA from the baseline value of normal breast epithelium, via fibrocystic disease without and with intraductal proliferation to invasive carcinomas. Measurement of MNA may aid in pinpointing cases of intraductal epithelial hyperplasia with malignant potential.     

The ABO(H) cell surface antigens in carcinoma and benign lesions of the breast

The ABO(H) cell surface antigens of 13 breast carcinomas and 17 benign breast lesions were tested with a specific red cell adherence assay (SRCA). All 13 breat carcinomas, including 2 lobular carcinomas in situ and 1 noninfiltrating ductal carcinoma, had lost their ABO(H) surface antigens. Fourteen of 17 benign breast lesions had retained their ABO(H) surface antigens. The benign lesions losing their antigens were 1 case each of atypical intraductal hyperplasia, sclerosing adenosis, and intraductal papilloma. SRCA may be a predictor of which benign breast lesions are in fact premalignant.     

Signet ring carcinoma of the female breast: a clinicopathologic analysis of 24 cases

Signet ring carcinomas of the breast have been separated recently as an aggressive subtype of breast cancer, distinct from mucinous (colloid) carcinomas. Twenty-four cases of signet ring breast cancer (2% of total breast cancers at the authors' institution) were analyzed. The authors' study indicates that histogenetically such lesions are derived from lobular, not ductal, cells since mucin patterns and ultrastructural features are shared. In addition, in each of our 24 cases, infiltrating lobular carcinoma was identified; in 11 of these (46%) lobular carcinoma in-situ (LCIS) was also noted. Signet ring carcinomas show an unusual metastatic pattern with a propensity to involve serosal surfaces and mimicking gastrointestinal disease or retroperitoneal fibrosis. These tumors are associated with a poor prognosis, with 60% of our 24 patients dead of disease at 7 years. The distinctive clinical and pathologic features of signet ring carcinoma warrant separation of this group of tumors from other forms of breast cancer.     

Tissue binding of lectins in disorders of the breast

Twenty breast lesions including seven scirrhous ductal carcinomas, one infiltrating lobular carcinoma, one colloid carcinoma, four fibroadenomas, and seven cases of fibrocystic disease were analyzed by fluorescence microscopy for the presence and distribution of lectin-binding carbohydrates. Paraffin-embedded tissue sections were tested with wheat germ agglutinin (WGA), Ricin communis agglutinin I (RCA I), peanut agglutinin (PNA), Soybean agglutinin (SBA), Dolichos biflorus agglutinin (DBA), Ulex europaeus agglutinin I (UEA I), and concanavalin A (Con A). Brightest and most consistent staining regardless of the nature of the breast lesion was obtained with WGA followed in approximate order of staining intensity by RCA, PNA, SBA/DBA and Con A. UEA I stained many of the benign breast lesions but no malignant lesions. Lectin binding carbohydrate in benign lesions was localized mainly along the apices of mammary epithelial cells but there was considerable variation in staining patterns among malignant tumors. The fluorescence microscopic arrangement of lectin binding carbohydrate appears distinct for each malignant neoplasm of breast but is more consistent in benign conditions.     

Expression of pp32 gene family members in breast cancer

The pp32 gene family consists of at least three closely related members, pp32, pp32r1 and pp32r2. In spite of a high degree of identity at the nucleotide level, pp32 functionally behaves as a tumor suppressor where as pp32r1 and pp32r2 are pro-oncogenic. The purpose of this pilot study was to determine pp32-related expression and whether alternative gene use among the pp32 family members occurred in human breast cancer. As a first step, in situ hybridization with a riboprobe capable of hybridizing with all the three members showed abundant pp32-related mRNA in benign ducts and acini and in infiltrating ductal carcinomas. A total of 100/102 cases were positive. Further, a detailed molecular analysis by RT-PCR, cloning, and sequencing was performed in five frozen infiltrating breast carcinomas and matched benign breast tissues. Oncogenic pp32r1 (5/5) and pp32r2 (3/5) expression was observed in carcinomas where as benign breast tissues expressed pp32. 4/5 carcinomas continued to express pp32 but one was devoid of pp32 expression. These results suggest that alternative expression of pp32 family members may be common in human breast cancer and the analysis of the profile of pp32-related expression might be helpful in understanding the role of these genes in breast cancer pathogenesis.     

Lewis blood group antigens (a and b) in human breast tissues. Loss of Lewis-b in breast cancer cells and correlation with tumor grade.

The Lewis blood group antigens (Lewis-a [Lea] and Lewis-b [Leb]) and their precursors are present on various normal human epithelial cell surfaces. The authors examined 35 benign and malignant human breast lesions using mouse monoclonal antibodies to synthetic Lea and Leb carbohydrate antigens. Normal breast lobular and ductal epithelium and benign breast lesions showed Leb staining but only occasional Lea staining. In invasive ductal carcinomas of breast, of all grades, a loss of Leb antigen staining was found in 80% of the breast cancer cases. This reduced Leb antigen expression increased with the grade of malignancy. Therefore, the loss of Leb blood group antigens on breast cancer cell surfaces may suggest altered fucosylation patterns in malignant cells and reflect the degree of malignancy and/or invasiveness.     

Clinical characteristics of different histologic types of breast cancer

Breast cancer is a heterogeneous disease, though little is known about some of its rarer forms, including certain histologic types. Using Surveillance, Epidemiology, and End Results Program data on 135 157 invasive breast cancer cases diagnosed from 1992 to 2001, relationships between nine histologic types of breast cancer and various tumour characteristics were assessed. Among women aged 50-89 years at diagnosis, lobular and ductal/lobular carcinoma cases were more likely to be diagnosed with stage III/IV, > or =5.0 cm, and node-positive tumours compared to ductal carcinoma cases. Mucinous, comedo, tubular, and medullary carcinomas were less likely to present at an advanced stage. Lobular, ductal/lobular, mucinous, tubular, and papillary carcinomas were less likely, and comedo, medullary, and inflammatory carcinomas were more likely to be oestrogen receptor (ER) negative/progesterone receptor (PR) negative and high grade (notably, 68.2% of medullary carcinomas were ER-/PR- vs 19.3% of ductal carcinomas). In general, similar differences were observed among women diagnosed at age 30-49 years. Inflammatory carcinomas are associated with more aggressive tumour phenotypes, and mucinous, tubular, and papillary tumours are associated with less aggressive phenotypes. The histologic types of breast cancer studied here differ greatly in their clinical presentations, and the differences in their hormone receptor profiles and grades point to their likely different aetiologies.     

Influence of infiltrating lobular histology on local tumor control in breast cancer patients treated with conservative surgery and radiotherapy

To determine the influence of infiltrating lobular histology on local tumor control, the authors studied 49 patients with Stages I and II infiltrating lobular breast carcinoma treated by limited excision of the tumor and radiotherapy between 1968 and 1981 (median follow-up, 75 months). Results were compared with those in 561 cases of infiltrating ductal carcinoma similarly treated during the same period. The 5-year actuarial risk of local recurrence was similar for patients with infiltrating lobular or ductal carcinoma when the latter was evaluated as a single group (12% versus 11%). However, the 12% 5-year actuarial local recurrence risk for patients with infiltrating lobular carcinoma was intermediate between that for patients with infiltrating ductal carcinomas with an extensive intraductal component (23%) and those without an extensive intraductal component (5%). The pattern of recurrence in the breast was similar in the infiltrating lobular and ductal groups. All recurrences in patients with infiltrating lobular carcinoma and 80% of recurrences in the infiltrating ductal group occurred in the vicinity of the primary tumor (P = not significant). None of the clinical or morphologic features examined significantly influenced the risk of local recurrence in patients with infiltrating lobular carcinoma. The authors conclude that combined conservative surgery and radiotherapy appear to be a reasonable treatment option for patients with infiltrating lobular carcinoma, but further follow-up will be required to confirm these results.     

HMGA1 protein overexpression in human breast carcinomas: correlation with ErbB2 expression.

We measured, by immunohistochemistry, HMGA1 protein expression in 212 breast tissue specimens: 6 normal samples, 28 hyperplastic lesions (13 with cellular atypia), 11 fibroadenomas, 10 in situ ductal carcinomas, 144 ductal carcinomas, and 13 lobular carcinomas. HMGA1 was not expressed in normal breast tissue; HMGA1 staining was intense in 40% of hyperplastic lesions with cellular atypia and in 60% of ductal carcinomas and weak in fibroadenomas and in hyperplastic lesions without cellular atypia. Because HMGA1 expression was similar among ductal breast carcinomas with different histologic grading, we evaluated the association between HMGA1 expression and that of other markers of breast carcinoma invasion (estrogen and progesterone receptors, Ki-67 antigen, and ErbB2) in 21 cases of grade 3 breast ductal carcinomas and 7 cases of breast lobular carcinomas. We found that HMGA1 expression tended to be associated only with c-erbB-2 expression (Spearman rho: 0.36; P=0.065). Taken together, these results suggest that HMGA1 expression might be a novel indicator for the diagnosis and prognosis of human breast cancer.     

Ultrasound-guided large-core needle biopsies of breast lesions: analysis of 962 cases to determine the number of samples for reliable tumour classification

The objective of this one-institutional study was to determine the number of large-core needle biopsies (LCNB), under three-dimensional ultrasound (3D-US) validation, that are sufficient to obtain a reliable histological diagnosis of a sonographically detectable breast lesion. Over an 28-month period, 962 sonographically guided LCNB were performed under 3D-US validation to assess 962 breast lesions. All biopsies were carried out with an automated core biopsy device fitted with 14-gauge (22 mm excursion) needles. Data of 962 biopsied breast lesions were gathered. Surgical follow-up was available for 659 lesions. Breast malignancies were diagnosed by ultrasound-guided LCNB with a sensitivity of 98.2% by performing three cores per lesion. In few cases, the open surgical specimen revealed the presence of invasive carcinomas in contrast to initial LNCB-based classification as ductal carcinomas in situ (DCIS, 11 lesions), lobular carcinoma in situ (one lesion), and atypical ductal hyperpasia (one lesion). Owing to disagreement between classification based on breast-imaging and histological findings, eight of these tumours were subsequently excised. Of the lesions that were removed at the patients' requests despite benign LCNB diagnosis, two were infiltrating carcinoma and one a DCIS. We demonstrate that three 3D-US-guided percutaneous core specimens are sufficient to achieve tissue for a reliable histological assessment of sonographically detectable breast lesions and allow the detection of malignancies with high sensitivity and low rate of false-negative diagnoses.     

Altered expression of E-cadherin in breast cancer. patterns, mechanisms and clinical significance

Reduced cell adhesion brought about by altered surface expression of E-cadherin has been implicated in invasive and metastatic malignant growth. We investigated the patterns of immunohistochemical E-cadherin expression in 120 breast carcinomas. Furthermore, we analysed DNA from the same samples for loss of heterozygosity (LOH) using three separate microsatellite markers on chromosome 16q22.1. Finally, the clinical outcome was ascertained for 108 patients. 19% (18/97) of infiltrating ductal carcinomas showed complete loss of E-cadherin expression compared with 64% (9/14) of infiltrating lobular carcinomas. LOH was detected in 46% (24/52) of infiltrating ductal carcinomas and 89% (8/9) of infiltrating lobular carcinomas. In the infiltrating lobular carcinomas, LOH was associated with complete loss of cell membrane expression of E-cadherin, although a cytoplasmic expression pattern was evident. In contrast, this association was not seen in the infiltrating ductal carcinomas. In a multivariate analysis, loss of E-cadherin expression was shown to be a significant independent risk factor for a poorer disease-free survival (P=0.019), in particular in the node-negative subset of patients (P=0.029). Significance was also approached for breast cancer corrected survival (P=0.056). We conclude that different mechanisms are involved in the altered E-cadherin expression seen in different subtypes of breast carcinomas. Furthermore, we implicate loss of E-cadherin, regardless of the genetic causes, as an independent prognostic marker for disease recurrence, especially in node-negative breast cancer patients, irrespective of the histological type.     

Cytogenetic findings in invasive breast carcinomas with prognostically favourable histology: A less complex karyotypic pattern?

Seventeen invasive primary breast carcinomas of histological types usually considered to be prognostically favourable (2 medullary, 3 papillary, 3 tubular, and 9 mucinous carcinomas) were analysed as part of an ongoing study of the cytogenetics of breast cancer. Thirteen of the tumours (7 mucinous, 2 medullary, 2 papillary, and 2 tubular carcinomas) showed clonal chromosome aberrations. Trisomy 7 and i(1q) were present as sole and recurrent aberrations in the mucinous tumours. The 2 tubular carcinomas and 1 papillary carcinoma had simple numerical changes only, whereas the second papillary tumour had a balanced translocation as the sole anomaly. Both medullary carcinomas had chromosome numbers in the triploid range, with clones displaying structural and numerical changes. Our data, especially when collated with information on previously published cases of mucinous, papillary, tubular, and medullary breast carcinomas, show that the former 3 histological types, in keeping with their recognised prognostic advantage, appear to exhibit relatively simple karyotypic changes, i.e., numerical aberrations, balanced translocations, and near-diploid chromosome numbers. Medullary carcinomas on the other hand, appear to have more complex karyotypes, similar to those described for the more common ductal and lobular subtypes of breast carcinoma. Int. J. Cancer (Pred. Oncol.) 79:361–364, 1998. © 1998 Wiley-Liss, Inc.