Knowledge of genetic expression of melanocytic lesions significantly reduced the number of indeterminate diagnoses made by dermatopathologists.
Loren Clarke, MD
Knowledge of genetic expression of melanocytic lesions significantly reduced the number of indeterminate diagnoses made by dermatopathologists, according to results from a prospective study on the utility of the Myriad myPath Melanoma molecular diagnostic test, presented November, 2014 at the 2014 American Society of Dermatopathology meeting in Chicago, Il.1
Each year in the United States, over 70,000 new melanoma cases are diagnosed, and more than 9000 patients die from melanoma. The 5-year survival rate for stage 1 melanoma is approximately 97%. Misdiagnosis, however, can lead to inadequate treatment with possible spread of the disease and increased stage. The 5-year survival rate for stage IV disease is approximately 15% to 25%.2
The current standard for diagnosis of malignant melanoma is histopathologic analysis. Numerous studies, however, have shown that the diagnosis can be difficult for practitioners, and discordance often occurs even among experienced dermatopathologists.
“There are approximately 1.5 million biopsies done in [the United States] alone for atypical moles in an effort to exclude the possibility of melanoma each year. We estimate…that approximately 15% of those, maybe more, are indeterminate or difficult to diagnose,” said Loren Clarke, MD, study coauthor and vice president of Medical Affairs of Dermatology at Myriad Genetics.3
"Unfortunately, some melanomas mimic benign skin lesions, making them very difficult to diagnose and an uncertain result is confusing for patients and clinicians. What we need is a new tool to help us make a more definitive diagnosis," said coauthor Sancy Leachman, MD, PhD, chair of the department of dermatology at the Oregon Health & Science University School of Medicine and director of the Melanoma Research Program at the Knight Cancer Institute.4
One such tool is a molecular assay that analyzes gene expression of the lesion. Prior research, using quantitative reverse transcription polymerase chain reaction (qRT-PCR), identified a 23-gene expression signature of melanocytic lesions. This gene signature includes genes that regulate cell differentiation, immune function, and cellular housekeeping.
Using the gene signature, a Melanoma Diagnostic Score (MDS) was calculated and used to differentiate between benign and malignant lesions. The MDS was shown to discriminate between benign nevi and malignant melanoma with 93% specificity and 89% sensitivity (P= 2 × 10-63).5
The clinical utility of the MDS was further validated with the current study. Melanocytic lesions were submitted by dermatopathologists with a questionnaire containing questions regarding diagnosis, diagnostic confidence, and recommended medical management. Prior to myPath testing of the 687 lesions, 14.8% had an indiscriminate diagnosis and 17.2% had lower diagnostic confidence. The lesions then underwent qRT-PCR and an MDS was calculated for each lesion.
The MDS was then given to the submitting dermatopathologist who was asked to complete a post-test questionnaire. The answers given on the questionnaires showed that with the additional gene expression information, 76.5% of indeterminate diagnoses were revised to more definitive ones. Most revisions (58.8%) downgraded the diagnosis to benign. After receiving the MDS, the pathologists recommended less invasive management in 23.5% of the cases and more invasive management in 11.6% of the cases.
Reducing the number of indeterminate diagnoses is highly desirable for patients and their doctors. "Patients and physicians with an indeterminate biopsy result face the challenging clinical question of whether to treat the lesion as melanoma or risk not treating a potentially fatal cancer," said Clarke.6
"In the validation study, Myriad myPath Melanoma was shown to differentiate malignant melanoma from benign skin lesions using traditional dermatopathology as a gold standard. This represents a significant contribution toward making a prompt and accurate diagnosis of potentially fatal melanoma," said Leachman.
The researchers note that this test should be incorporated into the current diagnostic approach. "These data strongly support the integration of the Myriad myPath Melanoma test into clinical practice to personalize and improve patient care," said Clarke. "The Myriad myPath Melanoma test objectively answers a vital clinical question for physicians: Does my patient have malignant melanoma that requires aggressive intervention, or a harmless skin lesion that should be monitored?"
Loren Clarke, MD, is an employee of Myriad