Invasive lobular carcinoma of the breast: the increasing importance of this special subtype

Abstract

Invasive lobular carcinoma (ILC) is the most common of the breast cancer special types, accounting for up to 15% of all breast cancer cases. ILCs are noted for their lack of E-cadherin function, which underpins their characteristic discohesive growth pattern, with cells arranged in single file and dispersed throughout the stroma. Typically, tumours are luminal in molecular subtype, being oestrogen and progesterone receptor positive, and HER2 negative. Since last reviewing the lobular literature (McCart Reed et al., Breast Cancer Res 17:12, 2015), there has been a considerable increase in research output focused on this tumour type, including studies into the pathology and management of disease, a high-resolution definition of the genomic landscape of tumours as well as the evolution of several potential therapeutic avenues. There abounds a huge amount of new data, which we will review herein.

Keywords: Genomics; ILC; LCIS; Lobular; Lobular breast cancer; Lobular neoplasia; Pathology.

Fig. 1

Multistep model of the evolution of classic ILC and its morphological variants. A lineage of ‘lobular’ disease evolves from a normal epithelial cell on a background of a loss of E-cadherin expression and function, and key early somatic alterations involving gain of chromosome 1q, loss of 16q, and mutations in PIK3CA, AKT1, or PTEN. The morphological and molecular diversity of in situ and invasive lobular lesions is likely to be a result of the subsequently arising pattern of molecular alterations that drive progression. Atypical lobular hyperplasia (ALH) is distinguishable from lobular carcinoma in situ (LCIS) based on the extent of proliferation within the lobule. Pleomorphic LCIS (PLCIS) and florid LCIS (FLCIS) can emerge either from ALH (presumably) or from classic LCIS (CLCIS), with an increasing level of genomic complexity and the accumulation of mutations in driver genes such as ERBB2, ERBB3, and TP53. Various morphological variants of ILC have also been described (see also Fig. 2), which exhibit either architectural or cytological atypia relative to the classic invasive type, which we imagine being the ‘default’ pathway of evolution. A number of important points to note: (1) the genomic alterations listed may arise during any stage of progression, though are likely to be acquired at the in situ stage, or earlier (e.g. amplification of 11q13 is evident in the in situ stage); (2) it is assumed FLCIS may progress to alveolar, solid, tubulo-lobular variants, or even the pleomorphic type; (3) it is uncommon for invasive tumours to be of a pure variant morphology, with tumours often also exhibiting classic and/or other variant patterns; (4) a variety of molecular alterations have been associated with some of these morphological variants, but these are not necessarily pathognomonic of the architectural variant; and (5) the interplay between the malignant cells and extracellular matrix may also impact the resulting growth pattern. -, loss; +, gain; dotted line, anticipated route of progression; solid line, demonstrated route of progression

Fig. 2

Histological examples of lobular variants. a CLCIS and CILC (as marked), × 40 magnification. b FLCIS shows the cytology of CLCIS with marked distention of lobular units to form a confluent mass-like lesion, × 40 magnification. c PLCIS with cytological atypia—nuclear pleomorphism with large vesicular nuclei and nucleoli—at least some × 4 the size of lymphocytes; × 600 magnification. d PILC, characteristic discohesion but with high-grade pleomorphic nuclei, with pink, foamy cytoplasm typical of an apocrine phenotype, × 400 magnification. e ILC with signet ring cell morphology, × 200 magnification. f Solid with sheets of classic type cells, × 200 magnification. g ILC showing mucinous/histiocytoid morphology, × 200 magnification. h Alveolar variant with cluster/globular arrangement of at least 20 cells, × 200 magnification. i Mixed ductal-lobular carcinoma, × 200 magnification. The variants of ILC rarely present in pure form and are more likely to occur as mixed lesions with classic type and/or other subtypes, e.g. classic, pleomorphic, and solid. CILC, classic ILC; CLCIS, classic LCIS; FLCIS, florid LCIS; PLCIS, pleomorphic LCIS

Fig. 3

Multistep model of evolution of tumours with morphological features indicative of mixed ductal and lobular carcinomas. a Co-existing lesions with both ‘ductal’ and ‘lobular’ morphology are frequently clonally related, suggesting shared origins of a common neoplastic clone. Early divergence leads to the co-occurrence of LCIS and DCIS, and in such cases LCIS and associated ILC are likely to be negative for E-cadherin. Tumour cells exhibiting a lobular pattern of growth can also emerge from the ‘ductal’ pathway, and in such cases E-cadherin might be positive or aberrantly expressed. Modified from McCart Reed et al. [58]. Immunohistochemical staining for E-cadherin in different tumours: b × 10 magnification showing co-existing E-cadherin-positive DCIS and E-cadherin-negative LCIS; c showing strong membrane E-cadherin positivity in tumour cell nests and aberrant (cytoplasmic) E-cadherin staining in adjacent single cells. DCIS, ductal carcinoma in situ; LCIS, lobular carcinoma in situ; IDC, invasive ductal carcinoma; ILC, invasive lobular carcinoma; - E-cad, E-cadherin loss; -/+ E-cad, variable expression (loss, positive, aberrant)