Diana Bolotin MD, PhD, discusses the future of Non-Melanoma Skin Cancer care.
[MUSIC PLAYING] DIANA BOLOTIN: My name is Diana Bolotin, and I am a board certified dermatologist, a fellowship-trained Mohs surgeon, and assistant professor of dermatology here at the University of Chicago Medicine. I also serve as a director of dermotologic surgery and ambulatory practice director of dermatology at the University of Chicago. Today, we'll focus on an update of non-melanoma skin cancer treatment and future directions. Skin cancer remains the most common malignancy. In fact, one in five Americans are known to develop a form of skin cancer during their lifetime. Over 3 and 1/2 million non-melanoma skin cancers are diagnosed in the US alone annually. Non-melanoma skin cancer actually is a fairly broad category of tumors. There are about 82 subtypes of different skin cancers that could be classified as non-melanoma skin cancer. The most common ones are basal cell skin cancer, which is known as BCC, and squamous cell skin carcinoma, known as SCC. BCC is the most common by far, making up 75% of the non-melanoma skin cancer category, with SCC a close second at 20%. Other skin cancers include merkel cell skin cancer, dermatofibrosarcoma protuberans, and a whole host of other, more rare cancers. Most non-melanoma skin cancers can be cured. And that's the good news, especially if they're detected early and treated appropriately. Non-melanoma skin cancer generally has a very low mortality rate, but it does carry significant morbidities, so that most of the time it is treated surgically, and therefore early detection becomes key. Risk factors for non-melanoma skin cancers include a history of extensive sun exposure, especially to UV light. Specifically, it also includes tanning bed use, which we see more and more in younger populations. Fair skin and propensity to burn become another skin cancer factor, and that includes Northern European descent. And we see a lot of patients with very fair skin from England and Ireland. Immunosuppression, such as in organ transplant recipients and patients with chronic lymphocytic leukemia, also is a risk factor for non-melanoma skin cancer, both for development as well as for more aggressive course down the line. Today, I'd like to just focus on the two most common skin cancers, which is basal cell carcinoma and cutaneous squamous cell carcinoma. An example of classic basal cell carcinoma is pictured in the left-hand panel. It is the most common skin cancer and most commonly comes up as a slowly growing, pink papule with a lot of these dilated blood vessels or telangiectasias. That's the classic subtype of basal cell-- the nodular subtype. There are many other subtypes, however, that present in various ways-- anything from a scar-like lesion to a superficial scaly area. These cancers favor sun-exposed areas of the body, such as the face and arms. And the good news is they have an extremely low risk for metastasis. They would have to be neglected in an immunosuppressed patient in order to really metastasize and cause a grave harm that way. Cutaneous squamous cell carcinoma is the second most common non-melanoma skin cancer. It does have potential to become more aggressive, both if neglected, very large, or in patients with risk factors for more aggressive course. It, too, is more common on sun-exposed areas, but can be mucosal, especially in smokers. There's a 65-fold higher risk in solid organ transplant patients, so patients with kidney transplants, heart transplants, and lung, and so on. And that is compared to the general population. Cutaneous squamous cell carcinoma, again, does have a low risk of metastasis in the absence of high risk features and when it is small. And as I already mentioned, it accounts for about 20% of all skin cancers. It also accounts for about 20% of skin cancer related deaths. Options for treatments of non-melanoma skin cancers can be divided into nonsurgical and surgical modalities. The more advanced or metastatic cancers of the skin require systemic therapies, and today we'll focus on the nonsurgical and surgical modalities only. Nonsurgical options include topical treatments. That-- Those include creams and chemotherapies that are applied topically, cryotherapy with liquid nitrogen, photodynamic therapy, and radiation therapy. Surgical modalities are either destructive, with electrodessication and curettage, excision-- which is the more standard type of therapy-- as well as Mohs micrographic surgery. Systemic treatments really are reserved for larger, advanced, and high-risk cases. Those include targeted molecular therapies, which are seen more and more often now for basal cell skin cancers as well as squamous cell, and combinatorial approaches, which really are becoming very important where multiple modalities are used-- both systemic chemotherapies, radiation, and perhaps surgery. So let's go over the nonsurgical options first. Cryotherapy is performed with liquid nitrogen. It is a very cold substance at minus 195.6 degrees Celsius. It destroys tissue through rapid freeze and thaw cycles, and typically we do about two or three of those cycles on any individual lesion. It can be used really for superficial and low-risk area lesions. It really is not to be used for highly-invasive skin cancers or large skin cancers. And the reason for that is that the cure rate is significantly lower, and the area has to heal by second intention. In other words, no stitches can be placed, and so a wound just has to heal on its own. It can result in a hypopigmented scar, but in some patients that is acceptable based on it-- their location as well as the type of skin cancer. Topical pharmacologic treatments primarily include either topical chemotherapy or immune modulating agents. The standard topical chemotherapy that is approved for treatment of non-melanoma skin cancer is 5-Fluorouracil-- known as 5-FU. It is approved for superficial basal cell as well as for precancerous lesions called actinic keratoses. Of note, actinic keratoses are precancerous lesions for cutaneous squamous cell carcinomas. There are no precancerous lesions for basal cell carcinomas. The treatment period is usually about four to six weeks as performed by the patient at home with once or twice daily applications. The expected response is progressive redness, inflammation, and even erosions. And that is really the difficult part of doing this treatment, in that the patient has to do this at home themselves for protracted course of a month to a month and a half, and it is a visible treatment that leaves redness and erosions that then subsequently have to heal. Most of the time, we use it as a field treatment for precancerous lesions, such as actinic keratoses. But again, in some patients, it's use for superficial basal cell is also approved and acceptable. Topical immune modulators, of which the standard of care is Imiquimod, is a toll-like receptor antagonist-- I'm sorry, agonist-- that results in cytokine secretion and stimulation of anti-tumor immune response. By doing this, it draws the immune system to the cancerous areas, which then subsequently destroy the area and allow it to heal, again by second intention. Just like topical chemotherapy, it is approved for actinic keratoses and superficial basal cell skin cancers only. Its cure rate for any other type is fairly low, on the order of 60%, so it's really rarely used. And lastly, radiation therapy. It can be used as either a primary treatment or adjuvant treatment for non-melanoma skin cancers. In the primary treatment, the cure rate is probably comparable to an excision of a low-risk skin cancer. However, primarily because of the number of treatments that is required, and the potential side effects of local reaction to radiation therapy, it's usually reserved for adjuvant treatment. As an adjuvant treatment, it's indicated in deeply invasive squamous cell carcinomas, specifically those with perineural invasion. So we'll move on to the surgical treatments. The most long-standing one is ED&C, otherwise known as curretage and electrodessication. It is performed usually in two to three cycles and relies on user expertise for the feel of tissue resistance. In other words, skin cancers themselves feel softer than the surrounding skin, and so therefore you know whether you've cleared the margin just based on the feel of the skin cancer of the area. Again, the wound heals by secondary intention, and does typically take about four to six weeks to heal. It can result in a round to stellate white scar, so it is important to consider the location of the skin cancer before deciding on whether ED&C is appropriate. Currently, it's mostly indicated for, again, superficial non-melanoma skin cancers as well as low-risk tumors. The contraindications for this treatment are infiltrative or more spheriform morphologies, specifically of basal cell skin cancers. Those are subtypes of basal cells that present as a scar-like lesion, and therefore they feel firm to the person doing the ED&C, so there's really no difference between the area treated and the surrounding normal skin. Infiltrative or high-risk squamous cell skin cancers also are not good candidates for this treatment, in that you want to make sure you have a histologic margin clearance with the treatment. And ED&C does not provide a histological analysis of the margins. And then, again, location is important in that soft tissue such as the lip, eyelid, or atrophic skin, are not good candidates for ED&C because those areas already feel soft, so really there's no way to tell the difference between an area of malignancy and the normal skin. So with all those caveats, with proper training and patient selection, ED&C is still a very cost-effective treatment, and is reutilized quite widely for non-melanoma skin cancer. By far the most common treatment for non-melanoma skin cancer, though, is an elliptical excision. Usually it utilizes standard margins that are taken around the visible area of skin cancer. And then-- It's shaped typically as an ellipse, and that ellipse is sent to the pathology laboratory for an evaluation of margins. The diagram of an elliptical excision is off to the right, and you can see the clearly clinically visible area in darker brown that is surrounded by the outline of the ellipse, or the margin taken. The ellipse is then suctioned in what is called the breadloaf method that you can see at the lower right-hand corner, marked A through F. In other words, the pathologist sees snapshots, essentially, of the margins as they're available under the microscope. The typical margins for non-melanoma skin cancers are four millimeters for basal cell skin cancers and six for invasive SCCs. And those can vary depending on the subtypes of each type. We already discussed the vertical tissue processing. The Important thing to understand about that is although it provides a significant amount of margin for the pathologist to examine, all in total we really are talking about a 1% of the entire margin that is examined through these snapshots. And then that really is what accounts for the higher rates of recurrence that are seen with poorly-defined lesions. So in other words, lesions that, to the clinical eye, you really cannot tell where they end and where they begin, and infiltrative morphology. Recurrent tumors also have a higher recurrence rate, both with pretty much any surgical modality, but specifically with elliptical excisions. Locations on the head and neck have a higher recurrence rate with elliptical excisions, mostly because it is difficult to get a good, wide margin presumptively on the head a neck. If you're treating an eyelid, and you want to take six millimeters around, that really becomes a very, very large margin of normal skin to take on a small area. And that's really where Mohs micrographic surgery comes in. So this is a special type of excision. It's still a surgical method. It's an excision, but it's special in the way that it's performed. It was actually invented by Dr. Mohs, and that's what accounts for the name. Everyone often asks if it's an acronym. In fact, it's not. It's named after the physician that brought it to our attention. He actually invented it when he was still a medical student. It's still done under local anesthesia and performed in the outpatient setting, typically in a dermatology clinic. Back in the 1930s, when Dr. Mohs first started performing these, it relied on in situ tissue fixation with zinc chloride, which is a fairly caustic fixative that was injected intralesionally. Subsequently, a staged excision was performed with analysis, and it was called chemosurgery precisely for that reason. Reconstruction was often postponed because such caustic compounds injected in the skin prevented any kind of suturing or reconstruction. This all changed in the 1950s when the fresh frozen tissue sections were implemented in Mohs surgery. And those were done both by Dr. Mohs and Dr. Tramovitch. These really allowed a faster turnaround time between stages, and fewer local side effects because no fixative had to be injected. The tissue was taken fresh from the patient, frozen, and analyzed at the same time. It also enabled the surgeon to proceed with immediate reconstruction, which really revolutionized the field of Mohs surgery. And this exactly is the way that we perform this procedure today. What makes Mohs special is really the tissue processing. So rather than using breadloafing processing, that just takes snapshots of the tissue margin, Mohs allows for 100% margin control. It allows us to see the margin completely. It is this orientation and margin mapping that really accounts for the higher cure rate, but also sparing the most amount of normal tissue possible because we don't have to guess with wide margins. We start out with narrow margins, and we keep going until we know the skin cancer is out, and we only move in the direction where there is skin cancer. We don't take normal skin. So all of that together makes Mohs an optimal treatment, but there are specific indications that have led to the development of the Mohs appropriate use criteria, which we'll talk about in a few minutes. And then, not all skin cancers require this procedure. Some can be very adequately treated with other modalities. This is just a little graphic representation comparing the standard elliptical excision in the column on the left, which we saw a few slides back, and Mohs surgery, which is in the column on the right. And you can see that much narrower margins are started out with, and subsequently the margin is examined with that shaded bright-- that kind of shaded brown panel that you can see. So the way that it is processed, with [INAUDIBLE] tangential sections, you're able to catch any little roots of skin cancer that are underground, under the skin that you cannot see with your naked eye. And those are the exactly the reasons for the higher curate that we see. This is an example of a patient that we treated, and really the point that hits home is that clinical size of the skin cancer really does not predict the actual size that is seen underneath the skin. So the clinical size is in the panel on the left. We're going to go from left to right on the top. You can see a fairly small, five millimeter area that had been biopsied. The second panel shows the Mohs defect, which really represents the extent of this gentleman's skin cancer. The final closure is the third panel, and then the final outcome after he's all healed, which I think is a very acceptable cosmetic outcome for him. The lower panels just should give a glimpse of the sections that the surgeon sees under the microscope. And you can see these blue islands of cells in the first panel on the left that represent the basal cell skin cancer and the positive margin in stage one. And then stage two is seen in the middle panel. It's a little more subtle, but we can see off on the left there is a little-- you can see a little cloud of blue clustered islands. If you were to look at higher power, you would definitely see an infiltrative basal cell-like morphology. And then the third stage, we did not put a picture in because it was completely clear. So in his particular case, Mohs probably did two things. It spared the most amount of normal tissue, but it also spared him multiple re-excisions, because a standard margin taken around this area would not have gotten the entire tumor. So the appropriate use criteria is something that came up in about 2012, and it was a multi-disciplinary panel that came up with the guidelines for utilization of Mohs surgery and treatment of non-melanoma skin cancer. Typically, it's divided by both location and tumor types. The high-risk locations are first, and those include the mask area of the face that you can see outlined here in brown, genitalia, hands, feet, nail units, and areolae. Those are areas-- They're called high-risk because they have a higher risk of recurrence and higher risk of aggressive skin cancers that may have more subclinical spread than meets the eye. Moderate-risk locations are cheeks, jawline, scalp, and neck, as well as pretibial leg. And pretibial leg made this category because the skin is so thin and close to the bone, and so it's important to be tissue sparing in that area. And then low-risk locations are trunk, so chest, back, arms, and really the rest of the extremities. So a brief outline of the appropriate use criteria. So in the high-risk areas, really the only inappropriate skin cancer type is the focal type. So sometimes we see patients with lots of areas of actinic keratosis or precancers with just very focal areas of SCC in situ, so very early SCC. Those are areas that can be treated by other means than Mohs. It really is not requiring Mohs. All the other basal cell and squamous cell skin cancers are appropriate for Mohs in the high-risk areas. Moderate areas also include-- its-- so same inappropriate use for actinic keratoses with focal SCC, as well as small superficial basal cells, typically can be treated by other means in the moderate areas. And then it's the low-risk locations that really have undergone a change in thinking. And that is that really in low-risk locations such as the trunk, where a wide margin can easily be taken with an elliptical excision, those really should be-- Mohs should really be reserved for recurrent or aggressive, large skin cancers, as well as patients in the immunosuppressed population who require a better, higher cure rate. And we know that those patients have often a more aggressive course. So a little bit on the cure rates by modality. This is from a publication in 2002 that shows the cure rates, again, are fairly good for all non-melanoma skin cancers. However, ED&C has some of the lower rates, as well as radiation, and Mohs micrographic surgery-- you can see a 99% cure rate for primary basal cell skin cancers, as well as 97% cure rate for primary SCCs. As expected, recurrent skin cancers have a lower cure rate, but still above 90%, which is very good. And now, this data is an aggregate that doesn't really take into account locations or subtypes specifically, but it is an important all-around number to keep in mind for our patients. This summarizes a study from Australia that has a large number of patients-- over 3,000 patients. And this really does focus just on head and neck basal cell and squamous cell skin cancers with five-year follow up. And again, you can see in the columns here that recurrence rates range between 1% and 3%, which again is very high for head and neck basal cell skin cancer. And then a similar companion study for squamous cell skin cancer was also published. Fewer patients, mostly head and neck as well, and again, a cure rate overall of about 4% to 8% was seen. So I hope I put across the fact that there are definitely treatment considerations when deciding what type of skin cancer to treat, what treatment to use, but also patient properties. So you want to consider who you're treating, not just what you're treating. You want to look at the lesion, but you also want to look at the patient. What are the comorbidities? How old is the patient? Will they be able to stay in, granted, an outpatient clinic, but still, stay in the operating room for a prolonged period of time for a procedure? Or would it be better to employ one of the lower cure rate therapies that may be easier for this patient to handle? The time and cost is important to patients, especially nowadays. The least expensive treatments include topical medications and cryotherapy. But as we've learned, those don't have as high a cure rate. Surgery and radiation are more costly. However, they have a higher cure rate. So again, you'd really have to discuss all of this with the patient. Wound care after treatment is important. The topical chemotherapy, the destructive modalities, usually have to heal on their own, and it can take up to several months. So if the patient doesn't have help at home to help them treat the area, this will all come into play. And then sutured, grafted wounds do heal a lot faster. So that's something we always discuss with their patients. Cosmetic outcome is important, especially with the non-melanoma skin cancers that happen on sun exposed areas such as the face, which is very visible. And then there are other considerations. And I mentioned patient anxiety, ability to withstand procedures, and so on. Those are important to consider. And last but not least, allergies. Everything we do is done under local anesthesia, so that's injectable Lidocaine typically, although there are others. But we do have to take into account whether a patient is able to have those injectable anesthetics. So I'm just going to conclude by summarizing and say that-- to remind you that basal and squamous cell carcinomas are the most common skin cancers. But they're very curable, and early detection is absolutely key. In some cases, there are-- if detected early enough, nonsurgical approaches are quite sufficient. However, surgical treatment does provide the best cure rate for operable lesions, and Mohs micrographic surgery, when used on the appropriate site and in the appropriate patient, have the highest cure rates. Proper patient selection is key, and really the treatment should be tailored to the individual.
