Time course and pattern of metastasis of cutaneous melanoma differ between men and women

Abstract

Background: This study identified sex differences in progression of cutaneous melanoma.

Methodology/principal findings: Of 7,338 patients who were diagnosed as an invasive primary CM without clinically detectable metastases from 1976 to 2008 at the University of Tuebingen in Germany, 1,078 developed subsequent metastases during follow up. The metastatic pathways were defined in these patients and analyzed using the Kaplan-Meier method. Multivariate survival analysis was performed using Cox modeling. In 18.7% of men and 29.2% of women (P<0.001) the first metastasis following diagnosis of primary tumor was locoregional as satellite/in-transit metastasis. The majority of men (54.0%) and women (47.6%, P = 0.035) exhibited direct regional lymph node metastasis. Direct distant metastasis from the stage of the primary tumor was observed in 27.3% of men and 23.2% of women (P = 0.13). Site of first metastasis was the most important prognostic factor of survival after recurrence in multivariate analysis (HR:1.3; 95% CI: 1.0-1.6 for metastasis to the regional lymph nodes vs. satellite/in-transit recurrence, and HR:5.5; 95% CI: 4.2-7.1 for distant metastasis vs. satellite/in-transit recurrence, P<0.001). Median time to distant metastasis was 40.5 months (IQR, 58.75) in women and 33 months (IQR, 44.25) in men (P = 0.002). Five-year survival after distant recurrence probability was 5.2% (95% CI: 1.4-2.5) for men compared with 15.3% (95% CI: 11.1-19.5; P = 0.008) for women.

Conclusions/significance: Both, the pattern of metastatic spread with more locoregional metastasis in women, and the time course with retracted metastasis in women contributed to the more favorable outcome of women. Furthermore, the total rate of metastasis is increased in men. Interestingly, there is also a much more favorable long term survival of women after development of distant metastasis. It remains a matter of debate and of future research, whether hormonal or immunologic factors may be responsible for these sex differences.

Figure 1. Probability for developing metastases.

Probability for developing metastases (A), and distant metastases (B) after the diagnosis of primary cutaneous melanoma in 7,338 patients, 3,347 men and 3,991 women. P values are based on the log-rank test.

Figure 2. Probability for developing metastases.

Probability for developing metastases (A), and distant metastases (B) in 1,078 patients (561 men and 517 women) who were diagnosed at the stage of primary cutaneous melanoma and then progressed by the time of analysis. P values are based on the log-rank test.

Figure 3. Three metastatic pathways of melanoma.

Pathway 1 – primary tumor, then satellite/in-transit metastases, pathway 2 – primary tumor, then regional lymph node metastasis, and pathway 3 – primary tumor, then distant metastasis. M, men; W, women.

Figure 4. Survival after recurrence.

Survival after recurrence in patients who progressed first to satellite/in-transit (A), regional lymph node (B), and distant metastases (C). P values are based on the log-rank test.