Elsevier

The Lancet

Volume 349, Issue 9064, 24 May 1997, Pages 1505-1510
The Lancet

Articles
Pathology of familial breast cancer: differences between breast cancers in carriers of BRCA1 or BRCA2 mutations and sporadic cases

https://doi.org/10.1016/S0140-6736(96)10109-4Get rights and content

Summary

Background

A few breast cancer cases are attributable to a hereditary predisposition to the disease. We aimed to compare the histological features of breast cancer in women carrying mutations in the susceptibility genes BRCA1 and BRCA2 with controls unselected for family history.

Methods

The morphological characteristics of specimens from 440 patients with familial breast cancer, including 118 in carriers of BRCA1 mutations and 78 in carriers of BRCA2 mutations, were compared with those from 547 age-matched controls, unselected for family history, by seven pathologists

Findings

Cancers in carriers of BRCA1 (p<0·0001) and BRCA2 mutations (p=0·04) were, on average, of a higher overall grade than in controls. For example, the proportions in grade 3 were 66% of 139, 41% of 58 and 36% of 368 specimens, respectively. However, when the three grade indices were considered independently, breast cancers in BRCA1-mutation carriers showed more pleomorphism (p=0·006), a higher mitotic count (p<0·0001), and less tubule formation than controls (p=0·006), whereas cancers in BRCA2-mutation carriers showed less tubule formation (p=0·003), but no difference in pleomorphism or mitotic count. The occurrence of invasive lobular carcinoma and invasive ductal carcinoma was not significantly different between carriers of BRCA1 or BRCA2 mutations and controls. Medullary or atypical medullary carcinoma was, however, found more often in BRCA1 (13%, p<0·0001) than in BRCA2-mutation carriers (3%) or controls (2%). Tubular carcinoma was less common in BRCA2-mutation carriers. The few mucoid carcinomas were all in familial cases. Carriers of BRCA1 mutations showed less ductal carcinoma in situ around the invasive lesion than controls (41 vs 56%, p=0·001). Lobular carcinoma in situ was less common in familial cancers (p=0·013), but differences were not significant for BRCA1-mutations or BRCA2-mutation carriers, separately.

Interpretation

The histology of breast cancers in predisposed women differs from that in sporadic cases, and there are differences between breast cancers in carriers of BRCA1 and BRCA2 mutations. The findings suggest that breast cancer due to BRCA1, has a different natural history to BRCA2 or apparently sporadic disease, which may have implications for screening and management.

Introduction

A small proportion of breast-cancer cases, in particular cancers diagnosed in young patients are attributable to a hereditary predisposition to the disease, which is transmitted as a highly penetrant autosomal dominant trait. There has been considerable progress in the identification of the genes responsible. The BRCA1 gene is located on chromosome 17q21 and encodes a protein of 1863 aminoacid residues, which includes a zinc-finger domain.1, 2 Mutations in BRCA1 are associated with a risk of breast cancer of about 80% and a risk of ovarian cancer of 40% by age 70.3, 4 The BRCA2 gene is located on chromosome 13q12-q13 and encodes a protein of 3418 aminoacid residues without extensive sequence similarity to other known proteins.5, 6, 7 Early estimates suggest that mutations in BRCA2 are associated with a similar risk of breast cancer to BRCA1, but that the risk of ovarian cancer is lower and the risk of breast cancer in male carriers is higher (Ford and colleagues, unpublished data). Mutations in BRCA1 and BRCA2 together account for about 80% of families with four or more cases of breast cancer diagnosed in patients younger than 60 years. Other genes that are known to raise the risk of breast cancer include the TP53 gene,8 the gene on chromosome 10q22-23 responsible for Cowden's disease,9 and, in men, the androgen-receptor gene.10 Abnormalities in these genes are rare compared with mutations in BRCA1 and BRCA2. In addition, certain alleles of the H-RAS1 gene, which are common compared with disease-associated variants of BRCA1 and BRCA2, may slightly raise the risk of breast and other cancers.11

Medullary carcinoma, tubular carcinoma, invasive lobular carcinoma, and lobular carcinoma in situ have all been reported as more commonly associated with a family history of breast cancer than other cancer subtypes.12, 13, 14, 15, 16, 17 Interpretation of these studies is often complicated by small numbers of cases, variable family histories and changes in the criteria for diagnosis and classification of breast cancer. No clear agreement has emerged that any particular type is more commonly associated with a family history than any other. Nevertheless, in a histological review of the populationbased series of 4071 breast cancers diagnosed between ages 20 and 54 years in the Cancer and Steroid Hormone Study,18 a higher familial risk was reported for lobular carcinoma in situ than for other subtypes. In a separate study of the Utah Population Database,19 a greater degree of familiality was detected for invasive lobular cancer than for breast cancer overall. Since the localisation and identification of breast-cancer susceptibility genes, there have been suggestions that cancers arising in breast-cancer families, and specifically those due to BRCA1, are of higher grade than sporadic cases.20, 21, 22, 23 We examined the pathology of breast cancers related to BRCA1 and BRCA2 in a large, collaborative study organised through the Breast Cancer Linkage consortium and compared the histological findings with those of controls unselected for a family history of the disease.

Section snippets

Breast-cancer specimens

From familial breast-cancer specimens in paraffin blocks, 5 μm sections, unstained or stained with haemotoxylin and eosin, were obtained from participating groups in the UK, USA, Ireland, France, Germany, Iceland, Switzerland, and the Netherlands. Each group gathered specimens from several histopathology departments. As controls, specimens from 187 apparently sporadic female breast-cancer cases diagnosed when the women were younger than 40, 144 diagnosed between the ages of 40 and 49, and 216

Results

440 cases of familial breast cancer were included in the study. The age distribution of the control and familial groups was similar (table 1). 118 (27%) familial cases were classified as attributable to BRCA1, 78 (18%) as attributable to BRCA2, and 244 (55%) as unknown. 113 cases were classified as BRCA1, because of a clear disease-causing mutation, and five cases after geneticlinkage analysis. 67 cases were classified as BRCA2 because of a clear disease-causing mutation and 11 cases after

Discussion

This study shows that the histological characteristics of breast cancers due to BRCA1 and, to a lesser extent, BRCA2 mutations differ from those of sporadic breast cancers. Moreover, our results show that cancers associated with BRCA1 and BRCA2 mutations differ from each other. The differences were detectable despite the incomplete agreement between pathologists, which indicates that the true associations are, in fact, stronger than those observed. For BRCA1, the data were based on 42 different

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