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Noninvasive Diagnosis of Melanoma for Today’s Dermatologist

Noninvasive Diagnosis of Melanoma for Today’s Dermatologist

Practically speaking, the utility of RCM may be best visualized as a rule-out study. In such context, there is a negative predictive value (NPV) of 99%, positive predictive value (PPV) of 87%, and NNB of 6.3. For comparison, those of dermoscopy alone is 95%, 40%, and 19.4, respectively.8 

Commercially available in vivo RCMs (VivaScope System) are Class II, 510(k)-cleared devices.

PLA. Though comparatively less literature exists on the evaluation of PLA, results to date have been just as impressive of that of its RCM counterpart. However, the PLA assesses gene expression changes that may not yet have morphological correlates, with potential to further enhance early detection. As outlined above, the assay tests for detectable levels of PRAME and LINC00518 RNA, with the presence of either or both mutations yielding 91% to 97% sensitivity, 69% to 91% specificity, and >99% NPV for the diagnosis of melanoma.9-11 

As with RCM, PLA’s noninvasiveness and high NPV may lend it best for ruling out lesions that are clinically equivocal. In fact, initial studies suggest proper usage of PLA could reduce surgical biopsies by approximately 90% while missing fewer melanomas.10,12 These preliminary findings have been further validated by follow-up registry data. Earlier this year, Ferris et al13 reported that their nationwide database failed to demonstrate a single case where melanoma had developed following PLA negativity (12-month monitoring period, N=734). 

Table 1 shows a comparison of RCM and PLA against visual assessment and histopathology (VAH).

Table 1

Cost
The purpose of this section is to review the financial implications for the patient, provider, and health care system as a whole.

RCM. In 2016, the Centers for Medicare and Medicaid Services (CMS) created six new Current Procedural Terminology (CPT) codes (96931-96936) for physician reimbursement of RCM for cellular and subcellular imaging of skin (Table 2). These codes cover image acquisition and/or interpretation, with relative value units (RVUs) comparable to the technical component and professional component (TC/PC) of 88305. The American Academy of Dermatology (AAD) voiced their support in the development of such codes and have since, along with the College of American Pathologists (CAP), gone on to publish position statements14,15 in support of their usage. However, several Medicare providers and large private payors have either failed to institute written policy for RCM or have deemed the procedure “experimental/investigational,” utilizing such as terms for claim denials. Both the AAD and CAP have formed In Vivo Microscopy Working Groups to facilitate physician education for image interpretation and billing, and the American Confocal Group (https://americanconfocalgroup.com/) has developed a committee in dedication to working with physicians and payors to reverse negative payment policies. A manufacturer of a clinical RCM device, Caliber I.D., is also aiding physicians with the appeals process.

Table 2

Evidence on the cost-effectiveness of RCM is particularly limited, with no economic analyses to date on the US health care system. While international studies appear promising, the vast differences between health care systems limit the utility of such data with regards to financial implications.12,16

PLA. In contrast to RCM, providers are not able to bill for a PLA sampling procedure directly. Similar to routine bloodwork (eg, complete blood cell count), neither the collection nor interpretation of PLA is reimbursable, though there may be implications on degree of management complexity. In fact, this increased complexity may even elicit reclassification of an encounter, depending on the complexity of the decision making, thoroughness of the skin exam, and other visit factors including patient history. 

Similar to RCM, issues have been reported with regards to insurers and claim denials. The PLA service price ranges from $350 to $500, though DermTech has developed extensive programs (eg, prior authorization, financial assistance) to minimize the risk of patient financial burden.

In terms of health economics, PLA has demonstrated potential for cost reduction while improving patient care. In a US economic model, PLA was shown to reduce surveillance and stage-related treatment costs by $119 and $433, respectively, with a total cost savings of $447 (47%) per lesion at PLA price of $500.17  

Table 3

Conclusion
For today’s dermatologist, both RCM and PLA can be utilized to assist in the diagnosis of melanoma. Based on clinical data, these techniques may reliably exclude malignancy and, in specific clinical setting, offer alternative to invasive biopsy procedures. Neither technique appears superior (Tables 3 and 4), and maybe even more important, the two do not appear to be mutually exclusive (the authors hypothesize that combination testing may have clinical benefits). The decision of which to use, however, appears less clear, and may ultimately come down to characteristics of both provider and patient.

Table 4

Dr Creel is a PGY-3 dermatology resident at Louisiana State University Health Sciences Center (LSUHSC) in New Orleans, LA.
Mr Boudreaux is a fourth-year medical student at LSUHSC-Shreveport in Shreveport, LA. Ms Harrington is a third-year medical student at LSUHSC-Shreveport.

Disclosure: The authors report no relevant financial relationships.


References
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2. Years of life lost. National Cancer Institute: Cancer Trends Progress Report. https://progressreport.cancer.gov/end/life_lost. Published February 2019. Accessed January 28, 2020.

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6. Elmore JG, Barnhill RL, Elder DE, et al. Pathologists’ diagnosis of invasive melanoma and melanocytic proliferations: observer accuracy and reproducibility study. BMJ. 2017;357:j2813. doi:10.1136/bmj.j2813 

7. Waddell A, Star P, Guitera P. Advances in the use of reflectance confocal microscopy in melanoma. Melanoma Manag. 2018;5(1):MMT04. doi:10.2217/mmt-2018-0001

8. Levine A, Markowitz O. In vivo reflectance confocal microscopy. Cutis. 2017;99(6):399-402.

9.  Gerami P, Yao Z, Polsky D, et al. Development and validation of a noninvasive 2-gene molecular assay for cutaneous melanoma. J Am Acad Dermatol. 2017;76(1):114-120.e2. doi:10.1016/j.jaad.2016.07.038

10. Ferris LK, Moy RL, Gerami P, et al. Noninvasive analysis of high-risk driver mutations and gene expression profiles in primary cutaneous melanoma. J Invest Dermatol. 2018;139(5):1127-1134. doi: 10.1016/j.jid.2018.10.041.

11. Ferris LK, Gerami P, Skelsey MK, et al. Real-world performance and utility of a noninvasive gene expression assay to evaluate melanoma risk in pigmented lesions. Melanoma Res. 2018;28(5):478-482. doi:10.1097/CMR.0000000000000478

12. Edwards SJ, Mavranezouli I, Osei-Assibey G, Marceniuk G, Wakefield V, Karner C. Vivascope® 1500 and 3000 systems for detecting and monitoring skin lesions: a systematic review and economic evaluation. Health Technol Assess. 2016;20(58):1-260. doi:10.3310/hta20580

13. Ferris LK, Rigel DS, Siegl DM, et al. Impact on clinical practice of a non-invasive gene expression melanoma rule-out test: 12-month follow-up of negative test results and utility data from a large US registry study. Dermatol Online J. 2019;25(5). 

14. Position statement on reflectance confocal microscopy (RCM) [position statement]. Rosemont, IL: American Academy of Dermatology; July 27, 2019. https://server.aad.org/forms/policies/uploads/ps/ps-reflectance%20confocal%20microscopy.pdf?. Accessed January 29, 2020.

15. Shevchuck MM, Tearney G, Glassy EF, Myles JL. In vivo microscopy [position statement]. Northfield, IL; College of American Pathologists; August 12, 2013. http://webapps.cap.org/apps/docs/hints/why_ivm.pdf. Accessed February 3, 2020.

16. Pellacani G, Witkowski A, Cesinaro AM, et al. Costbenefit of reflectance confocal microscopy in the diagnostic performance of melanoma. J Eur Acad DermatolVenereol. 2016;30(3):413-419. doi:10.1111/jdv.13408

17. Hornberger J, Siegel DM. Economic analysis of a noninvasive molecular pathologic assay for pigmented skin lesions. JAMA Dermatol. 2018;154(9):1025-1031. doi:10.1001/jamadermatol.2018.1764

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