Risk factors for melanoma metastasis differ depending on whether the route is through the lymphatic system or the blood. These findings were published in JAMA Dermatology.1

Cutaneous melanoma is widely thought to spread through both lymphatic and hematogenous routes. The former route is believed to involve locoregional disease spread to skin and lymph nodes whereas the latter is associated with metastases to distant organs via the blood. What is less clear, however, is whether these processes occur sequentially or simultaneously, and whether they are dependent on each other.

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Although one model describes the progression of melanoma as involving early spread to locoregional lymph nodes and later involvement of the blood — justifying the use of sentinel lymph node biopsy in these patients — another model is based on the occurrence of simultaneous metastases through these 2 routes. Finally, a central tenant of a third model is based on differential disease spread where some melanomas are able to spread only through the lymphatic system, whereas other tumors metastasize either through the blood alone or simultaneously through the lymphatic system and the blood.

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This retrospective longitudinal cohort study conducted at a single institution used prospectively recorded demographic and clinicopathologic data on 1177 patients with cutaneous stage I/II melanoma diagnosed between January 2000 and December 2015. These patients underwent wide excision, as well as sentinel lymph node biopsy if the primary tumors were more than 0.75 mm thick. Tumor mutational status, involving BRAF, NRAS, and TERT, was assessed when possible. Markers for lymphatic invasion, including immunostaining for CD31 and antibody testing for D2-40, were evaluated in tumor specimens of all patients with evidence of vascular invasion. 

At a median follow-up of 75 months, no metastasis, lymphatic metastasis, and hematogenous metastasis developed in 1026 (87.2%), 108 (9.2%), and 108 (9.2%) patients, respectively. Of the 216 patients exhibiting metastasis, 65 had evidence of both of lymphatic and hematogenous disease spread.

On multivariate analysis, independent factors associated with increased risk for lymphatic spread of melanoma were age older than 55 years, head/neck or acral location, greater Breslow thickness, and the presence of vascular invasion or satellite lesions. In the case of hematogenous spread of disease, independent risk factors were greater Breslow thickness and the presence of TERT and BRAF mutations. In addition, the presence of histologic regression (ie, a reduction of cancers cells within an area of the tumor that is replaced by fibrosis, new vessels, and inflammatory infiltrate) was identified as a protective factor with respect to disease metastasis through the blood.

In commenting on these results, authors of an accompanying editorial stated “that increasing tumor thickness was associated with increased risk of recurrence, either lymphatic or hematogenous, comes as no surprise” and “the associations between older age and tumor location are a bit more cryptic, and may or may not represent true biologic phenomena.”2 They further commented that “the most intriguing finding of this paper is the strong potential association of the combination of both mitogen activated protein kinase (either BRAF or NRAS) and TERT promoter mutations with poor survival.”2

Study limitations included its retrospective design, as well as the absence of data on tumor mutational status for many patients.

“Our study shows that the prognostic factors associated with lymphatic and hematogenous metastasis differ, supporting the model of differential spread,” noted the study authors.

“A greater understanding of the clinical, histopathologic, and molecular factors involved could help to identify patients with an increased risk of recurrence and guide the design of individualized follow-up programs and adjuvant targeted therapies,” commented the study authors.


1. Calomarde-Rees L, García-Calatayud R, Requena Caballero C, et al. Risk factors for lymphatic and hematogenous dissemination in patients with stages I to II cutaneous melanoma. JAMA Dermatol. 2019;155(6):679-687. 2. Coit DG. The changing kinetics of advanced melanoma. JAMA Dermatol. 2019;155(6):657-659.