Molecular genetics provides biological and imaging insights into DCIS subtypes

Ductal carcinoma in situ, which was a rare disease two decades ago, can now be found in 15% to 20% of all newly diagnosed cases of breast cancer. Despite increasing awareness of DCIS, however, the disease is confusing for physicians as well as patients because of its wide variety of presentations and treatment options.

New information from molecular genetics suggests that subtypes of DCIS have different DNA roots and patterns of development, raising even more questions about the progression to invasive carcinoma and the classification of ductal and lobular forms of carcinoma. In the process, it is opening the door to a deeper, biological understanding of the complexities of the disease.

Since most patients with DCIS have nonpalpable lesions, the diagnosis depends on mammography. Radiologists who report mammography, particularly those involved in regular mammographic screening, need to appreciate the molecular nuances between low-grade and high-grade DCIS subtypes so they can work up patients properly, said Dr. Clive Wells, a consultant pathologist at St. Bartholomew's Hospital in London.

Although DCIS is considered to be a precursor for invasive breast cancer, it becomes invasive at different rates, depending on its subtype. Low-grade DCIS takes up to 18 years to progress to invasive carcinoma. High-grade DCIS can turn into invasive carcinoma in only three to five years.

Molecular analysis of breast lesions indicates that low- and high-grade DCIS may develop along separate pathways because of their genetic variation. Low-grade DCIS loses genetic material from chromosome 16q. High-grade DCIS, on the other hand, does not lose any material from chromosome 16q, and it gains material on chromosomes 1 and 17.

These discoveries challenge the theory that high-grade DCIS evolves from the low-grade subtype. They also show similarities between low-grade DCIS and tubular as well as grade 1 invasive carcinoma, both of which also lose material from chromosome 16q.

Although the route of development of high-grade DCIS is not clear, low-grade disease may begin with changes in columnar cells and progress to the appearance of flat epithelial atypia or "clinging carcinoma," atypical ductal hyperplasia, and low-grade micropapillary and cribiform DCIS, and eventually produce tubular and grade 1 invasive carcinoma.

"The relationship between preneoplastic changes and DCIS needs to be understood because detecting atypical ductal hyperplasia is not as important as people make it out to be," Wells said. "It will take many years for atypical ductal hyperplasia to develop an invasive cancer. People assumed that intermediate and high-grade DCIS arose from atypical ductal hyperplasia, and they were not looking as hard as they should for precursors of high- and intermediate-grade DCIS."

The relationships between preneoplastic changes in breast tissue and the development of DCIS subtypes have implications for radiologists who interpret mammographic findings to make treatment recommendations.

"My understanding is that microcalcifications in a lobule of low suspicion on mammography can often be associated with atypical ductal hyperplasia or even low-grade DCIS. The more branching linear microcalcifications associated with high-grade DCIS, however, are the lesions that radiologists need to investigate thoroughly," Wells said.

Detecting and treating high-grade DCIS should prevent the development of a significant number of grade 3 invasive cancers. The downside is that detecting large numbers of cases of low-grade DCIS may subject women to unnecessary treatment.

"Failing to immediately follow up calcifications, which could be low-grade DCIS or atypical ductal hyperplasia, is not such a bad thing in terms of the natural history of the disease. Failing to follow up calcifications that are actually high-grade DCIS, however, could be disastrous in a very short time scale," he added.