Histological types of breast cancer: how special are they?

Abstract

Breast cancer is a heterogeneous disease, comprising multiple entities associated with distinctive histological and biological features, clinical presentations and behaviours and responses to therapy. Microarray-based technologies have unravelled the molecular underpinning of several characteristics of breast cancer, including metastatic propensity and histological grade, and have led to the identification of prognostic and predictive gene expression signatures. Furthermore, a molecular taxonomy of breast cancer based on transcriptomic analysis has been proposed. However, microarray studies have primarily focused on invasive ductal carcinomas of no special type. Owing to the relative rarity of special types of breast cancer, information about the biology and clinical behaviour of breast cancers conveyed by histological type has not been taken into account. Histological special types of breast cancer account for up to 25% of all invasive breast cancers. Recent studies have provided direct evidence of the existence of genotypic-phenotypic correlations. For instance, secretory carcinomas of the breast consistently harbour the t(12;15) translocation that leads to the formation of the ETV6-NTRK3 fusion gene, adenoid cystic carcinomas consistently display the t(6;9) MYB-NFIB translocation and lobular carcinomas consistently show inactivation of the CDH1 gene through multiple molecular mechanisms. Furthermore, histopathological and molecular analysis of tumours from conditional mouse models has provided direct evidence for the causative role of specific genes in the genesis of specific histological special types of breast cancer. Here we review the associations between the molecular taxonomy of breast cancer and histological special types, discuss the possible origins of the heterogeneity of breast cancer and propose an approach for the identification of novel therapeutic targets based on the study of histological special types of breast cancer.

Figure 1

Histological special types of breast cancer preferentially oestrogen receptor positive. (A) Tubular carcinoma, (B) cribriform carcinoma, (C) classic invasive lobular carcinoma, (D) pleomorphic invasive lobular carcinoma, (E) mucinous carcinoma, (F) neuroendocrine carcinoma, (G) micropapillary carcinoma, (H) papillary carcinoma, (I) low grade invasive ductal carcinoma with osteoclast‐like giant cells.

Figure 2

Histological special types of breast cancer preferentially oestrogen receptor negative. (A) Adenoid cystic carcinoma, (B) secretory carcinoma, (C) acinic‐cell carcinoma, (D) apocrine carcinoma, (E) medullary carcinoma, (F) metaplastic carcinoma with heterologous elements, (G) metaplastic carcinoma with squamous metaplasia, (H) metaplastic spindle cell carcinoma, (I) metaplastic matrix‐producing carcinoma.

Figure 3

Histological special types and molecular subtypes. Tumours from each of the histological special types are more homogeneous than invasive ductal carcinomas (IDC) of no special type. IDC with osteoclastic‐like giant cells, mucinous and tubular carcinomas preferentially harbour a luminal phenotype, whilst adenoid cystic, medullary and metaplastic breast cancers preferentially display a basal‐like phenotype. Some metaplastic breast cancers and medullary carcinomas may display a claudin‐low phenotype. Classic lobular and micropapillary carcinomas are preferentially of luminal or HER2 phenotypes. Apocrine carcinomas are either of molecular apocrine or HER2 phenotype, whereas pleomorphic lobular carcinomas may be of luminal, HER2 or molecular apocrine phenotype. The dashed line represents a hypothetical association. Note that the HER2 group here is defined by the presence of HER2 gene amplification and not the ‘intrinsic gene’ defined HER2 group.

Figure 4

Histological special types may be driven by specific genomic hits regardless of the target cells. (A) In the Blg‐Cre;Brca1F/F/Trp53+/− mouse model, Brca1 was inactivated in luminal epithelial cells of the mouse mammary gland and all cells harboured only one functional copy of Trp53. In the K14cre;Brca1F/F;Trp53F/F mouse model, Brca1 and Trp53 were inactivated in the basal/myoepithelial cells of the mouse mammary gland. Histopathological and immunohistochemical analysis of tumours developing in mouse models where Brca1 and Trp53 were inactivated in different lineages of the mouse mammary gland revealed that tumours had morphological and immunohistochemical features that recapitulated those of human basal‐like breast cancers (Liu et al., 2007; McCarthy et al., 2007) (i.e. a convergent phenotype driven by the type of genetic hits). (B) Representative scanning and medium power magnification micrographs of a tumour developing in Blg‐Cre;Brca1F/F/Trp53+/− mouse model and in a patient with a pathogenic BRCA1 truncating germ‐line mutation.