Technology vs. skin cancer

RCM and OCT

RCM and OCT both provide non-invasive visualization of skin lesions in real time, and both allow longitudinal analysis, but they differ in their depth of penetration, cellular resolution, and field of view. Using a low-power laser beam, RCM “creates an image by detecting backscattered light from illuminated tissue and displaying it on a monitor in high resolution and contrast,” according to a Cutis article providing an overview of the technology (2015;95(5): E39-46). RCM provides an en face (horizontal), or cross-sectional view of the tissue, “similar to what you see in dermoscopy, so people think of RCM as a bridge between the dermoscopic view and pathology,” said Orit Markowitz, MD, associate professor of dermatology at Mount Sinai Medical Center and an early adopter of both RCM and OCT. “We can use it to diagnose up to 300 micrometers in depth, and it has the highest cellular clarity of all the non-invasive imaging devices.”

Confocal images of skin areas measuring up to 8 x 8 mm are stitched together into a mosaic, providing information from different layers and facilitating diagnosis. Dr. Markowitz uses RCM, after clinical and dermoscopic examinations, to confirm a suspicion of malignancy or, in some cases, to rule it out. The result is fewer unnecessary biopsies, particularly in cosmetically sensitive areas. If a basal cell carcinoma is diagnosed with RCM, the Mohs surgeon to whom she refers the patient “doesn’t have to start with an already scarred biopsy to the lesion.” If the diagnosis is melanoma, “I can go ahead and excise the lesion in the same visit and not have to do histology, have the patient come back, and then have to cut around the scars that they have.”

Using infrared light, OCT provides a greater depth (up to 2mm) and field of view than RCM, Dr. Markowitz said, but with less cellular clarity. “The deeper you go, the less cellular clarity and the broader the field of view. A lot of what we see is with architecture. As of a few years back, we’ve also been able to add some vessel flow dynamics that help with diagnosis.” The size of the OCT probes allows physicians a view of subtle lesions in areas where the larger probe of the RCM won’t fit, Dr. Markowitz said. In addition, OCT provides her with valuable information for the patient: “If, for example, we know that we have a basal cell proven by RCM, I can get a better idea of how extensive that lesion is, how deep it is, and potentially, what kind of subtype.” She pointed out that there are a variety of OCT devices with different cellular clarity and different depths. “It’s a little bit confusing, I would imagine, because sometimes that’s not clearly categorized within the literature.” Ultimately, the hope is that RCM and OCT will be married into one machine so that physicians can see the lesion on a cellular level and determine the depth all at the same time.

Non-invasive molecular tests

Two proprietary molecular tests from DermTech, Inc., allow dermatologists to obtain a tissue sample by using adhesive patches; the sample is then sent to DermTech for analysis. The Pigmented Lesion Assay (PLA) analyzes RNA extracted from the sample for expression of two genes, PRAME and LINC00518, known to be overexpressed in melanoma. It is designed for use in adult patients with pigmented lesions measuring 5mm or larger and suspicious for melanoma. According to a study published in Skin Therapy Letter (2018;23(5): 1-3), the PLA has a higher negative predictive value than histopathology (>99% vs. 83%) and a high sensitivity (91-95%). The PLA is available in all 50 states and in Canada.

An additional test, Nevome™, analyzes DNA from the sample for hotspot mutations of the BRAF, NRAS, and TERT promoter genes. Currently on the market in every state except New York, Nevome is offered as a reflex test to PLA-positive cases to add molecular melanoma risk factor information. The same tissue sample can be used for the PLA and Nevome. DermTech data demonstrate that the combined RNA/DNA test has a sensitivity of 97% and a negative predictive value of >99%. In a study published online in the Journal of Investigative Dermatology (doi:10.1016/j.jid.2018.10.041), the authors stated that “expression of LINC and PRAME determined noninvasively via PLA is highly correlated with the presence of somatic mutations in three genes (BRAF non-V-600E, NRAS, and TERT) known to be important in melanoma development and progression.”

smartphone apps

Now in its third release, MoleMapper is one of many smartphone apps designed for patient self-surveillance. What sets it apart: It’s free and open source, it was developed by dermatologists at Oregon Health & Science University, and patients can allow the use of their images for OHSU’s melanoma research. The app guides users through the process of mapping, measuring, and monitoring their moles over time. They can store the images on their phones to share with health care providers or give their consent to share de-identified images and information with OHSU researchers. “We’re trying to provide a service that allows people to follow the moles that they’re worried about, and let us know what they look like as part of a research project,” said Sancy Leachman, MD, PhD, professor and chair of dermatology at OHSU and director of the melanoma research program at the Knight Cancer Institute. “We want to identify what it is about the moles that makes them concerned, and we’re trying to get people to tell us whether they’ve had something removed or not.”

ACHIEVING STANDARD OF CARE

None of the non-invasive technologies previously discussed is used in the day-to-day practice of most dermatologists. However, as their champions and early adopters continue to publish research supporting their use, and payers follow with reimbursement, further market penetration may be likely — unless the technology is perceived as too costly for the physician or the patient. In a section titled “Emerging Diagnostic Technologies,” the new AAD guidelines for the management of primary cutaneous melanoma (J Am Acad Dermatol. 2019;80[1]:208-250) name RCM, OCT, and adhesive patch “biopsy,” among other technologies, noting that “the uptake of one or more of these technologies will eventually depend on cumulative evidence regarding their effectiveness, clinical utility, cost versus benefit, and competing strategies.” So far, RCM is the only new technology to have been awarded valued CPT codes.

“I don’t practice one day seeing patients without utilizing dermoscopy, RCM, and OCT, so technically for my practice it is standard of care,” said Dr. Markowitz. “However, the percentage of RCM devices within U.S. practices is still relatively low. I do think that with reimbursement in the picture, that will potentially spur more rapid growth and drive it toward becoming standard of care.” RCM received its category I CPT code in 2016. “From my experience in New York at a large academic institution, I’ve had some pretty good reimbursement,” Dr. Markowitz remarked. “Different states probably reimburse better than others, but I think that the more it’s utilized, and the more that insurance companies are aware of it, the better the reimbursement will be as time progresses.” The AAD recently issued a position statement on RCM, voicing support for its use “when clinically appropriate” and recommending that dermatologists and their staff become conversant with federal and state laws relating to billing for RCM, as well as the CPT coding definitions.

Position statement on RCM

To view the Academy’s position statement on RCM, visit staging.aad.org/Forms/Policies/ps.aspx.

OCT is behind RCM in terms of adoption and reimbursement. “We’re only 30 years behind Europe on adoption [of both RCM and OCT],” noted former AAD president Daniel M. Siegel, MD, MS, professor of dermatology at SUNY Downstate Medical Center, who uses both devices. Dr. Siegel, who has an ownership stake in clinical and research imaging company Caliber I.D. and serves on its board of directors, said, “One reason for the slow uptake in non-invasive imaging is someone will say, ‘What kind of laser can I buy that will produce the most revenue as quickly as possible?’” The CPT codes for RCM are “fairly valued, and people can make a living with it,” he added. But OCT, with only a category III code for tracking utilization, “is still a few randomized trials away” from getting a category I code that enables reimbursement. Drs. Markowitz and Siegel will be holding a meeting called Autumn Dermatology Conference: Innovations in Aesthetic, Medical and Diagnostic Dermatology, on Nov. 2-4 in New York, where speakers will discuss incorporating new imaging technologies into mainstream dermatology.

According to DermTech’s Chief Medical Officer, Burkhard Jansen, MD, the PLA is fully validated with demonstrated utility and run in a state of the art CLIA- and CAP-accredited laboratory. Dr. Siegel, who serves on DermTech’s advisory board, said DermTech’s PLA is “not used enough. It’s very sensitive…but a lot of payers are still not paying for it.” Part of this issue, he noted, is the need to send the sample to DermTech for analysis. “I spend two days a week at the VA, and to send something out of there is almost impossible without spending hours of your time to get approved. You may also get pushback from pathologists, who will argue that histopathology is the gold standard.” Dr. Jansen indicates that the adhesive patches collect tissue from the entire pigmented lesion in question, while pathology generally only looks at 1-2% of lesion tissue. With the PLA, “you’re going to get a sample of everything in that ‘soup’ below, so the assay may actually be more sensitive than pathology,” said Dr. Siegel. Despite these obstacles, Dr. Jansen said the PLA has gained more than 600 regular users in the U.S. and provided information to more than 30,000 patients since its pilot launch in 2016. He added that the PLA has CPT codes for the lab assay, the company accepts all insurance except Medicaid, and DermTech offers patient assistance programs, even when both the PLA and Nevome are run. Nevome is new to the market, and Dr. Jansen commented that “feedback to its introduction has also been very positive.”

ENGAGING CONSUMERS

Increasingly, consumers are taking advantage of smartphone technology to monitor and improve their own health and fitness. According to a study of mobile app rankings in dermatology, co-authored by Dr. Markowitz and published as a “Tech Talk” item in Cutis(2018;102(4): 252-256), 11 of 18 patient-targeted dermatology apps (among the top 1,500 medical apps in Apple’s App Store) were designed for self-surveillance. Since the most recent update of MoleMapper in December, nearly 5,000 consumers have installed the app and 10,000 mole measurements have been taken, said Dr. Leachman, for a total of 27,600 installations and 20,500 measurements.

Fortunately for her research team, 25% of those who have installed the app consented to share their data. One repository of that data is the War on Melanoma registry housed behind the OHSU firewall. “We do various studies using the data, and we invite people to participate in surveys that yield a lot of valuable information,” Dr. Leachman said. She also views MoleMapper as a tool for primary care physicians, who may not have the resources in their office to track moles over time, to recommend to their patients. Longer term, she hopes to use the data “to see if we can start to develop algorithms that will effectively and successfully triage people and, ultimately, work with already existing algorithms to create a diagnostic. But that’s way in the future. The real thing now is to figure out how to make these images available for research and get the research done so we know we’re standing on firm ground with respect to the data.”

Dermatologists are cautious about predicting the future of teledermatology and AI apps. “I’m not a big fan of how consumer apps have evolved,” said Dr. Siegel. In the study published in Cutis, Dr. Markowitz wrote that the highest-ranked dermatology app was a teledermatology app that “did not meet the American Telemedicine Association standards for teledermatology apps,” sacrificing accuracy for ease of use. A less frequently used teledermatology app “boasted professionalism and accuracy, but from a user standpoint, it may have been too time-consuming.” Regarding AI, Dr. Siegel noted, “if it’s not FDA cleared you don’t know how good the data is. Some AI systems are wonderful, some are not. There’s a lot of chicanery out there.”

Dr. Markowitz remarked that “to give overconfidence to the user that the AI has already reached the threshold of being helpful…in the U.S. we have to be careful making those assumptions. There are many apps leading consumers to believe that they’re doing things the technology hasn’t quite reached. It’s an important subject, because there’s a lot of enthusiasm about what we can accomplish with very well-written algorithms, and I think we have to be a little careful about what we’re promising consumers — and even if we’re not making promises, what consumers may be assuming. I do think as physicians and diagnosticians, we have to be very careful to make sure that patients are properly consented, meaning that they understand the risk and benefit and that they have an understanding of what is a realistic expectation of the technology that they’re utilizing. We can’t think of these apps as a kind of toy.”

A new generation of non-invasive tools and apps reduces unnecessary biopsies, promotes self-surveillance