Defining the molecular genetic signature of the pleomorphic variant using high-resolution comparative genomic hybridisation, microarray-based comparative genomic hybridisation and chromogenic in situ hybridisation.

Pleomorphic lobular carcinoma

Invasive lobular carcinoma accounts for 5-15% of invasive breast tumours and its incidence has been increasing over the last 20 years, mainly in women over 50. These tumours are characterised by rather discohesive cells individually dispersed or arranged in a single-cell-file pattern immersed in a fibrous stroma. These cells are characteristically round-to-ovoid and small, with eccentric and mildly atypical nuclei. Lobular carcinomas show a proclivity for metastatic dissemination to rather peculiar anatomical sites, such as bone, gastro-intestinal tract, uterus, meninges, ovary and serosal cavities.

In recent years, a new variant of lobular carcinoma, known as pleomorphic lobular carcinoma, has been described. The pleomorphic variant shows most of the architectural features of classic lobular carcinoma, but is composed by large and pleomorphic cells. In addition, this variant is reported to be have a more aggressive clinical behaviour when compared to its classic counterpart. In fact, the behaviour of the pleomorphic variant is more similar to that of high grade ductal rather than lobular carcinomas.

Both classic and pleomorphic lobular carcinomas consistently lack the expression of E-cadherin, an adhesion molecule associated with cell survival and regarded by some as a tumour suppressor protein. Inactivation of E-cadherin through gene mutation, loss of heterozygosity and gene promoter methylation has been reported in >95% of lobular carcinomas and is known to be altered in a very small proportion of ductal carcinomas.

Although the morphological and immunohistochemical aspects of classic and pleomorphic lobular carcinomas have been addressed in the literature, the molecular genetic signature that defines the pleomorphic variant is yet to be described. In addition, it is not clear whether pleomorphic lobular carcinomas evolve through a molecular pathway similar to that of classic lobular carcinomas or are high grade ductal carcinomas with E-cadherin inactivation.

We have been analysing a series of classic and pleomorphic lobular carcinomas using high-resolution comparative genomic hybridisation, microarray-based comparative genomic hybridisation and chromogenic in situ hybridisation to define:

• if these tumours show chromosomal aberrations similar to those of classic lobular carcinomas and
• the oncogenes and tumour suppressor genes associated with the pleomorphic variant.

This knowledge may ultimately lead to the identification of therapeutic targets for these aggressive neoplasms.