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Standard Light Microscopy Illuminates a Molecular Mystery

Why do triple negative breast cancers in BRCA-1 patients have a better prognosis?


Basic light microscope offers time-tested unique perspective

Alan Hollingsworth, MD has been blogging about this for a while now and his message rings more and more true as research moves forward. As molecular biology takes a larger role in diagnosis and prognosis, one should not overlook the value that histology adds to breast cancer analysis and treatment planning. Here is an edited excerpt from his September 2 blogatorial “The Premature Burial of Breast Cancer Histology”:

At the 2017 San Antonio Breast Cancer Symposium Investigators presented 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.

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. 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. 

The Premature Burial of Breast Cancer Histology, states the rest of the story,  a perfectly reasonable explanation bringing recent breakthroughs in understanding host factors together with classic histology.

TME Commentary.  Pat Whitworth, MD

His second example is that of pure tubular carcinoma as defined by light microscopy. His review of the benign clinical behavior of these tumors, even when node positive, is in sync with what David Page called and told me years ago: “Do not treat this patient with systemic adjuvant chemotherapy, she’s cured with surgery”. Even more interesting is Dr. Hollingsworth’s well-founded suspicion that these are the tumors are at least partly responsible for the phenomenon so often cited as over-diagnosis these days. The biological assay we are seeking turns out to be light microscopy in this case.

This recent blog is another of the many reasons I remain a big fan; when Alan Hollingsworth talks I always learn something new.

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