Clinical Use of a Diagnostic Gene Expression Signature for Melanocytic Neoplasms

Ambiguous melanocytic neoplasms evaluated without the aid of molecular adjuncts often result in equivocal or less-than-definitive diagnoses, and further surgical intervention is commonly undertaken to mitigate against the possibility of a missed melanoma.¹³ In this study, treatment that was aligned with the benign test result allowed most patients to avoid further surgical intervention, which suggests that adjunctive use of the gene signature can contribute to reductions in the physical and economic burdens imposed by unnecessary surgical interventions.^15,16 Moreover, any means of increasing accurate and definitive diagnoses may produce an immediate impact on health outcomes by reducing the anxiety that uncertainty often provokes in patients and health care providers alike.

Study Limitations
This study must be interpreted within the context of its limitations. Obtaining meaningful patient outcome data is a common challenge in health care research due to the requisite length of follow-up and sometimes the lack of definitive evidence of adverse events. This is particularly difficult for melanocytic neoplasms because of an apparent inclination for patients with benign diagnoses to abandon follow-up and an increasing tendency for even minimal diagnostic uncertainty to prompt complete excision. Additionally, the only definitive clinical outcome for melanocytic neoplasms is distant metastasis, which (fortunately for patients) is relatively rare. Not surprisingly, studies documenting clinical outcomes of patients with ambiguous melanocytic neoplasms tested prospectively with diagnostic adjuncts are scarce, and this study’s sample size and clinical follow-up compare favorably with the few that exist.^17,18 Although most melanomas declare themselves through recurrence or metastasis within several years of initial biopsy,^1,19 some are clinically dormant for as long as 10 years after initial detection.^20,21 This may be particularly true for the small or early-stage lesions that now comprise the majority of biopsied neoplasms, and such events would go undetected by this study and many others. It also must be recognized that uneventful follow-up, regardless of duration, cannot prove that a biopsied melanocytic neoplasm was benign. Although only 5 patients had a follow-up time of less than 2 years (the time frame in which most recurrence or metastasis will occur), it cannot be definitively proven that a minimum of 2 years recurrence- or metastasis-free survival indicates a benign lesion. Many early-stage malignant melanomas are eradicated by complete excision or even by the initial biopsy if margins are uninvolved.

Because these limitations are intrinsic to melanocytic neoplasms and current management strategies, they pertain to all investigations seeking insights into biological potential through clinical outcomes. Similarly, all current diagnostic tools and procedures have the potential for sampling error, including histopathology. The rarity of adverse outcomes (recurrence and metastasis) in patients with benign test results within this cohort indicates that false-negative results are uncommon, which is further evidenced by a similar rarity of adverse events in prior studies of the gene expression signature.^8-10,22 A particular strength of this study is that most of the ambiguous melanocytic neoplasms followed did not undergo excision after the initial biopsy, an increasingly uncommon situation that may increase their likelihood to be informative.

It must be emphasized that the gene expression test, similar to other diagnostic adjuncts, is neither a replacement for histopathologic interpretation nor a substitute for judgment. As with all tests, it can produce false-positive and false-negative results. Therefore, it should always be interpreted within the constellation of the many other data points that must be considered when making a distinction between benign nevus and malignant melanoma, including but not limited to patient age, family and personal history of melanoma, anatomic location, clinical features, and histopathologic findings. As is the case for many diseases, careful consideration of all relevant input is necessary to minimize the risk of misdiagnosis that might occur should any single data point prove inaccurate, including the results of adjunctive molecular tests.

Conclusion

Ancillary methods are emerging as useful tools for the diagnostic evaluation of melanocytic neoplasms that cannot be assigned definitive diagnoses using traditional techniques alone. This study suggests that patients with ambiguous melanocytic neoplasms may benefit from diagnoses and treatment decisions aligned with the results of a gene expression test, and that for those with a benign result, simple observation may be a safe alternative to surgical excision. This expands upon prior observations of the test’s influence on diagnoses and treatment decisions and supports its role as part of dermatopathologists’ and dermatologists’ decision-making process for histopathologically ambiguous melanocytic lesions.