Is the Diagnosis of Breast Cancer Subjective?

A recent article in J.A.M.A. (Journal of the American Medical Association) prompted national media coverage followed by fleeting anxiety in the breast cancer community. Why “fleeting?” Because the same problem has been exposed every few years since 1991, but the ramifications are so overwhelming that it’s easier to ignore the problem entirely. The title of the article was misleading – “Diagnostic Concordance Among Pathologists Interpreting Breast Biopsy Specimens.” A more accurate title would have replaced “Concordance” with “Discordance,” given that the findings were shocking (unless you’ve followed this controversy for the past 24 years). In brief summation of the study, pathologists don’t agree on which patients have atypical hyperplasia (AH) vs. ductal carcinoma in situ (DCIS) even though the clinical implications are huge. For the former (AH), at most, the recommendation is a wide excision at the site of the AH. A comprehensive breast center will also refer the AH patient for high-risk counseling and interventional options such as aggressive screening. But if the flipped coin lands on DCIS, it’s “cancer,” and that includes radiation therapy and possible endocrine therapy. Some women even opt for bilateral mastectomies.

 

In lieu of going to the animal lab my “research year” of surgical residency, I opted to spend the academic year of 1977-78 in a surgical pathology fellowship at UCLA, in what turned out to be the pivotal year of my career. If I had to describe, in one word, my most lasting impression from that experience, I would choose “subjective.” Clinicians without pathology experience believe that the findings under the microscope are completely objective and as close to pure science as anything in medicine. Often, this is the case. But not always. And certain problems, such as ADH vs. DCIS, are highly subjective.

 

In the 1970s, David Page, MD (Vanderbilt) introduced breast cancer risk levels associated with various benign biopsy findings, which brought “atypical hyperplasia” out of the lab and into the clinic. Critics countered with an article by Rosai et al in the American Journal of Surgical Pathology in 1991 that revealed the classification system as being too subjective for clinical use, with wide disagreement in diagnoses among experts. Dr. Page and other experts responded in 1992 with an article in that same journal showing that strong agreement could be achieved after consensus training – among experts, that is. There was no extrapolation to general pathologists. Even then, the agreement was in the eye of the beholder. In the view of pathologists, concordance was excellent. But from the perspective of clinicians, not so much. When the distinction between AH and DCIS was considered, at least one expert disagreed with the other 5 in most of the cases. Yet, clinicians have been treating these diagnoses as black-and-white entities for decades.

 

So, in the 2015 article now making a splash, it’s a double whammy. If experts don’t agree, how did these researchers establish the “true” diagnosis for each biopsy by which the “average” pathologist was to be compared? The fine print reveals that 3 experts were unanimous on the diagnosis in only 75% on the first try, though differences were eventually hashed out to form a consensus-derived diagnosis. In the second whammy, the same biopsy slides were reviewed by the study group, that is, 115 pathologists who then proved to be disturbingly discordant from the consensus, especially when it came to differentiating AH from DCIS. (I won’t belabor here the shocking discordance in 5 of 72 cases of completely benign findings where a significant number of pathologists called the lesions “invasive cancer.” Nor will I address here the equally shocking finding that at least one pathologist labeled 22 of these 72 completely benign cases as DCIS. Those findings are a different problem than “subjectivity.”) In short, the 2015 conclusion is identical to what many have been saying all along, only using remarkably sophisticated techniques and statistics to add punctuation to a sentence that was written 24 years ago.

 

In 1991, still fresh from my subjective enlightenment at UCLA, I made a 35mm teaching slide for academia that claimed serious trouble would eventually brew if we didn’t acknowledge this problem and merge AH and low-grade DCIS into one diagnosis – call it “borderline” if you will. Treatment, I claimed, should be the same for both entities, i.e., wide excision alone. The gynecologists had the same issue going on with “severe dysplasia” of the cervix vs. “carcinoma in situ,” but they had already done the smart thing, recommending the same treatment (cervical cone) for both diagnoses. The distinction is subjective, the treatment is not. In 1993, results of the NSABP B-17 clinical trial indicated that all women with mammographically-discovered DCIS should undergo lumpectomy and radiation therapy. Other studies confirmed the same, always using the dichotomous approach of separating ADH from DCIS as distinct entities, treating the latter aggressively.

 

Dr. Mel Silverstein and Dr. Mike Lagios have done more than any of us with regard to this problem by introducing a scoring system (Van Nuys Prognostic Index in 1997) that ends up guiding treatment so that small areas of low grade DCIS are excised as you would AH, without radiation. But acceptance of “no radiation” came only after 12 years of mud-slinging conflict, and even today, the evidence-based medicine forces make sure that everyone knows that “excision alone” for selected cases of DCIS is only “2b” evidence (weak evidence, as opposed to prospective, randomized trials).

 

The controversy has far-reaching implications, not only with regard to correct diagnosis and treatment, but also when it comes to screening. Anti-screening activists love to parade this issue around in its nakedness when discussing the harms of screening. And, in fact, they are correct. As long as we stumble over the subjectivity of AH vs. DCIS, as long as we keep irradiating women with borderline lesions, as long as women undergo bilateral mastectomy for these marginal lesions, then this controversy is truly the greatest harm of screening, as it is mostly a by-product of widespread mammography followed by subjective pathology. Forget mammography call-backs, “unnecessary biopsies” and the like, highly overstated as harms by anti-screening critics. The real potential for harm is not with radiologic standards, but with our unwillingness to adopt a “borderline lesion” approach in this problem of AH vs. low-grade DCIS, thus avoiding overtreatment.

 

There is very little discordance when it comes to high-grade comedo-type DCIS. The problem is distinguishing low or moderate grade DCIS from atypical ductal hyperplasia (AH or ADH). A diagnosis in this category should be called a “borderline lesion,” and standard treatment should be wide excision followed by high-risk counseling. Then, the benefit of knowing about a significant risk factor is enhanced, the harms of screening minimized, and everyone is happy, sort of. Will it happen? Of course not. It’s far too sensible, and would require retractions from countless experts.

I’ve been harping about this controversy since Rosai’s 1991 article, even before results from the clinical trials that added radiation therapy to DCIS management. Considering all of the above, perhaps it’s not so strange that I limit my new patient practice to women with “tissue risks” found on breast biopsy, e.g. AH/DCIS. It’s considered “going the extra mile” when I opt for an additional pathology opinion from well-known experts. Yet, if the experts don’t agree…what next? A big part of my role is explaining the nature of this controversy while, at the same time, offering guidance, erring on the side of caution.

 

 

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