Genetic Analysis Confirms Intermediate Lesions with Malignant Melanoma Potential

Genetic mutation analysis confirms the malignant potential of intermediate skin lesions that are neither benign moles nor yet melanomas, researchers report in TheNew England Journal of Medicine.¹

The study “identified an intermediate category of melanocytic neoplasia, characterized by the presence of more than one pathogenic genetic alteration and distinctive histopathological features,” the authors reported.¹

The researchers sequenced 293 cancer-associated genes from formalin-fixed, paraffin-embedded melanoma tumors and adjacent precursor lesions from 37 patients. They conducted micro-dissections to sequence mutations from 150 areas of the primary melanomas and adjacent precursor lesions, and asked eight pathologists to independently examine the micro-dissected biopsy samples.¹

“There’s good agreement between the pathologists’ assessments at the extremes of the spectrum, but less so with intermediate lesions” said Dr. Shain. “On a genetic level, however, this work clearly shows that there are intermediate lesions. These things really exist-it’s not a binary situation.”

“Unequivocally benign lesions harbored BRAF V600E mutations exclusively, whereas those categorized as intermediate were enriched for NRAS mutations and additional driver mutations,” explained lead author A. Hunter Shain, PhD, of the UC San Francisco Helen Diller Family Comprehensive Cancer Center, and coauthors.¹ “A total of 77% of areas in intermediate lesions and melanomas in situ harbored TERT promoter mutations, a finding that indicates that these mutations are selected at an unexpectedly early stage of the neoplastic progression.”

In contrast, CDKN2A inactivation mutations were found only in invasive melanomas, while PTEN and TP53 mutations were found only in advanced melanomas.¹

The study also bolstered the epidemiologic understanding of ultraviolet radiation as a “major factor in both the initiation and progression of melanoma,” the authors reported.¹ “The point-mutation burden increased from benign through intermediate lesions to melanoma, with a strong signature of the effects of ultraviolet radiation detectable at all evolutionary stages.”

The study might help resolve a longstanding controversy about the malignant potential of morphologically intermediate lesions.

“What happens to patients now is totally unstandardized,” noted senior study author Boris Bastian, MD, PhD, Gerson and Barbara Bass Baker Distinguished Professor of Cancer Research at the UC San Francisco Helen Diller Family Comprehensive Cancer Center.

“Some doctors consider these ‘intermediate’ types of lesions to be entirely benign, or shave off only part of the lesion and leave something behind,” Dr. Bastian said. “But others treat it as an early melanoma.”

The new study should “open the door to understanding how risky these lesions are when they should be completely removed,” he said.

References:

1. Shain AH, Yeh I, Kovalyshyn I, et al. The genetic evolution of melanoma from precursor lesions. N Engl J Med. 2015; 373:1926-36.