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