The Premature Burial of Breast Cancer Histology

Poe

The conference room could have held 8,000, but many of the seats were empty. So I’m guessing that at least 3,000 witnesses at the 2017 San Antonio Breast Cancer Symposium heard the same presentation about triple-negative breast cancer that I did.

Investigators had discovered an unusual and unexplained finding – triple-negative cancers arising in BRCA-1 gene-positive patients had a better prognosis than triple-negatives in the general population. At the end of the presentation, curious audience members approached the microphones to question the presenter and offer scientific challenges.

The answers went something like this, no matter what the question: “We simply don’t have an explanation for our findings, so more work needs to be done on this.” No thoughts from the podium. None from the floor. Yet, the answer was easy, obvious and available 20 years ago, before this study was even conceived.

However, the answer has been lost in a frenzy of molecular biology. We no longer impress our scientific colleagues by using “old” terms that emanated from such clunky tools as the light microscope. We prefer terms like Luminal A, Luminal B, triple negative, etc., to describe our cancers being studied. Problem is, we have 50-75 years of quality information that is based on the light microscope, and those truths did not disappear just because DNA microarray was invented. Yet, histologic sub-types have become passé, even buried, prematurely.

The key word that was left out of the San Antonio presentation was “medullary.” No one mentioned it, and I wouldn’t be surprised if some of the basic scientists had never heard of it. But when BRCA-1 was first identified, a wave of articles soon appeared revealing a disproportionate rate of medullary carcinomas occurring in BRCA-1 positive patients. Even those cancers that did not qualify for “pure medullary” met some of the requirements and were called “atypical medullary carcinomas,” again in disproportionate numbers in BRCA-1 positive women. Were they triple negative? Most of them, yes, only we didn’t use that particular phrase, even though the 3 markers were routinely tested.

Not all triple negatives are medullary (or atypical medullary), nor are all medullary cancers triple negative. But when a classic medullary was diagnosed in a BRCA-1 positive patient, it didn’t take long for researchers to figure out that the prognosis was better in these patients, consistent with the favorable prognosis in cases of medullary carcinoma in the general population. Stated alternatively, the 2017 results being presented were actually known under the guise of “medullary” 20 years ago.

In spite of their ominous appearance (the worst cytologic features anywhere in breast pathology), medullary carcinomas paradoxically have a much better prognosis than non-medullary triple-negatives. This was the missing link at San Antonio. The researchers were likely encountering medullary cancers without recognizing them as such. After all, they were focused entirely on the molecular biology of “triple negative” breast cancer using highly sophisticated DNA arrays, while the light microscope was buried somewhere in another department.

In my view, medullary carcinoma is the most intriguing histology in breast cancer, bar none. Zero glandular formation, wild pleomorphism, large and multiple nucleoli, bizarre mitotic figures everywhere, so that the tumor looks as if it might be growing in front of your eyes in spite of formalin fixation. Amazingly, these features are somehow countered by the mystery of the lymphocytes that have corralled the nests of highly malignant cells into small groups, locking them inside the tumor, so to speak.

This “corral effect” is seen at the perimeter of the tumor as well, with a sharply circumscribed, pushing border, once again as if the lymphocytes have wadded up a piece of trash into a tightly compacted ball so that no cells can escape. Oddly enough, we do not see large necrotic areas in medullary from its rapid growth (doubling times of one month have been reported), indicating the cells are held in check by lymphocytes only temporarily. In fact, there is evidence to support that notion in that the “favorable” outlook of medullary tends to wane as tumors increase in size, especially after node positivity.

Nearly 30 years ago, I recall telling medical students who rotated with me on the breast service at the University of Oklahoma that if someone can figure out what those lymphocytes are doing in medullary carcinoma, then they’ll find a cure for breast cancer. Without claiming supernatural prescience, today we have intense investigations into TILs (tumor infiltrating lymphocytes), and ways in which those lymphocytes can be activated with immune therapies.

And here’s a wild thought – what if the unusual appearance of medullary cancer is due to the host’s unique immune system, rather than the specific, pseudo-aggressive tumor biology? In such a case, one person’s triple-negative tumor is another person’s medullary carcinoma, even though both individuals have identical tumor molecular biology. In fact, medullaries routinely test as super-aggressive, using proliferative markers or whatever, indistinguishable from the profiles of other triple negatives. The difference in natural history can only be told using light microscopy.

 In my wild conjecture, the tumor morphology would be the result of the immune system, NOT the inherent biology of the tumor. If this “host” stuff sounds familiar, Dr. Bernie Fisher first proposed host immunity as being of equal importance as tumor biology in the formulation of his “alternative theory” in the 1950s. Although he was referencing all invasive cancers, perhaps medullary histology is revealing how the optimal immune response can occur naturally. (As an aside, Dr. Fisher is still living, having turned 100 on August 23, 2018.)

Today, researchers know that cancer cells have a powerful mechanism that cripples the immune system, that is, the presence of PD-L1 on the cancer cell surface that binds to a PD-1 receptor on T-cells to prevent their activation. What if a medullary is nothing more than someone’s immune system that blocks this binding, allowing the T-cells to do what they should – corral the cancer?

The lymphocytic distribution in invasive cancer was recognized over 75 years ago, with the degree of inflammatory response proposed as part of the routine prognostic information. The idea was a good one, but it didn’t quite pan out enough for clinical utility. But go to any breast cancer meeting today, and someone will be talking about TILs (tumor-infiltrating lymphocytes), or other inflammatory cells/responses that might be of critical importance in outcomes, completely separate from inherent tumor biology. DNA microarrays might turn out to be only HALF the story.

In the BRCA-1 positive population that was discussed at San Antonio, not all the tumors were medullary, of course, but it wouldn’t take many to tilt survival in favor of the BRCA-1 positive patients with triple-negative cancer, given the large prognostic edge to medullary. The remarkable feature was that the word “medullary” was never used. The only language spoken was “molecular biology.”

I’ve noticed a trend wherein pathologists rarely use histologic sub-types as the final diagnosis. Instead, a tumor will be called “Invasive ductal carcinoma, with medullary features.” Such a soft call doesn’t allow for customized prognostic information to be given to the patient. Instead, “medullary” becomes a curiosity rather than a histologic sub-type with specific, associated behavior. And with this shift in attitude, hundreds of articles on the clinical behavior of medullary carcinoma have gone up in smoke, while researchers stand at the podium, mystified at their own results.

 

Another example of histology denied – Tubular Carcinoma

 

Largely a product of mammographic screening, the use of the term “tubular” has fallen by the wayside, lying in the gutter with “medullary.” Yet, there is a large body of evidence that tells us that this tumor is different than the standard Grade 1 breast cancer. Tubulars are not simply “well-differentiated,” they are “super-well-differentiated,” so much so that even the experts have a hard time distinguishing certain benign sclerosing lesions from tubulars.

What difference does it make? Well, given a pure tubular (90% minimum surface area meets classic tubular criteria, while remaining 10% is no worse than Grade 1), if it’s under 1.0cm in size, I’m not sure anyone has ever died in recorded medical history. One publication was just ambiguous enough that I can’t be 100% certain about the 100% survival rate, but it’s no worse than 99% (better than some DCIS). As for node-positivity with a pure tubular under 1.0cm, it hovers between 1% and 2%, less than the complication rate of sentinel node biopsy and well below 10-20% node positivity seen with garden variety breast cancer of the same size. Even when larger tubular cancers spread to lymph nodes, the outlook is still remarkably good, better than your non-tubular Grade 1.

As for multi-gene tumor assays that claim to trump histology and tumor size, I would say, “Not so fast.” While the majority of tubular carcinomas score low on these assays, some tubulars make it into the intermediate range. Granted, TAILORx takes the pressure off, but if someone is contemplating chemotherapy for a classic, pure tubular under 1.0cm, I’d say, “If you can improve upon 99% survival, then have at it.”

Virtually all pure tubulars are strongly positive for ER/PR, and endocrine therapy is often employed (although for the pure tubulars under 1.0cm, the systemic benefit is close to nil, while risk reduction for a new primary might be substantial). But what if you get back a report claiming that a pure tubular is ER/PR negative/negative? Odds are that you have a quality control issue. I’ve seen a triple-negative tubular once – and when I asked pathology to repeat the study, there was groaning and complaining. This was a number of years ago when the methodology was cytosol measurement rather than IHC. But when the case was analyzed, the original values had used a piece of the lumpectomy specimen (pre-core-bx-era) that had no tumor (normal breast cells are triple-negative, after all). When the study was repeated on actual tumor, it was strongly ER/PR positive/positive.

Other explanations are out there for ER/PR being low or negative, including the “tubular” designation being incorrect (due to high grade nuclei). However, a negative ER/PR for tubular should be a red flag for a problem somewhere.

Now, once you go below 90% purity, or increase the size above 1.0cm, all bets are off. But one of the most intriguing things about tubular carcinoma is the relationship between purity and tumor size.

Tubulars are known for their small size. Given a 0.5cm tumor discovered on mammography, it’s likely to be a tubular. And that brings up one of the most important facts in the tubular literature, mostly forgotten today (though I try to resurrect it from the dead at every available opportunity) – pure tubulars morph into routine invasive ductal as they grow. Okay, maybe I shouldn’t be so dogmatic, so let me defend that statement, as the implications here are huge – not for clinical management per se, but in the epidemiologic debate surrounding screening mammography and overdiagnosis.

Let me back up. When was the last time you encountered a 3.0cm pure tubular carcinoma? For me, the answer is “Never.” In fact, pathology studies were done long ago that correlated “purity” with “size.” That is, a direct correlation exists between the percentage of tubular histology and tumor diameter. To me, the conclusion is obvious and, importantly, without an alternative explanation — as tubulars gradually increase in size (slowly at first), they become less and less “pure,” eventually losing the “tubular” moniker. So, the pathology report might not even mention tubular features once the purity drops, let’s say, below 50%. The larger the tumor, the lower the percentage of tubular features.

I believe tubulars de-differentiate over time as part of their natural history. Hard to prove, since one can’t follow a single tumor to measure purity over time. But from the studies of multiple tubulars, the trend is impressive when purity and size are correlated. De-differentiation is the pathology term for what the basic scientists call tumor “progression,” that is, malignancies becoming “more malignant” over time with additional somatic mutations. (Note: the anti-screening epidemiologists abhor the concept of tumor progression.)

Tumor progression is at the heart of the debate on “overdiagnosis” of invasive cancer, a criticism of screening mammography. One cannot measure or recognize overdiagnosis as it is happening. Its existence is theorized entirely through indirect observations. One of the most common of these observations is the “excess” number of cancers that occur in the screened population in any of the historical studies. The attempt is then made to point out that these cancers would never result in the death of the patient as they do not progress. If they did, the number of cancers in the unscreened group should eventually catch up to the number found in the screened group.

However, in spite of the anti-screeners focusing on “excess, non-progressing cancers” drudged up through mammography, their indirect calculations force the necessity of a direct observation, a critical question rarely discussed – Where do these excess cancers go in the unscreened population? There are only two possibilities, if these “non-cancers” (as they’ve been called) are not found through screening – 1) dormancy – tumors reach a certain size then stop growing, or 2) they must regress, that is, they form, but then self-destruct, so to speak, without anyone ever knowing they existed. No matter how sophisticated and convincing the indirect evidence for “overdiagnosis” might be, one still has to account for those “excess” cancers being found on mammography.

And here’s where we circle back to tubular carcinoma, an ideal candidate to label as “overdiagnosis.” Even the lowly tubular, with its indolent course, will grow over time and, with additional mutations, eventually progress into a potentially life-threatening tumor. If tubulars can de-differentiate as they grow, one has to be very concerned about any invasive cancer having the same potential. The reason a tubular can be a functional “overdiagnosis” is because the age of the patient does not allow enough time for the lesion to progress, which can take many years. (Epidemiologists try to demonstrate that there are excess cancers with screening even in younger patients, but I don’t want to digress any further in this blogatorial).

Returning to our TWO (and only two) POSSIBLE OUTCOMES for “excess breast cancers” – dormancy or regression – theorized to explain the claims of the anti-screening epidemiologists, let’s address dormancy first. If tumors form, but then stagnate and quit growing, reaching a peaceful settlement with the host, then they should be found a-plenty at autopsy. Yet, from the pre-mammographic era of unscreened women, an analysis of all available autopsy studies (Ann Intern Med 1997; 127:1023-1028) showed only a 1.4% incidence of invasive carcinoma at autopsy (range = 0% to 1.8%), a strong indictment against the concept of tumor dormancy as 1% is exactly what one would expect from a single prevalence screen using mammography. (DCIS is another matter, not addressed here.)

As for tumor regression, the idea was so outlandish that those of us at the front lines tried to brush it away. But the “overdiagnosis voices” got stronger and stronger, apparently realizing that dormancy wasn’t going to fly, so they should focus on tumor regression. After all, it’s the perfect explanation, since the evidence has “disappeared.” Yet, as any breast radiologist will tell you, “I’ve never seen a breast cancer regress on serial mammograms.”

How would they know? They know from “untreated” cancers generated by: 1) refusal to proceed with treatment after diagnosis, 2) comparisons of newly diagnosed cancers to imaging done in prior years, and 3) “missed” cancers on mammography, where the radiologist gets to see the tumor develop (grow) year-over-year.

But these cavalier dismissals of tumor regression were anecdotal and couldn’t start to influence the evidence-driven epidemiologists. Fortunately, the Society of Breast Imaging put together a formal study (J Am Coll Radiol 2017;14:863-867) to look at “untreated cancers,” that is, diagnosed by core biopsy, but then no treatment, for whatever reason. At any single facility, this sequence of events is relatively rare, so in this study, engineered by Dr. Ed Sickles, it took 42 sites to pool their data, and – lo and behold – out of 240 cases of “untreated” invasive breast cancer (and 239 DCIS cases) there was not a single case of tumors shrinking or disappearinga strong indictment against the concept of tumor regression.

 Without dormancy and without regression, “overdiagnosis” becomes a relatively rare phenomenon, exaggerated largely by failure to account for enough lead time in the historical screening studies. Yes, the elderly patient with a 0.8cm pure tubular has probably been overdiagnosed, but not due to her tumor biology, as much as her life expectancy. In contrast to the relatively small rate of overdiagnosis (5-10% is reasonable), the outrageous estimates of 50% and higher that are being spoon-fed as fact to the U.S. media are beyond the pale.

And this entire diatribe is brought forth just because pure tubular carcinoma de-differentiates as it grows. It’s always fascinating how there can be so many implications from a single, arcane fact. The bigger question, of course, is how to reconcile tumor progression as promulgated by basic scientists and light microscopy versus the undying belief in tumor regression as proposed by anti-screeners.

Returning to my primary point: With today’s research techniques and strategies, ALL pure tubular carcinomas – recognized only through old-fashioned light microscopy — are going to be tossed into the larger batch of Grade 1 breast cancers, or Luminal A cancers, where the critically important phenomenon of tumor progression/de-differentiation would never have been seen.

Yet in spite of direct evidence against dormancy or regression, empowering tumor progression as very real, this is what we hear mostly today: “This implies that many small cancers are not destined to progress to large cancers; instead, their detection results in overdiagnosis.” (New England Journal of Medicine, June 8, 2017). Epidemiologists do not look through the microscope; they only look at numbers.

This is a cautionary blogatorial — tubular and medullary are only examples. We’ve not only buried the light microscope in breast cancer research, but we’re also starting to forget that it ever existed.

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