Risk Factors for Lymphatic, Hematologic Metastasis of Melanoma

Risk factors differ for early-stage melanoma metastasis via the lymphatic system and the bloodstream, according to a retrospective single-center cohort study of 1,177 patients published in JAMA Dermatology. Experts contacted by Cancer Network cautioned that additional work is needed to validate the findings.

“Follow-up and adjuvant treatment strategies may therefore need to be adapted to individual clinical, histopathologic and molecular characteristics,” concluded senior study author Eduardo Nagore, MD, PhD, of Valencia Catholic University Saint Vincent Martyr, in Spain.

Patients were diagnosed with stage I or II melanoma between 2015 and 2018. They underwent wide excision and also sentinel lymph node biopsy (SLNB) when primary tumors were thicker than 0.75 mm at diagnosis or 0.75 mm or thinner with ulceration, vascular invasion, microscopic satellite loci, or at least 1 dermal-component mitosis, the authors reported.

At a median follow-up of 75 months, 216 patients had suffered metastasis (half experienced hematogenous and half lymphatic dissemination). In multivariate analyses, the risk of hematologic spread was associated with older patient age (diagnosed at age 55 years or older); primary melanoma located on the head, neck, or acral (finger, palm, sole, or nail bed) anatomies; and vascular invasion, the team reported.

Risk of hematogenous metastasis was associated with TERT promoter and BRAF mutations, although mutation status was assessed in a minority of cohort patients. The risk for both lymphatic and hematogenous metastasis was associated with greater Breslow thickness (> 4.00 mm).

The study “adds to our understanding of the biology of thin melanomas,” commented Richard Carvajal, MD, medical oncologist at Columbia University Irving Medical Center in New York. “Although a deeper evaluation of molecular mechanisms of variable dissemination patterns of thin melanomas is needed, this work provides important clinical features that, with further validation, may impact our surveillance strategies and potential use of systemic adjuvant therapies in the future.”

“With the approval of multiple effective adjuvant therapies, including nivolumab, pembrolizumab, and the combination of dabrafenib and trametinib, for lymph node–positive melanoma after primary therapy, there is greater urgency for an improved understanding of disease recurrence from earlier stage disease,” Carvajal told Cancer Network. “Indeed, even though over 90% of patients with thin stage I melanomas are cured of their disease with surgery alone, recurrence and deaths due to disease still occur, and it is critical that we develop means to identify those patients at highest risk so that we may develop preventative treatment strategies for them.”

However, the patient cohort was limited to stage I and II (sentinel node–negative) patients, cautioned Victoria Mar, PhD, MBBS, FACD, director of the Victorian Melanoma Service at Alfred Hospital and associate professor at Monash University in Melbourne, Australia.

“They have therefore excluded patients with lymphatic spread detected early with SLNB from the analysis,” she explained.

“When we analyzed a prospective cohort of just over 1,048 patients, we found that, of the 306 that developed metastatic disease, 62% developed nodal disease as the site of first metastasis, 24% direct hematogenous spread, and 12% in transit,” Mar noted. “There was little evidence to suggest that the pathway of progression to distant disease differed by mutation status, though there was a significant association between BRAF mutation status and lymph node metastasis and sentinel node positivity.”

Mar and colleagues also recently published an analysis of sentinel node–negative (stage I to II) patients in which they reported that patients with tumors harboring BRAF or NRAS mutations experienced nearly twice the hazard of relapse. When the team separately analyzed hematogenous dissemination, however, they found no evidence that mutations were associated with an elevated risk of hematogenous spread.

“Our own work does not suggest that mutation profile is a major determinant of direct hematogenous spread,” Mar told Cancer Network.

Mar had concerns with the Spanish study team’s suggestion that patients with a high risk of hematogenous metastasis (that is, those with BRAF or TERT promoter mutations) would not benefit from SLNB.

“From our own data, patients with a BRAF mutation have a significantly increased odds of SLN positivity (adjusted odds ratio, 1.55; P < .005), as well as poorer melanoma specific survival (adjusted HR, 2.95, P = .001),” she noted. “They are therefore the patients most likely to benefit from adjuvant therapy following a positive sentinel node.”

Given that a relatively low proportion of stage I to II patients will develop metastatic disease, testing mutation status as an indicator of high risk in this group would falsely assign a large number of patients as high risk, Mar said. “Like any test, we must consider how we will act on a positive result before we order it,” she noted.

“[T]here is currently no evidence that more intensive surveillance in this group of patients will improve survival,” she said. “[I]n fact, there are potential harms from false positive imaging results.”