Breast Biopsy Uncertainties for DCIS and Atypia

Alexander M. Castellino, PhD

March 19, 2015

For the 1.6 million women in the United States who undergo breast biopsy to confirm screening mammogram or breast examination findings, a diagnosis of ductal carcinoma in situ (DCIS) or atypical ductal hyperplasia (atypia) might be unsettling, according to a report published in the March 17 issue of JAMA.

In about one of five cases, there was disagreement among pathologists on the diagnosis of DCIS, and in almost half of the cases, there was disagreement on the diagnosis of atypia, report Joann G. Elmore, MD, MPH, from the Department of Medicine at the University of Washington School of Medicine in Seattle, and colleagues.

Several factors contribute to this disagreement, one of which is breast density. "Our findings show that, particularly for women with dense breasts, the lack of consensus in diagnoses of atypia or DCIS is considerable," coauthor Tracy Onega, PhD, from the Norris Cotton Cancer Center at the Dartmouth-Hitchcock Medical Center in Lebanon, New Hampshire, said in a statement.

The experts Medscape Medical News spoke with agree that the significant message from this report is that women who receive a diagnosis of DCIS or atypia might want to seek a second opinion. There are reasons for this.

"A diagnosis of DCIS is not the same as invasive cancer, although women diagnosed as having atypia or DCIS are at increased risk for a subsequent diagnosis of invasive cancer," Dr Elmore said.

"If a woman receives a diagnosis of atypia or DCIS, she has time to gather more information and consider asking for a second opinion. She does not need to get immediate treatment; she has time to verify the diagnosis and learn what it means to be at increased risk of breast cancer," she explained.

"It's not overly cautious to seek a second opinion with one of these diagnoses. It's likely a good idea," Dr Onega said in a press release.

"The disagreements in the diagnosis of DCIS and atypia are disconcerting because of the unnecessary testing and treatment these women may receive," Dr Elmore told Medscape Medical News.

In clinical practice, a woman with a diagnosis of DCIS might go through surgery, radiation, or hormonal therapy, much like a woman does if she has early-stage invasive breast cancer. Women with a diagnosis of atypia are potential candidates for annual screening with MRI and chemoprevention, she said.

"The findings from this well-designed, conducted, and analyzed study are important and suggest that improvements need to be made," write Nancy E. Davidson, MD, from the University of Pittsburgh Cancer Center, and David L. Rimm, MD, PhD, from the Department of Pathology at the Yale University School of Medicine in New Haven, Connecticut, in an accompanying editorial.

This study "should be a call to action for pathologists and breast cancer specialists," they add.

Evaluating Accuracy of Pathologists

There are challenges when interpreting breast tissue biopsies. The goal of this study was to evaluate the accuracy of pathologists' evaluations of biopsy tissue, Dr Elmore explained in an interview posted on the JAMA Network.

The researchers randomly selected 240 of 19,498 breast biopsy specimens (excision or core needle biopsies) from pathology registries in New Hampshire and Vermont.

Cases of atypia and DCIS were oversampled to provide "statistical precision" in estimates for concordance. Also oversampled were biopsies from women 40 to 49 years of age and from women with documented dense breast tissue.

Three experts independently interpreted the biopsies and then met in person for four full days to arrive at a consensus on their diagnoses. "These are very experienced breast pathologists who have written textbooks," Dr Elmore told Medscape Medical News.

Their consensus was that 30% of the 240 samples were benign without atypia, 30% were atypia, 30% were DCIS, and 10% were invasive carcinoma.

Dr Elmore and her colleagues sent 60 slides each to 115 pathologists from eight states, who provided 6900 individual interpretations. The slides were identical to the slides examined by the consensus team.

The diagnoses provided by the pathologists were compared with those provided by the consensus team.

For invasive carcinoma, there was 96% agreement in diagnoses between the pathologists and the consensus team. For biopsies identified as benign, there was 87% agreement.

"It was very reassuring that there was near-perfect agreement in the diagnosis of invasive breast cancer," Dr Elmore noted.

However, it was "eye-opening" and "disconcerting" that there was 84% agreement in diagnoses for DCIS and only 48% agreement in diagnoses for atypia, she said.

Why This Discordance?

This study indicates that disagreement with the consensus diagnoses was higher when the biopsies were interpreted by pathologists with a lower weekly case volume, if they were from nonacademic centers or smaller practices, and if the samples were from women with dense breast tissue.

"It is much easier to reproducibly and adequately categorize invasive breast cancer. The in-between diagnoses are much more challenging," Dr Elmore told Medscape Medical News.

Because pathologists have many terms for atypia, "it is incumbent on the pathology community to refine the definition of atypia so that it is more reproducible between viewers and standards are promulgated widely," Drs Davidson and Rimm write in their editorial.

They note that objective molecular criteria could be used to better classify atypia.

"Overall, the disparity is unsettling," said Oscar Bronsther, MD, chief executive officer and chief medical officer of MetaStat, a molecular diagnostic company. "It may result in either the overtreatment or undertreatment of women with newly diagnosed (and potentially inappropriately diagnosed)breast lesions."

"Although the pathologists have substantial experience analyzing biopsy results, there is still a measure of subjective judgment involved," he told Medscape Medical News.

"It is important to understand that the morphological criteria and definition of cancer have not changed for decades. It is inevitable that in the absence of more detailed analysis, opinions among the two groups regarding specific slides will vary," Dr Bronsther added.

"Even though the task of defining atypia is more daunting, with the efforts of pathologists and breast cancer scientists, a better and more reproducible histologic and molecular classification of atypia could emerge," Drs Davidson and Rimm write.

However, in clinical practice, diagnosis still relies on pathologists, Dr Elmore told Medscape Medical News. Molecular testing, she explained, is a far way off.

Study Limitations

Although this study had several limitations, some might have uniquely contributed to the disagreement reported.

The study was conducted in a "testing situation," and was not part of the pathologists' routine clinical practice. It is difficult to secretly include a study slide into the daily practices of such a large number of pathologists, Dr Elmore said in her interview on the JAMA Network.

Importantly, interpretations were based only on one slide per case. "This too could decrease concordance, as tissue recuts are frequently performed in difficult cases," the editorialists note.

Finally, as Drs Davidson and Rimm indicate, although the pathologists had the luxury of time to arrive at their diagnoses, they "did not have the option to consult with others, as would be common in daily practice."

The challenge of classifying some breast lesions is evidenced by the fact that there was disagreement among members of the consensus team.

In her interview, Dr Elmore stressed that the variability and disagreement seen in the study is not unique to pathology or breast cancer. Similar discrepancies have been noted in other fields of medicine, such as radiology, cardiology, and internal medicine, she noted.

What This Means for Women Undergoing Breast Biopsy

"An undesirable short-term outcome from the study by Elmore et al will undoubtedly be heightened anxiety among women who undergo breast biopsy and concern among their physicians about the accuracy of the pathologic diagnosis," Drs Davidson and Rimm write.

Dr Elmore and colleagues report that, on the basis of their findings, "clinicians and patients may want to obtain a formal second opinion for breast atypia prior to initiating more intensive surveillance or risk reduction using chemoprevention or surgery."

"It is axiomatic that an abnormal breast biopsy is certainly a cause for concern but does not constitute a medical emergency. Extra time and care devoted to confirmation of the histologic diagnosis and a thoughtful discussion of the treatment options are imperative," Drs Davidson and Rimm explain.

Getting a second opinion does not need to be done routinely. "Many diagnoses are routine and reproducible, as this study shows. Difficult biopsies are generally reviewed by more than one pathologist in a practice as part of providing high-quality care," Dr Davidson told Medscape Medical News.

But certainly, if there is ambiguity for the pathologist or the treating doctor or the patient, it is reasonable to consider a formal second opinion, she added.

Drs Davidson and Rimm write that the study "identifies areas of uncertainty that must be addressed, providing a framework for process improvement in the pathology and scientific communities, especially in the diagnosis of atypia."

In the era of ever more precise evidence-based medicine, the goal should be to match emerging biologic information about breast carcinogenesis with opportunities for tailored treatment, they add.

In the future, information on the biopsy slide will likely be digitized and computer-aided detection programs will aid in the diagnoses, Dr Elmore told Medscape Medical News.

She stressed the need to cut down on the number of biopsies that are performed each year. The 1.6 million biopsies translate to up to 160,000 women being diagnosed with atypia annually, Dr Elmore and her colleagues report.

Although women might not be comfortable with watching and waiting if a subtle abnormality is noted on screening mammography, it might be a more prudent approach for some women. Dr Elmore stressed the importance of providing as much information as possible to women so that they can decide for themselves the approach they are most comfortable with.

The study was funded by the National Cancer Institute and the Breast Cancer Surveillance Consortium, which is funded by the National Cancer Institute. Dr Elmore reports serving as a medical editor for the nonprofit Informed Medical Decisions Foundation. Study coauthor Kimberly Allison, MD, from the Stanford University School of Medicine in California, reports receiving personal fees from Genentech. Dr Rimm reports receiving personal fees from several pharmaceutical companies.

JAMA. 2015;313:1109-1110, 1122-1132. Abstract, Editorial


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