Intro: Welcome to UAB MedCast, a continuing education podcast for medical professionals, providing knowledge that is moving medicine forward. Here's Mlelanie Cole.

Melanie Cole, MS (Host): Welcome to UAB MedCast. I'm Melanie Cole. And today, we're highlighting surgical treatment of melanoma. Joining me is Dr. Tania Arora. She's the Vice Chair of Access and Engagement in the UAB Department of Surgery. Dr. Arora, thank you so much for being with us today. So when you're evaluating a suspicious pigmented lesion, what clinical features raise your concern for melanoma? What key biopsy principles help ensure that accurate diagnosis and staging? So, help us to recognize those clinical features.

Dr. Tania Arora: Yes. Thank you, Melanie, for having me. Melanoma is, of course, a really interdisciplinary disease process. And so, the biopsies are typically done by our dermatologists. And we're very fortunate in having such qualified physicians in our own practice who send us a variety of conditions. But the biopsies often are obtained from shave biopsies or punch biopsies. I think the stronger the suspicion on the part of the dermatologist guides them to make the choice. And certainly locations, more difficult locations may lend themselves to certain kinds of biopsy. We are often biopsying things in the office as well. And since most patients that come to see us are high risk, we're generally doing punch biopsies.

The reasons that lesions are suspicious really go back to those fundamental findings of nevuses or moles that tend to have things that follow the pattern of the ABCDE framework. It really still remains the most useful model that helps us look at a mole or a lesion that has asymmetry, border irregularity, a color variation, a large diameter, recognizing that some melanomas are smaller than the reported six millimeters, that raises suspicion. And then, the E stands for evolution. Evolution is really one of the most important features. We often will sit down with a patient to sort of find out how long has it been there and how has it changed. And certainly some high-risk features that patients will complain about are itching or spontaneous bleeding of a lesion that raise our suspicion as well.

The features of a biopsy I think that are most critical to us are, one, the diagnosis of an invasive melanoma and certainly our pathology colleagues. I mentioned this was an interdisciplinary disease process. And so, of course, our partners in pathology assist us greatly in some of the lesions that are straightforward and some of those that are really more complicated. So, they give us the insight into whether or not a melanoma is on the spectrum of atypia to dysplasia to in situ, a lesion that does not have the potential to spread or an invasive melanoma. And then, we start to look at other features when we're making surgical decisions.

Melanie Cole, MS: Well, thank you for that. And I agree, it's definitely an interdisciplinary and multidisciplinary situation, both in diagnosis and then when we get to treatment. But Dr. Arora, once the pathology report comes back, the next challenge is really understanding what those findings mean. Breslow thickness remains one of the most important prognostic factors. Can you walk us through how Breslow depth, ulceration, nodal involvement, metastatic spread, as you mentioned, all come together to determine that stage and prognosis?

Dr. Tania Arora: Yeah, that's an important question. And something most patients, I think, are the most focused on when they come to see us is what stage am I and the prognosis, and then what are the next steps. So first, once the biopsy is done, and ideally the preferred type of biopsy is a punch biopsy. So, we get full thickness. The full thickness tells us that Breslow's depth, and it's really the vertical thickness in the skin that drives the first part of staging, which is the T stage. And then, we look at the clinical features. So, our physical exam, and then sometimes imaging help us to incorporate whether or not regional nodes are involved.

The other facet of staging that might show up on a biopsy are what's called in-transit lesions or microsatellite lesions. These are lesions that are sometimes seen adjacent to a biopsy of a primary mole and tell us about the overall stage even within the biopsy.

Our physical exam findings are then equally as important. If it hasn't been biopsied, but there are adjacent lesions that are highly suspicious, we can biopsy those in the office as a part of a staging procedure. And then, for anyone with a lymph node that's palpable on exam, that is something we work up prior to any surgical treatment.

So, final staging, we often think of as determined by the surgery, but there are multiple phases of staging, both first by that initial biopsy, second by the examination of lymph nodes in the office. Thirdly, again, I referenced sometimes imaging is involved. For patients that already are clinically stage IIB or above, we're often getting PET scans and MRIs along with their workup prior to any surgical treatment.

And so, it's really critical for us to really move in those stepwise methodical fashions to make sure that our staging is accurate and as it guides our treatment.

Melanie Cole, MS: So, Dr. Arora, I mean, it's a really exciting time in this field, and there's a lot more tools that you have available, and surgery's still the foundation of treatment for localized melanoma. So, how do current guidelines determine appropriate excision margins? How has that approach evolved over time? I'd like you to speak about some of the current surgical management, including those margins and indications. You mentioned sentinel lymph node biopsy. So, speak a little bit about the current surgical management and guidelines.

Dr. Tania Arora: So as a system, we of course follow the AJCC staging guidelines and the National Cancer Consensus Guidelines for treatment management. And within that are the most evidence-based guidelines in terms of guidance for the margin of excision that's done based on the depth of melanoma.

So for instance, a melanoma in situ, the recommended clinical margin is 0.5 to 1 centimeter. For those melanoma that are less than a millimeter in depth, our recommended margin is a centimeter. For those greater than a millimeter to two millimeters, the recommended margin is between 1 to 2 centimeters. This is generally individualized based on the anatomy, how an area might close, and then the morbidity to the patient.

And then, for those lesions that are greater than 2 millimeters, we employ a margin of 2 centimeters. And really, trials thus far have never shown a survival advantage for a margin wider than 2 centimeters.

For sentinel lymph node biopsy, this is a validated procedure for many years for both breast cancer and melanoma. And it is a staging procedure that we employ in the operating room when the primary mole is removed, one with the recommended margin. Sentinel lymph node biopsy is not indicated when there are clinically palpable nodes that are positive for cancer. So, it is with the understanding that a sentinel lymph node biopsy done to stage the cancer is done when the patient does not have any clinically evident lymph node disease. It's generally recommended for a patient with approximately 0.8 to 1 millimeters in depth or those that are less than 0.8 millimeters, but with ulceration seen on their pathologic specimen from biopsy.

This is typically employed because the risk of a sentinel lymph node positivity at 0.8 millimeters with or without ulceration is generally thought to be about 5%. And then, with greater depth, we know that that increases. And we at least start the consideration for a sentinel lymph node biopsy at that depth. The sentinel lymph node biopsy, of course, adds to the surgical risk and the surgical duration, but certainly is important for the final pathologic staging.

Melanie Cole, MS: So Dr. Arora, historically, surgery came first, followed by additional therapy if needed. Today, we're hearing much more about neoadjuvant treatments. Can you explain the current role of adjuvant and neoadjuvant systemic therapies and how recent studies like the SWOG S1801 and NADINA have really influenced your clinical practice.

Dr. Tania Arora: We are sort of in an era where I still pinch myself with patients. When I started medical school, there was one treatment for advanced melanoma and not many people were agreeing to take it, because of the side effects. And it only offered really months of survival in terms of the rationale.

And so, we, think about the miracles that have happened in this era of immune therapy. But the trials you reference have been practice-changing. And so, employment of treatment prior to surgery or neoadjuvant treatment is really so that we can take advantage of the behavior of both the growth pattern of melanoma, but also the spectrum of disease along the immune system.

So, clinically, neoadjuvant therapy gives us a couple of advantages. It not only lets us know about the response to in vivo treatment, but it also gives us a prognostic marker if patients respond. So, immunotherapy gives us a lot of information. But because of its effect particularly in some stage IIB and particularly in stage III melanoma, it's certainly something we start to discuss more and more.

Some advantages are also thought to be because of a large burden of disease may actually be reduced. So, it can reduce surgical morbidity. But the trials you reference, I think, are important for our audience as well because really important practice-changing. SWOG S1801 was a randomized phase II trial in patients with high-risk resectable stage III or IV melanoma.

And both groups, they received about a year of pembrolizumab. In one group, this was a preoperative treatment followed by surgery and then adjuvant treatment. And the difference between that group and the group that received adjuvant treatment alone was really an event-free survival, a significant increase in survival with those that received neoadjuvant. It really established the advantage of neoadjuvant treatment in resectable disease.

NADINA was something that furthered the move towards neoadjuvant treatment. NADINA was a phase III trial for resectable macroscopic stage III melanoma, where patients really received drugs like ipilimumab plus nivolumab. This was followed by surgery. And we know that, similarly, the advantage was that we saw the response in these treatment group, the postoperative treatment and the neoadjuvant group, some didn't require additional therapy.

And similarly, when we look and compare the neoadjuvant group to those that received adjuvant, we saw some with major pathologic responses, but also similar to SWOG 1801, a greater event-free survival.

Once again, emphasizing not only the decreased burden of disease, but also an important implication for recurrence-free survival.

Melanie Cole, MS: Well, tell us about some of the unique offerings that you have for patients with recurrent disease or refractory to standard treatments for patients with metastatic melanoma. Treatment options have expanded. Tell us a little bit about how surgery, immunotherapy, targeted therapy all work together today.

Dr. Tania Arora: I think that the greatest strength we have here at UAB is our tumor boards and our multidisciplinary care, not only the interaction between ourselves, medical oncology, radiation oncology surgeons from ENT and those, you know, across with pathology, radiology, you name it.

We have the best that come together bringing all of their expertise. And so, even in stage III and stage IV advanced disease, there have been a major advances in treatment. And so, while challenging, there are still offerings now that were previously unavailable.

So, while I think there are still challenges to those with CNS disease, we're seeing greater survival even in the stage IV population due to the availability of drugs like nivolumab plus ipilimumab, additional anti-PD-1 therapies combination of drugs that are available.

And then, TIL is another therapy that we employ as another line of treatment. But our medical oncologists are certainly foundational in helping us to navigate these patients to the best lines of care, and then, of course, second and third lines if needed.

Melanie Cole, MS: Dr. Arora, this is really such an interesting topic and so many advances. As we wrap up, prevention is still our best strategy. What does the evidence tell us about reducing risk and the randomized data that support regular sunscreen use and surveillance recommendations? I'd like you to speak to clinicians now, dermatologists, providers that are seeing these patients first line. And really, your best advice to them, the key takeaways that you would like them to know from your work on melanoma

Dr. Tania Arora: When we think about modifiable risk factors for melanoma, I think that's the first thing that we always want to educate patients and re-educate. They're coming to my office with a known skin cancer. And so, by then, they've already come through the hands of likely through a dermatologist who's given them the best practice advice.

But my dermatology colleagues know better than me. The randomized trials that exist that really emphasize that sunscreen use is important to prevent the next melanoma. And so, it's something we emphasize with every conversation from first meeting to last, and through the surveillance that we do on all of our patients as well. So, there was a trial in Australia that randomized patients to the use of SPF 15 sunscreen or just their discretionary use. And then, in long-term follow-up, we know that it decreased incidence of melanoma.

Really, the most important thing, I think the guidelines and may vary from year to year. But certainly, there is no doubt that sunscreen use is the best method of prevention. What I tell my patients that are already coming to us with their first melanoma, they're already a high-risk population. But for all of us, we know that ultraviolet exposure in a variety of forms, including indoor tanning bed use is avoidable. And so, we want to be able to prevent intense sun exposure.

And certainly, we see patients still with tanning beds in their home or casual recreational use. And so, those modifiable risk factors are really the most critical area, I think, to make a difference on. But prevention of the next melanoma certainly is backed by evidence. And so, we emphasize that.

Regular skin checks with a dermatologist from head to toe. and our dermatologists, again, are really the frontline providers that have many tools in their toolkit, including dermoscopy that can be an incredible adjunct to diagnosing lesions. Most of us have some skin lesions, but it's really important to see an expert for that reason. But sunscreen, I think, is one of our most important methods of prevention that we know of.

And certainly, I would also emphasize patients that come to us may have other areas that create high risk. For instance, family history of cancers and overlapping with pancreatic cancer, with breast cancer and patterns of disease that we have seen help us to funnel patients to appropriate genetics counseling where it's applicable.

Melanie Cole, MS: Thank you so much, Dr. Arora, for joining us today and telling us about all the exciting advances in the world of melanoma. Thank you again. And for more information, you can visit our website at uabmedicine.org/physician. That concludes this episode of UAB MedCast. I'm Melanie Cole.