Dr. Pauline Funchain:
Welcome to the ASCO Post Roundtable Series on Evolving Skin Cancer Management. I'm Dr. Pauline Funchain. I'm a medical oncologist at Stanford University. I am the co-director of the Skin Cancer Genetics Program and the co-director of the Immunotherapy Toxicity Program, and joining me today are two of my fabulous colleagues. Dr. Vidimos, if you could introduce yourself?
Dr. Allison Vidimos:
Hi, I'm Allison Vidimos. I am the chairman of the Department of Dermatology at the Cleveland Clinic, and I am a dermatologic surgeon and Mohs surgeon, and I practice cutaneous oncology.
Dr. Pauline Funchain:
And Dr. Zaba, if you could introduce yourself?
Dr. Lisa Zaba:
Hi, my name is Lisa Zaba, and I am a dermatologist at the Stanford Cancer Center, and I specialize in Merkel cell carcinoma, and I run the multidisciplinary Merkel cell carcinoma clinic there.
Dr. Pauline Funchain:
Thank you, both of you, for joining. Today, we'll be discussing the treatment of skin cancer with four patient cases. Our third installment will focus on the early management and detection of Merkel cell carcinoma. So let me introduce you to case three.
Mr. Johnson is a 72-year-old Caucasian male. He has an history of extensive sun exposure over the course of his life. He presents with a rapidly growing, painless, firm, 1.5 centimeter nodule on the back of his hand. So Dr. Zaba, let me start with you. What is the differential diagnosis for the skin lesion, and any red flags in the history or exam that would make you a little bit more concerned?
Dr. Lisa Zaba:
Yes, so this is a rapidly growing lesion, which is somewhat concerning for Merkel cell carcinoma. Many times they present as dermal modules, as is the case here. A lot of times Merkel cell carcinomas are confused with cysts or many other skin growths. And the key here is that when you have a rapidly growing nodule, it's always very important to do a biopsy and to biopsy deep enough so that you can make sure that you get the pathology. That's my encouragement for the general dermatologist is, if there's something that's rapidly growing, please biopsy it.
Dr. Pauline Funchain:
So not being a dermatologist, I'm with you, because I see Merkel cells and I wish we could get them in sooner, because they often give us a story of somebody saw it and they weren't that worried, and then it kept growing, and then the patient themselves got worried because of the rate of growth. And is there anything other than rapidly growing that triggers attention or is there anything that you could advise to a dermatologist? Because I'm assuming if they saw every rapidly growing cyst and did a deep biopsy, there'd be some hesitations about over-diagnosing or causing unnecessary pain and suffering. Any words of wisdom you can give?
Dr. Lisa Zaba:
What I discuss with the residents is that this is something that you don't want to miss; and so therefore, if you biopsy 20 cysts and one Merkel cell carcinoma, that is a worthwhile ratio. The other thing to note, I think, is also that Merkel cell carcinoma does tend to have satellite lesions if they're left long enough. And so if you have a high index of suspicion for Merkel cell carcinoma when there's a rapidly growing lesion, please feel around the nodule to see if you can feel any other dermal nodules in the area. Feel the lymph node. Feel the lymph node basin in that area. If you're at the point where you're feeling lymph nodes, you're probably at the point where you need to do a biopsy.
Dr. Pauline Funchain:
And typically, we think of Merkel cell as in an older Caucasian person. So would a quickly growing lesion on a younger person make you less concerned? Are there demographics that would help rule in or rule out?
Dr. Lisa Zaba:
So that's accurate, Dr. Funchain. It is true that older patients, as well as lighter skin tones, and men tend to be afflicted with Merkel cell carcinoma. Merkel cell carcinoma is caused, however, in two modalities, either with a polyomavirus or through UV damage through multiple hits to the DNA. Therefore, it's not inconceivable that someone of a younger age actually can develop Merkel cell carcinoma. I have many patients who are younger and have Merkel cell carcinoma. So even though it's less likely, it is certainly not impossible.
I will say that if it is a child, that is extremely rare. There are genetic diseases that can manifest Merkel cell carcinoma, but they are extremely rare. So your index of suspicion in a child will not be as high for Merkel cell carcinoma, but starting in the 20s and 30s, please have a good suspicion.
Dr. Pauline Funchain:
That's really helpful, thank you. So let me go on now with the treatment. So this gets a deep biopsy because of the suspicion of something rapidly growing. And there was an exam looking for lymphadenopathy, and there was not. So now you've got this lesion. It is biopsy-proven Merkel cell. There is no palpable lymphadenopathy. What are your general treatment principles? What are the things that a dermatologist needs to keep in mind, or is this the point where they refer off to other practitioners?
Dr. Lisa Zaba:
So there is indication in the literature that management of these cases at an academic center does improve survival significantly. There is a website, Merkelcell.org, where you can go and figure out who the expert is locally to you, so I do recommend referring. The best thing that you can do as a general practitioner is to actually order the PET scan and get that done quickly as the patient is being referred to the academic center.
Because the rate is so high of metastasis, even from a small Merkel cell carcinoma, we do perform PET scans on every patient that comes in. Also, the rate of sentinel node biopsy, even for a stage I Merkel without lymphovascular invasion, the lowest risk that you can possibly have for a positive sentinel node is 10%. So with that in mind, we do need a PET scan to fully address the concerns of the patient and make sure that they get the right treatment. And we do typically do a sentinel lymph node biopsy for every patient unless there is a compelling reason to not do it, such as low anticipated lifespan or difficulty with going under general anesthesia.
Dr. Pauline Funchain:
So even though nothing on exam, you feel like you've got this regional thing or this tiny thing on a finger, still do a sentinel and do a PET scan?
Dr. Lisa Zaba:
Yes, this is a highly metastatic disease.
Dr. Pauline Funchain:
Yeah. Do you do surveillance of these patients with... So let's say it gets taken out, plus or minus radiation. Would you follow with PET scans for a certain time period? What's your general practice there? Or does it matter how big it is, what the stage is?
Dr. Lisa Zaba:
Good question. This is a very timely question. So we can actually calculate the risk of recurrence based on the features of the Merkel cell. Based on the age of diagnosis, the length of time since diagnosis, whether or not the patient has lymphovascular invasion, the location of the Merkel cell carcinoma, all of these things come into play as to the risk of recurrence. As per NCCN guidelines, we typically do image patients every 3 to 6 months until their risk falls below 5%.
The one thing that a dermatologist needs to know, however, in addition to the imaging that we perform for surveillance, is that we do actually have two blood tests now in which we are able to look for recurrence in a very sensitive and specific manner. 50% of patients, as I mentioned before, have a Merkel cell caused by polyomavirus. And because of that, the immune system reacts to polyomavirus and we can use a blood test called the AMERK that is performed out of the University of Washington to look at the titers of reactivity toward polyomavirus.
However, we have started now actually moving to a test called circulating tumor DNA, which you can use for all Merkel cell carcinoma patients. You are able to use circulating tumor DNA to detect a recurrence in a highly sensitive and specific manner. We are now performing circulating tumor DNA every 3 months on Merkel cell carcinoma patients, and we're able to pick up 98% of recurrences even approximately 3 months prior to it becoming apparent on a scan.
So these are the methods that we are using to detect a recurrence. I suspect that in the future, as we perform trials with circulating tumor DNA, likely scans are not going to be quite as important.
Dr. Pauline Funchain:
Interesting. So with my other hat in genetics and genomics, I know there are multiple types of ctDNA tests, right? And so there are these sort of general ctDNA tests, where you just send blood, you don't need tumor, and there are more specialized ctDNA tests where you're really basing the testing on what the tumor looks like. Do you have a preference between the two?
Dr. Lisa Zaba:
Yes. The test that we are using and that we have validated and is currently in review at JCO, the test that we have validated is a specific test where you sequence the primary tumor, you then sequence the genomic DNA of the patient through their white blood cells, you subtract out the normal genome from the tumor, and by doing that you identify the specific mutations that the patient's tumor has. It's very specific to that tumor even. And then the company that does this is called Signatera. They then develop a specific assay for the patient with 16 essentially PCR primers to look at that specific tumor.
This is so specific that we have had patients develop second primary Merkel cell carcinomas, and the test that was developed for their initial Merkel cell carcinoma will not pick up the second tumor. That's how specific this test is, and it is highly sensitive.
Dr. Pauline Funchain:
Right. But in the genomics world, we kind of think that the sort of general ctDNA tests are good for certain purposes and the tumor designed tests are better for sensitivity with a tumor that doesn't change over time as much. So it makes sense that Merkel, not necessarily being super genetically divergent, like, for instance, melanoma can be, that a tumor-specific test based on one biopsy is actually going to be really sensitive for something that changes in volume very quickly like Merkel cell does. So that makes sense.
So Dr. Vidimos, if I can just ask a quick question?
Dr. Allison Vidimos:
Mm-hmm.
Dr. Pauline Funchain:
As a chairwoman, one of your tasks is to sort of get community dermatologists on board to try to find these rare things, to keep an eye on these things. And so from your perspective, how do you address that? This is something rare. It doesn't get seen very often. How do you keep the community dermatologists up to date?
Dr. Allison Vidimos:
I think with education efforts. We have clinical meetings four times a year, and presenting rare cases, and just putting it on their radar. We educate a lot about our Mohs practice, not just for basal and squamous cell carcinomas, but for Merkel cell carcinoma, for DFSP, mucinous carcinoma, MACs and such. So they know once they come across these rare tumors, they need to send them to us, but, number one, to think about it.
It's like with the pediatric DFSPs, I've had a few of those lately.
Dr. Pauline Funchain:
Right.
Dr. Allison Vidimos:
And when you look at the literature, the average age of diagnosis for a congenital DFSP, so present at birth, is 14 years old. They go 14 years until they're biopsied and they were born with it, so that's another area where I feel like we can educate the pediatricians to think about it. It's not just a scar. Same thing with Merkel cell, rapidly growing. That's what we drill into our residents as well, as Dr. Zaba said, rapidly growing and rapidly growing. I call it purple Merkel. It's purple frequently, not always. Purple Merkel rapid growth. Just think about it.
The other point I did want to make was the surgical approach to these, because we now have a series of Mohs surgery for Merkel cell carcinomas that we're analyzing. And I think when you look at the literature, sometimes Mohs is done without a sentinel node, and that is important to know that the sentinel node needs to be done. And so when we looked at 22 patients a couple years back that we treated with Mohs, we use the standard margins as recommended by NCCN, standard depth, and 13 out of 22 still had positive margins with the standard margins.
So I think, because this tumor is so apt to recur and it's frequently radiated and such, and obviously we've got systemic therapies now, but I feel like your best bet is to get it all out. So we are doing Mohs on these. And the way we're dovetailing it with the sentinel lymph node biopsy is, once the patient's been biopsied, they've had their PET/CT, we send them to nuclear medicine in the morning. They get their injection around the tumor. They come to us in the outpatient unit. We do Mohs with standard margins, clear it, and we usually clear it in one to two stages, put a bandage on. Then they go to the operating room that same day, have their sentinel node and their repair all in one day. We call it Merkel in a day and we think it's very efficient for the patients. A lot of these are elderly patients, and coming from multiple visits and such is challenging. So that's one way we've addressed the complete margin check and the sentinel node all in one fell swoop.
Dr. Lisa Zaba:
That's fantastic, Dr. Vidimos. I'm so happy to hear that you're combining Mohs with the sentinel node, which is so frequently not done when Mohs is performed, but is so critical for us to be able to manage. And that is because, unlike melanoma, when you have a positive sentinel node, it does change your management. You do then radiate the nodal basin. And so sentinel node is critical.
And also we know that margin control is extremely important. We know that if you have a positive margin, the patient has a less likely chance of not having a recurrence. Margin control is extremely important. And then, of course, if there are any high risk features, like lymphovascular invasion, or being on the head and neck, or larger than 2 centimeters, or having an immunosuppressive condition, those are the indications in which we would then also radiate in addition to having margin control.
Dr. Allison Vidimos:
Right.
Dr. Lisa Zaba:
So thank you for your Mohs in a day. That's exactly the aim.
Dr. Pauline Funchain:
Yeah, Merkel in a day.
Dr. Allison Vidimos:
Merkel in a day.
Dr. Lisa Zaba:
Oh, I'm sorry, Merkel in a day.
Dr. Allison Vidimos:
Merkel in a day.
Dr. Lisa Zaba:
Merkel and Mohs in a day.
Dr. Allison Vidimos:
You made another good point. We always send our non-marginal tissue to the lab to look for LVSI, perineural invasion, and confirmed depth of invasion, because those tendrils of tumor that went deep were in muscle. They were beyond our fascial plane. And if you think that you could send that same specimen to the lab where they would bread loaf it for their margin check, they could miss those small extensions of tumor, so that's why we're doing this.
Dr. Pauline Funchain:
That is super cool. Great discussion. Thank you both. So let me see if I can summarize our takeaways here. So I think we can all agree that early detection is very important in this tumor, that it is a challenging diagnosis, can be a challenging diagnosis. But the keys here are the rapid growth, and deep biopsies, and to not be afraid to biopsy, that even though it is rare, it is something you don't want to miss, so I like that phrasing.
And that it is very important to look for spread of tumors. So absolutely even in the lowest risk case, a 10% chance of finding a positive sentinel lymph node, so do a sentinel lymph node biopsy, do a PET scan right off the bat. And there are data to show that outcomes can be better going to an academic center because of the rare nature. And it sounds like things are evolving in Merkel cell. That's true for oncology too. So that's really great to hear. So education is important as the management evolves, and that there are new technologies coming in which are actually available now, which would be things like surveillance with ctDNA or the Merkel polyomavirus for the 50% that are positive.
Wonderful discussion. That is the end of case three. Please see other segments for further discussion about the latest data in skin cancer or visit ASCOpost.com.
