The Best Breast Blogatorials

Is The Diagnosis of Breast Cancer Subjective?

NOTE: This essay was the initial blogatorial that launched my web site, published in April 2015. Although based on a longstanding and little-known controversy that is addressed mostly by denial, this new study was far more comprehensive than similar attempts in the past. Importantly, there is a sub-text here as the authors have an anti-screening bent, and the pathology problems discussed below occur almost entirely as a result of mammographic screening. I address this same issue in much greater detail in my book on early diagnosis (did I mention my book yet?), Chapter 19 – A Journey to the Pathology Lab to View the By-products of Screening. That chapter is an eye-opening account of the trouble that was stirred long ago in the nationwide study that put mammographic screening on the map in the 1970s. Here we go…

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 four decades or so).

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 pharmacologic risk reduction and/or aggressive screening. But if the coin flipping lands on DCIS, it’s cancer, and that likely includes radiation therapy and possible endocrine therapy. Some women even opt for bilateral mastectomies.

In lieu of going to the animal lab during 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 almost entirely 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, remain 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. 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 current researchers establish the true diagnosis for each biopsy by which the average pathologist was to be compared? The fine print reveals that the 3 chosen 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 many 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 at the time) 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 helped 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 aficionados 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 regarding 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 borderline 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 the above, perhaps it’s not so strange that I focus my new patient practice on 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.

ADDENDUM: To be fair, the pathologists in this 2015 study were put at a marked disadvantage, in that they were given prepared microscope slides, and nothing more. Thus, they could not ask for deeper cuts, they could not ask for special stains, they could not consult with colleagues (all standard practice today). Still, there are individual cases that are disturbing in this report – the most memorable being the sclerosing lesion where the three reference experts could not come to an agreement as to whether it was invasive breast cancer…or a benign lesion. And this was before the slides were submitted to the larger study group.

2

Nothing Like A False Dichotomy

To Promote Truth

April 2016 – Debate continues to rage over mammography screening guidelines

I can’t recall the last time I read a pro-screening mammography article in one of the major journals. It’s simply not cool. In contrast, the anti-screening militia is using every weapon imaginable in order to re-program the medical community and the American public to believe that less is more when it comes to the early detection of breast cancer. But no matter how fashionable it is to be an anti-screening iconoclast, or a personalized medicine advocate who favors less screening through miraculous prescience as to who is truly headed for breast cancer, the fact remains that less screening means more lives lost to breast cancer.

Recently, an editorial was published in JAMA (2016; 315:977-978), one of the Big Four journals, entitled A Public Health Framework for Screening Mammography: Evidence-based vs. Politically Mandated Care, written by a public health aficionado (Kenneth W. Lin, MD, MPH) and a lawyer (Lawrence O. Gostin, JD). The punchline seems straightforward enough – politics should play no role in medical guidelines. But there’s more than a punchline here.

The authors can’t say enough to extol the virtues of the U.S. Preventive Services Task Force and their evidence-based conclusion that we should screen with mammography every 2 years (rather than annually) starting at age 50 (rather than 40). In their view and that of the Task Force, screening women in their 40s results in more harm than benefit.

As I’ve stated on many occasions, evidence-based medicine can give you objective measures of benefits and harms, but that final step – weighing harms versus benefits – is 100% subjective. You can’t put unnecessary biopsies on one end of the teeter-totter and lives saved on the other end, using any semblance of science. That doesn’t stop evidence-based crusaders from doing so, however. In fact, it doesn’t seem to occur to them that the last step is totally subjective – instead, they speak of their scientific purity from beginning to end.

Authors Lin and Gostin simply gush about the high-quality evidence used in the Task Force process, then use the age-old false-dichotomy approach to point out the evils of political interference. It’s as though there’s no valid position that opposes the Task Force and its recommendations that is not politically motivated.

In fact, quite a few physicians believe the Task Force is way out of line, and it has nothing to do with politics. We can barely be civil about it (based on scientific evidence, by the way), and it has paradoxically hurt the cause of screening. Witness the total frustration of Dr. Dan Kopans, a pioneering mammography expert, who called the 2009 Task Force idiots, whereupon he was promptly blacklisted. Oh, you didn’t realize there are blacklists in medicine? Dr. Kopans can’t get a word published in mainstream journals anymore. He has been throttled into preaching to the choir in the friendly radiology journals where the readers agree that the Task Force are idiots.

Many of us believe that the Task Force is politically motivated to begin with, making the false dichotomy in this JAMA article even that much more bizarre – both sides are products of politics. I agree that we need to keep politics out of medicine, and a good starting place would be to dissolve the U.S. Preventive Services Task Force. Or, at least modify their structure so that they are required to include members with expertise in the areas being governed. A committee of bean counters has no place telling the farmers how to grow those beans.

The epidemiologists and public health care aficionados have hijacked many areas of medicine, including breast cancer screening. They have no room for the experts. Experts are, by their definition, motivated entirely by financial gain. To the Task Force, it is inconceivable that someone examined the evidence and chose their specialty based on that evidence. No, instead, doctors were once starry-eyed innocents until they picked a specialty whereupon they morphed into greedy, biased individuals who can no longer weigh evidence objectively. You can’t have providers establishing policy! is the battle cry of the hijackers who now control preventive medicine.

It’s not quick or simple to expose the shaky foundation of the Task Force guidelines. My favorite point of argument is that the 2009 guidelines – no screening during the decade of the 40s – was reversed from 2002 based on so-called new evidence. But the 2002 group who recommended the opposite, that is – yes, screen in the 40s – calculated a 15% relative reduction in mortality, which was completely unchanged when re-evaluated in 2009. Not a single percentage point difference. The 2009 group (the Task Force rotates members frequently) and their new evidence found nothing new regarding benefit. So, what did change then? Well, harms. That’s right. Despite better mammography, fewer call-backs, easier biopsies, better pathology, the Task Force used new modeling methods to calculate greater harms than had been considered in the past. So, the benefits of mammography as performed 30-40 years ago in the historical trials were balanced (subjectively) against modern and mysterious harms, such as permanent psychological damage after a benign biopsy. Benefits minimized, harms inflated. It was an easy formula.

The more you know about this travesty of common sense, the more disturbing it is. And to make matters even more disgusting, the new 3-D mammography does exactly what mammography critics have been asking for: 1) it lowers the callback rate, and 2) it raises the detection rate. What does that do for that delicate balance of harms-to-benefit ratio? What does it do to the teeter-totter? Harms are lower, benefits are greater, so you’d think this 3-D development would be welcomed with open arms.

Instead, the Task Force has already spoken (2015 update) – there’s not enough evidence to rule on 3-D tomosynthesis mammography. Okay, then when will there be enough evidence? Answer: probably never. Why? Because the Task Force considers any breast imaging modality used in screening to be unproven unless it has been shown to lower mortality in a prospective, randomized trial. And, since there won’t be prospective, randomized trials with mortality as the endpoint for each and every new development in breast imaging, the Task Force is sitting in the catbird seat with their Insufficient Evidence ranking. So, they will always be playing catch-up, rendering their negative opinions on obsolete technology.

Is everyone who is against the Task Force on this issue simply motivated by politics? Hardly. There is a legitimate argument against the Task Force that isn’t about emotion, politics, or gamesmanship. It’s about the abiding belief – held by those physicians who actually practice breast cancer screening – that the Task Force is dead wrong, and that their influence is going to result in thousands of breast cancer deaths each year. In my abiding opposition to the Task Force, I decided to write down all my objections – the result was a 400-page manuscript, due out in late 2016 or 2017 from McFarland Publishing (Jefferson, NC). If you read that book, you won’t be calling the organized opposition to the Task Force political. Instead, you will appreciate that it’s the government-funded Task Force that’s the political animal in the room.

Update: In fact, several ongoing trials have included a mortality reduction as an endpoint (secondary) with new technology. One trial is comparing 3D vs. 2D digital mammography, while another compares MRI plus mammography to mammography alone in Level D density patients. I’m hopeful, but skeptical, that this endpoint will be realized as successful. Why? No placebo group. The original mammography screening trials were mammography vs. no mammography, and most failed to reach statistical significance in terms of saved lives. It took combining the results (meta-analysis) to prove that mammography saves lives. Today, it would be considered unethical to randomize women to no mammography. The trials in progress now will be trying to demonstrate a mortality reduction with new technology in excess of that mortality reduction provided by the control group. And that’s why mortality reduction is a secondary endpoint in those trials, relying instead on surrogates for saved lives – that is, the rate of interval cancers (those that arise between screenings) or diminution in the number of advanced cancers. I hope I’m wrong and the newer technology saves lives outright, as this is the only result that will move the Task Force to come to their senses. Currently, they endorse ONLY mammography for women with dense breasts, yet if you rank order all methods of breast imaging, and then study women with Level D density, you’ll find mammograms coming in dead last in cancer detection rates (CDRs) with the lowest sensitivity of all options. Indeed, the Task Force is completely lost in the woods on this issue.

3

New Evidence Clashes with More New Evidence While Old Wins

Published June 6, 2015, this blogatorial addresses controversies that surround lumpectomy technique.

Today’s headlines from the AP were a bit misleading: Study Sees Benefit from More Extensive Breast Cancer Surgery. A presentation at the American Society of Clinical Oncology (ASCO) at the end of May described a prospective, randomized trial led by Yale Cancer Center, addressing breast conservation technique. More extensive surgery is the misleading part, conjuring up images of a return to the Halsted radical mastectomy. In fact, the clinical trial was merely adding thin shavings of the lumpectomy cavity to reduce the chance of returning to the operating room for positive margins. In the study, returns to the operating room for wider excision were cut in half by the shaving technique. Commentary indicated this was a new and revolutionary concept that will impact as many as 100,000 women per year.

Prospective randomized trials are the mainstay of evidence-based medicine, so we have a new standard of care proposed. But wait a minute! This very issue was recently addressed by a large consensus panel with multi-expert firepower, and for the first time since breast conservation was introduced, the verdict came loud and clear – You don’t need to do anything more than what was done in the original NSABP B-06 trial in the 1970s. Unless ink touches tumor cells, there’s no need to re-excise. This new standard (in fact, about 35 years old) was adopted by the Society of Surgical Oncology (SSO) and the American Society for Therapeutic Radiology and Oncology (ASTRO) in 2013 after a meta-analysis was performed on local recurrence rates as related to margin status.

So, we have high quality evidence about to appear in the New England Journal of Medicine that suggests one should do more at the time of surgery to get better margins, while high quality evidence also suggests a surgeon doesn’t need to do anything more than get the tumor out with no ink touching tumor cells on final pathology.

For those of us who were practicing surgeons at the time breast conservation was introduced, there was considerable caution used in patient selection. At the time, according to B-06 protocol, if you didn’t get clear margins on the first attempt, the patient was returned to the operating room – not for re-excision – but for mastectomy. This prompted many of us to be compulsive in our attention to detail to make sure we got clear margins the first time around.

Having done a year of surgical pathology, I was very cognizant as to how tissue was processed and how it subsequently appeared on the microscope slide. So, early on, circa 1989, I adopted a compulsive approach where I would submit the primary lumpectomy specimen, oriented for the pathologist to allow inking of margins, but then I would take an additional 5mm (or so) shaving around the lumpectomy cavity at those margins where the lumpectomy specimen interfaced with breast tissue (as opposed to fat, muscle, or skin). I would then orient these shavings and place India ink myself on the new outer rim while in the operating room so that the pathologist could bread-loaf the shaving and give me a report on the second set of margins. Not only did this give me greater assurance of margin status, but it also afforded the opportunity to re-create the tumor and its extensions in a 3-dimensional pattern.

In the academic setting, we once debated whether a return to the operating room for wider excision should be listed as a surgical complication (final vote – No). In the discussion, I explained how I kept my returns to the OR at a minimum, but a colleague was astounded at the ‘wasted’ time I spent in the operating room fussing about margins: You can’t possibly be doing that on every lumpectomy patient. He was wrong. I was.

A few years later, at a breast cancer meeting, a prominent breast surgeon described how he was using this exact same technique. At the end of his presentation, he said, There are four of us doing this now. Wow. Certainly, he meant, In my limited circle of academic friends who are breast surgeons, there are four of us doing this now. But it came across as a terribly constricted view of the world. Nonetheless, it helped validate what I was doing at the time (even if only five of us were doing it instead of four).

My decision to perform breast conservation in this fashion was 100% rational thought based on my experience in the pathology lab coupled to what I was learning about tumor growth patterns for different histologic types. Does it really take a prospective, randomized trial before we can settle any and all issues?

It say it all too frequently – "I’m not opposed to evidence-based medicine. I’m opposed to the glorification of evidence-based medicine to the exclusion of rational thought." And believe it or not, one sees such exclusion of logic on a regular basis.

In this case, a prospective, randomized trial about shaved margins is being regarded as an historical moment in the annals of breast conservation surgery (okay, that’s a bit of a stretch) – a new concept – but in fact, common sense arrived at the same conclusion 25 years ago (for at least 5 of us).

And how do we respond to the opposing 2013 recommendation from a Who’s Who list of experts who told us no ink on tumor is good enough. Paraphrased: Don’t worry about close margins. Don’t worry about the method of pre-op imaging to design a roadmap for accurate lumpectomy. Go in, get the tumor out, and don’t be concerned about your margin status unless ink touches a tumor cell, exactly what the NSABP said in the 1970s.

Those who want prospective randomized trials for everything done in medicine are going to be sorely disappointed. We will never have high quality evidence for every situation. Rational thought is the tool that fills in the blanks, and while empiricists love to point out examples where rational thought failed miserably, I have no trouble coming up with examples where pure empiricism failed miserably. Good science is not synonymous with empiricism – it is a blend of empiricism and rationalism. Unfortunately, humans are not particularly good at balancing opposing concepts.

4

The BEST Way To Screen For Breast Cancer

How would you answer this: What’s the best way to screen for breast cancer? Nearly everyone, including breast cancer specialists and radiologists, will routinely answer this question with Mammography. But they’re wrong, at least by one definition of best. The question is not as simple as it seems. If one is using best to mean, the most practical, then YES, it’s screening mammography. First, mammography has the infrastructure and expertise in place so that we can screen all women in the U.S. who are interested in doing so. And secondly, mammography is the only imaging modality that has revealed in prospective, randomized trials that fewer women die of breast cancer when screened (although this proof did not come easy).

But what if best means best? That is, what if best means detecting cancers most reliably at the earliest stage? I think this is what most women hear when the word best is used, but those clinicians who are answering the question with mammography are using best to mean something else entirely. In fact, the best method for detecting breast cancer for the individual patient is MRI (magnetic resonance imaging). Very close at the heels of MRI is MBI, or molecular breast imaging, a nuclear medicine study (I’m including PEM here as well – positron emission mammography). In fact, MBI can lay claim to having fewer false-positives and thus, preferred over MRI. Both MRI and MBI require the injection of a contrast agent — gadolinium for MRI and a radionuclide for MBI. Although MRI is widely accessible, with MBI playing catch-up, only time will tell about the safety of annual or biennial gadolinium vs. radionuclide, and this may be the deciding difference.

And catching up quickly is contrast-enhanced 3-D mammography, which is generating images that look much like MRI and where comparative studies are underway. Two concerns: 1) roughly 20% of the population is allergic to the iodine-based radiologic dye, and 2) all of us are allergic to the fact that radiation exposure cranks back up with this technology (unlike MRI with zero radiation exposure).

Then, for those women with dense breasts (white) on mammography, ultrasound will find as many or more cancers than mammography. For those with extreme density (Level D – over 75% white on X-ray), the fact is that mammography comes in dead last of all available options. For women with more modest levels of density, but still more than 50% of the area on mammography being white, it’s a toss-up as to whether mammography or ultrasound will find the most cancers. And when it comes to the new 3-D mammography (a definite improvement in cancer detection), ultrasound still identifies additional cancers missed by this new technology.

Mammography is far from best when one is talking about early detection capability. The bigger picture here is troubling — the so-called best recommendation for the general population is not always what is best for the individual. Currently, MRI screening is used only in high-risk individuals, where published detection levels (sensitivity) are 90% compared to only 40% using mammography alone. A similar gap would be present in normal risk individuals as well, but screening the general population with MRI is so impractical that it has never seriously been considered…until now.

A new fast MRI may make screening larger