Non-Invasive Detection of Genomic Atypia Increases Real-World NPV and PPV of the Melanoma Diagnostic Pathway and Reduces Biopsy Burden

Main Article Content

Maral Skelsey
Brook Brouha
Jim Rock
Michael Howell
Burkhard Jansen
Loren Clarke
Gary Peck

Keywords

Melanoma, LINC00518, PRAME, Genomic Atypia, Non-Invasive, Precision Genomics

Abstract

Background: Management of pigmented lesions currently relies on visual assessment with surgical biopsy and histopathologic examination for those lesions suspicious for melanoma. A non-invasive genomic assay that detects two melanoma-associated biomarkers (PLA, 2-GEP) has recently been validated as an adjunct to visual assessment for distinguishing high-risk pigmented lesions appropriate for biopsy from those that can be safely monitored via clinical surveillance.


Objectives: To calculate NPV and PPV of the PLA in real-world use and determine the distribution of PLA-positive lesions among categories in the MPATH-Dx classification scheme for melanocytic neoplasms.


Methods: Real-world NPV was determined by following a cohort of 1,233 PLA-negative pigmented lesions for evidence of malignancy for up to 36 months and by re-testing a separate prospective cohort of 302 PLA-negative lesions up to 2 years after initial testing. Real-world PPV was determined by identifying melanoma diagnoses among PLA-positive lesions within a US-based registry of 3,418 PLA-tested cases.


Results: Ten early-stage melanomas (4 in situ and 6 pT1a) were identified among 1,233 PLA-negative lesions (0.8%), corresponding to a real-world NPV of 99.2% (CI 95% = 98.5 - 99.6). Of 302 initially PLA-negative lesions subjected to repeat testing an average of 15 months later, 34 were PLA-positive. Biopsy revealed 3 melanomas (all in situ), further confirming an NPV of > 99%. Among 316 PLA-positive cases, 59 were diagnosed as melanoma by histopathology, corresponding to a PPV of 18.7%. Of all PLA-positive lesions, 30.5% had histopathologic diagnoses corresponding to high-risk MPATH-Dx categories (Classes III-V).


Conclusions and Relevance: The PLA has an NPV of >99% within the real-world intended use population.  The PLA has a PPV of 18.7% for melanoma and also detects high-risk lesions such as dysplastic nevi with severe / high-grade atypia that are generally targeted for complete excision.  

References

1. Howlader N, Noone AM, Krapcho M, Miller D, Brest A, Yu M, Ruhl J, Tatalovich Z, Mariotto A, Lewis DR, Chen HS, Feuer EJ, Cronin KA (eds). SEER Cancer Statistics Review, 1975-2017, National Cancer Institute. Bethesda, MD, https://seer.cancer.gov/csr/1975_2017/, based on November 2019 SEER data submission, posted to the SEER web site, April 2020.

2. Anderson AM, Matsumoto M, Saul MI, Secrest AM, Ferris LK. Accuracy of skin cancer diagnosis by physician assistants compared with dermatologists in a large health care system. JAMA Dermatol. 2018 May; 154(5):569-573.

3. Nachbar F, Stolz W, Merkle T, Cognetta AB, Vogt T, Landthaler M, Bilek P, Braun-Falco O, Plewig G. The ABCD rule of dermatoscopy. High prospective value in the diagnosis of doubtful melanocytic skin lesions. J Am Acad Dermatol. 1994 Apr; 30(4):551-9.

4. Elmore JG, Barnhill RL, Elder DE, Longton GM, Pepe MS, Reisch LM, Carney PA, Titus LJ, Nelson HD, Onega T, Tosteson ANA, Weinstock MA, Knezevich SR, Piepkorn MW. Pathologists' diagnosis of invasive melanoma and melanocytic proliferations: observer accuracy and reproducibility study. BMJ. 2017 Jun 28;357:j2813.

5. Welch HG, Mazer BL, Adamson AS. The Rapid Rise in Cutaneous Melanoma Diagnoses. N Engl J Med. 2021 Jan 7;384(1):72-79.

6. Piepkorn MW, Barnhill RL, Elder DE, Knezevich SR, Carney PA, Reisch LM, Elmore JG. The MPATH-Dx reporting schema for melanocytic proliferations and melanoma. J Am Acad Dermatol. 2014 Jan;70(1):131-41.

7. Lott JP, Boudreau DM, Barnhill RL, Weinstock MA, Knopp E, Piepkorn MW, Elder DE, Knezevich SR, Baer A, Tosteson ANA, Elmore JG. Population-Based Analysis of Histologically Confirmed Melanocytic Proliferations Using Natural Language Processing. JAMA Dermatol. 2018 Jan 1;154(1):24-29.

8. Brouha B, Ferris LK, Skelsey MK, Peck G, Moy R, Yao Z, Jansen B. Real-World Utility of a Non-Invasive Gene Expression Test to Rule Out Primary Cutaneous Melanoma: A Large US Registry Study. J Drugs Dermatol. 2020 Mar 1;19(3):257-262.

9. Gerami P, Yao Z, Polsky D, Jansen B, Busam K, Ho J, Martini M, Ferris LK. Development and validation of a noninvasive 2-gene molecular assay for cutaneous melanoma. J Am Acad Dermatol. 2017 Jan;76(1):114-120.e2.

10. Luan W, Ding Y, Ma S, Ruan H, Wang J, Lu F. Long noncoding RNA LINC00518 acts as a competing endogenous RNA to promote the metastasis of malignant melanoma via miR-204-5p/AP1S2 axis. Cell Death Dis. 2019 Nov 11;10(11):855.

11. Haqq C, Nosrati M, Sudilovsky D, Crothers J, Khodabakhsh D, Pulliam BL, Federman S, Miller JR 3rd, Allen RE, Singer MI, Leong SP, Ljung BM, Sagebiel RW, Kashani-Sabet M. The gene expression signatures of melanoma progression. Proc Natl Acad Sci U S A. 2005 Apr 26;102(17):6092-7.

12. Shain AH, Yeh I, Kovalyshyn I, Sriharan A, Talevich E, Gagnon A, Dummer R, North J, Pincus L, Ruben B, Rickaby W, D'Arrigo C, Robson A, Bastian BC. The Genetic Evolution of Melanoma from Precursor Lesions. N Engl J Med. 2015 Nov 12;373(20):1926-36.

13. Rivers JK, Rigel DS. Ruling out melanoma: A practical guide to improving performance through non-invasive gene expression testing. Skin Therapy Letter, Family Practice Edition. 2019; 14(1): 4-6.

14. Lott JP, Elmore JG, Zhao GA, Knezevich SR, Frederick PD, Reisch LM, Chu EY, Cook MG, Duncan LM, Elenitsas R, Gerami P, Landman G, Lowe L, Messina JL, Mihm MC, van den Oord JJ, Rabkin MS, Schmidt B, Shea CR, Yun SJ, Xu GX, Piepkorn MW, Elder DE, Barnhill RL; International Melanoma Pathology Study Group. Evaluation of the Melanocytic Pathology Assessment Tool and Hierarchy for Diagnosis (MPATH-Dx) classification scheme for diagnosis of cutaneous melanocytic neoplasms: Results from the International Melanoma Pathology Study Group. J Am Acad Dermatol. 2016 Aug;75(2):356-63.

15. Piepkorn MW, Longton GM, Reisch LM, Elder DE, Pepe MS, Kerr KF, Tosteson ANA, Nelson HD, Knezevich S, Radick A, Shucard H, Onega T, Carney PA, Elmore JG, Barnhill RL. Assessment of Second-Opinion Strategies for Diagnoses of Cutaneous Melanocytic Lesions. JAMA Netw Open. 2019 Oct 2;2(10):e1912597.

16. Wachsman W, Morhenn V, Palmer T, Walls L, Hata T, Zalla J, Scheinberg R, Sofen H, Mraz S, Gross K, Rabinovitz H, Polsky D, Chang S. Noninvasive genomic detection of melanoma. Br J Dermatol. 2011 Apr;164(4):797-806.

17. Elder DE. Melanoma progression. Pathology. 2016 Feb;48(2):147-54.

Most read articles by the same author(s)