Age at Diagnosis Impacts Timing and Extent of Melanoma Metastases

Elderly patients diagnosed with melanoma appear to experience less extensive metastatic disease than adults diagnosed at younger ages, despite shorter distant metastasis-free survival (DMFS) times, according to a study published in the Journal of the American Academy of Dermatology.

“The number of metastatic sites decreased with increasing age at melanoma diagnosis” [P < .001], the authors reported. “Distant metastases occurred earlier and more synchronized in patients older than 70 years than in patients aged 50 years or younger…Pattern, timing and extent of distant metastasis change as people age.”

Women had lower numbers of metastatic sites than men, the authors also reported.

Lung metastasis rates were comparable across ages, but only 30% of patients older than age 70 years had central nervous system (CNS) metastases, compared with 50% of those younger than age 50 years. Elderly patients also had significantly lower rates of metastasis to distant lymph nodes, liver, bone, or intestine than did younger patients.

The study was not population-based research, the authors cautioned. A cohort of 1,457 patients in the German Central Malignant Melanoma Registry and 1,682 patients from 5 different cancer centers were included in the analysis.

Melanoma incidence rates are known to increase among older people, and older age is known to correlate with better immunotherapy response among patients with late-stage melanoma. Previous research has also shown that older age at melanoma diagnosis is associated with a lower rate of sentinel lymph node involvement.

The study’s findings bolster the case that the aging process might also modulate the risk of metastasis among those who are diagnosed with melanoma. But the nature of the association between aging and the molecular processes that drive metastasis are not yet clear, the authors noted.

The study might have under-represented later-emerging metastatic disease, such as CNS and intestinal metastases, according to the investigators. But lower rates of distant melanoma metastasis among elderly patients might also reflect slower growth of micrometastases because of angiogenic dormancy (poor tumor neovascularization), they noted.

“This is an interesting study, and I think an increasingly important area for future study – the better understanding of the differential pattern of recurrence of melanoma across age groups and the differential responsiveness to immunotherapies with respect  to age,” commented Giorgos C. Karakousis, MD, associate professor at the Abramson Cancer Center, University of Pennsylvania, in Philadelphia.

“The findings are particularly intriguing since many prior studies have generally shown a decrease in regional lymph node metastases thickness for thickness of primary melanomas yet a worse disease-specific survival in older patients compared to younger patients,” Karakousis told Cancer Network.

There are “several plausible explanations” for age-related differences, Karakousis said, including differential lymphatic permeability across age groups-an effect Karakousis and colleagues have separately demonstrated.

But the field of age-related tumor biology is still young, he cautioned. “We still lack a very good understanding of what is happening from a tumor/host interaction perspective as we age,” Karakousis said.

“Metastasis is a multistep process that requires cancer cells to invade the surrounding tissue, enter the circulation, seed at distant sites, and grow,” the study authors noted. “In the last few decades, it has become increasingly evident that tumor progression is not solely determined by cell-intrinsic mechanisms but also by factors and nonmalignant cells in the tumor microenvironment that can exert inhibitory or promoting effects on metastasis formation and underlie age-related changes.”

In an interview with Cancer Network, Sapna Patel, MD, associate professor at The University of Texas MD Anderson Cancer Center in Houston, noted, "Older age at cancer diagnosis has been associated with less aggressive phenotypes in other cancers-specifically, breast, colon, and kidney cancers. So this finding of lower number of metastasis in melanoma may be part of the same age-related phenomenon."

"Additionally, increasing age has been associated with less sentinel lymph node positivity in melanoma. There may be many age-related changes to explain these findings, specifically changes in the tumor microenvironment and the vascularization of tumors as we get older,” Patel said.