Misdiagnoses and Sequencing in Melanoma

Ben Leach
Published Online: Tuesday, November 5, 2013
Dr. Jeffrey Weber

Jeffrey S. Weber, MD, PhD
Director, Donald A. Adam Comprehensive Melanoma Research Center, Moffitt Cancer Center and Research Institute, Tampa, FL

After decades with few available therapies, a flurry of FDA drug approvals has provided oncologists with a variety of options for treating patients with advanced melanoma. Although it is an exciting time in the field, there are fresh challenges in managing toxicities associated with new therapies and finding the best ways of sequencing these agents to maximize efficacy. Additionally, some struggles continue to affect physicians’ ability to treat patients, such as a high rate of misdiagnosis for primary melanoma in the community.

These topics were among those discussed at the Update for Clinicians on Diagnosis and Treatment of Melanoma and Other Cutaneous Malignancies, a one-day conference that Physicians’ Education Resource (PER) hosted September 28 at the Moffitt Cancer Center in Tampa, Florida.

Jeffrey S. Weber, MD, PhD, senior member and director of the Donald A. Adam Comprehensive Melanoma Research Center at Moffitt, served as one of the course directors of the meeting. A longtime translational researcher, Weber has worked extensively on immunotherapies including ipilimumab and the emerging PD-1 and PD-L1 checkpoint antibodies, as well as targeted therapies, such as the recently approved dabrafenib and trametinib.

In an interview with OncologyLive, Weber discussed current and emerging issuesin the treatment of melanoma.

OncologyLive: One startling statistic regarding melanoma is that as many as 30% of cases are not diagnosed properly in the community. Where is that number coming from?

Weber: That is the estimate by our surgical colleagues who see the primary melanomas, and they estimate that probably 30% of them are not diagnosed correctly. That means you could have a Spitz nevus that’s really a melanoma or a melanoma that’s really a Spitz nevus. You could have an early-stage melanoma that’s really more of a stage I diagnosis instead of a stage II diag - nosis. You could have someone who has ulceration that wasn’t noted. It’s not missed diagnosis—it is misdiagnosis.

Often, the outside reads do not contain all of the information that our specialists [at an academic medical center] would require as the minimum information needed to accurately stage a primary melanoma.

So, if you add up missed diagnoses—which thank goodness we don’t have that often—misdiagnoses, and improperly stated diagnoses, our surgeons think it is probably about 30%, and that’s a big number.

Will the increased understanding of melanoma genetics improve the accuracy of initial diagnoses?

Those data and that technology are not part of the diagnosis of a primary melanoma. Even today, melanoma is diagnosed with a “mark one eyeball,” with a dermatopathologist—or at least we hope a dermatopathologist—looking at slides. The problems arise when you don’t have a trained dermatopathologist. You have a regular anatomic pathologist who is making the diagnosis, who is not experienced with the skin, which in small communities can happen.

Oftentimes, the diagnosis of primary melanoma could be a little difficult. Many dermatopathology clinics have two pairs of eyes that look at it and sometimes you may not have those two pairs available easily. The genetic tests are not used to make the diagnosis of primary disease. They are only used in disease that’s at stage III or more to determine eligibility for therapy.

It is a tough business diagnosing melanoma as a dermatopathologist. When I first looked at slides that I was shown many years ago, I had no clue how anybody could possibly diagnose the difference between a nevus and a melanoma. It was incredibly obscure. With metastatic disease, that’s easy. The cells look ugly. But for primary diagnosis, it is tough, and I absolutely believe that a 30% misdiagnosis rate is believable.

What actions are being taken to curb the rate of misdiagnosis?

I think there has been more of a tendency in the last 10 to 20 years to centralize the reading or rereading of melanoma slides in big referral centers so that pathologists who don’t do a lot of dermatopathology will tend to let them be read by the specialists, who can identify some of the things that people would not have been conscious of in the past, such as angiolymphatic invasion, the number of mitoses per high-power field, and ulceration. Centralization and specialization has improved things, but it still leaves a lot to be desired.

In June, both dabrafenib and trametinib received FDA approval as single agents. What is the appeal of these drugs, and how revolutionary are these approvals in terms of their effect on the treatment of advanced melanoma?

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