Molecular techniques explain potential nevoid pathways to melanoma

Panama City, Panama - Many of the current definitions of skin diseases used in dermatology have changed and morphed over the years, as clinicians learn more and amass volumes of new information regarding many different features, characteristics and associations of dermatologic diseases.

The establishment of currently accepted definitions of different dermatologic diseases was - and in some cases still is - a work in progress. In many areas this has been refined by the current studies in molecular pathology, according to a clinician who spoke at the North American Dermatological Society meeting recently.

Steven Kossard, M.D., presented a 30-year retrospective of his observations and publications. Under the theme “Defining Dermatological Diseases,” one of the topics was atypical lentiginous nevi of the elderly as a precursor to lentigo maligna, originally defined by his group in 1991.

“Ultimately, the most significant definitions combine distinct clinical features with distinct histopathology that permit both clinicians and pathologists to reach the correct diagnosis. Others may have either distinct clinical or distinct histopathology features that can be recognized and finally, both aspects may be indistinct but in combination represent an important tissue reaction such as urticarial dermatitis defined by our group,” says Dr. Kossard, associate professor of dermatology, Skin & Cancer Foundation Australia, Darlinghurst.

Melanoma precursors

Following his return to Australia in 1980 after training at the Mayo Clinic, Dr. Kossard says some of the biggest challenges were the boundaries in defining malignant melanoma simulating nevi. The most common melanoma in elderly patients with chronic sun exposure is lentigo maligna, which traditionally is mainly localized to the facial skin. Dysplastic nevi had been defined at the time by Wallace Clark, M.D., with onset in young individuals and were often multiple. These dysplastic nevi were not usually a direct precursor to melanoma except in the familial cases but were a risk factor.

Dr. Kossard’s group recognized a distinct subset of dysplastic (atypical) nevi occurring in elderly sun-damaged patients that were usually located on the trunk and limbs. These nevi were usually recognized clinically as atypical by dermatologists. Significantly, these nevi shared features with melanoma particularly when examined by dermoscopy, a tool that was introduced into clinical practice at that time.

Lentiginous dysplastic nevus of the elderly is often a large lesion greater than 1 cm in diameter and typically solitary. According to Dr. Kossard, the main challenge and controversy was the histopathology, which had a nevoid pattern with nests of often-bland melanocytes localized to the tips of the rete ridges. Understandably, these nevi were equated to the dysplastic nevi described by Clark.

At least 60 percent of the nevi in the original study by Dr. Kossard’s group, however, showed areas of epidermal atrophy and confluence of small hyperchromatic nevoid melanocytes as well as superficial dermal fibrosis representing regression. These features closely matched the histopathology seen with lentigo maligna of the face. At that time, these lesions were not recognized as a variant of lentigo maligna because of the nevoid precursor. On the face, lentigo maligna often starts with increased atypical melanocytes at the junction, Dr. Kossard says, which in time become confluent and extend down the appendages but are usually not nested or nevoid.

“At the time, it seemed that with chronic sun-damaged skin, a pathway to developing nevi existed but in this setting, the nevi were atypical and were unstable in contrast to the majority of Clark’s nevi,” he says. “Our group subsequently described more advanced melanomas that were nevoid and nested that evolved from the dysplastic nevi of the elderly. These concepts were very controversial at the time.”

Next: Nevoid progression

Nevoid progression

According to Dr. Kossard, it is only recently that there has been molecular work utilizing in situ hybridization and comparative genomic analysis techniques that these variants have gained more general recognition. The lentiginous dysplastic nevi of the elderly and nevoid nested forms of melanoma and the wider spectrum of lentigo maligna has been recognized due to mutational features detected by these techniques that have been demonstrated in other melanoma variants.

“I do think that there are dysplastic nevi in the elderly that have not evolved into melanoma but still represent a precursor rather than a marker for melanoma. There are usually few such nevi at any time and conservative removal is recommended,” Dr. Kossard says. “Larger lesions with transition to melanoma should be treated as such. There are rare elderly individuals who have multiple atypical nevi and melanomas and need to be monitored and managed on a regular basis.”

The controversy regarding this nevoid pathway to melanoma has decreased as a result of the recent findings provided by these molecular techniques. However, the significance and the ultimate prognosis of these nevoid melanoma variants still need to be established. According to Dr. Kossard, lentigo maligna evolving from dysplastic nevi of the elderly has the same indolent in situ phase as those observed on the face.

“The challenge of defining this variant of melanoma was significantly helped by correlating the clinical and dermoscopy features with the histopathology and was a lesson,” he says.

Disclosures: Dr. Kossard reports no relevant financial interests.