Weight-bearing acral melanomas (high load; HL) develop on stress-bearing areas of the foot (forefoot, plantar foot, and lateral borders), whereas non-weight-bearing tumors are classified as low load (LL). HL areas experience mechanical stress, which triggers DNA damage through a YAP-mediated mechanism independent of aging.1–2 To address the limited understanding of AM pathogenesis, we compared clinicopathologic features and outcomes to define distinct clinical phenotypes and identify care disparities.
As previously described, we retrospectively identified AM cases diagnosed 2007–2022, at University of California – San Francisco Health and Zuckerberg San Francisco General Hospital.3
HL and LL groups were based on pathology narratives, clinical images, and encounter notes. After excluding in situ cases (n = 92) and 4 patients with incomplete survival data, invasive cases were compared using Fisher’s exact and Mann-Whitney U tests (P < .05). Survival was evaluated using Kaplan-Meier curves, Cox regression (centered at age 65), and Johnson-Neyman plotting using RStudio (Posit, version 2024.12.0).
Of 283 patients, 145 (51.2%) had LL and 138 (48.8%) had HL AM. HL tumors disproportionately affected Black and Hispanic patients (p = 0.016) and presented with greater median Breslow depth (p = 0.050). HL AM was preferentially managed via wide local excisions (WLEs) (p < 0.001) whereas LL AM (of which 44% (n = 60) involved the nail unit) were primarily amputated (p < 0.001). (Table 1)
Table 1:
Demographic and Clinicopathologic Characteristics of Acral Melanoma Cohort Stratified by Weight-Bearing Status (N=283). High-load (HL) tumors were significantly more frequent among Black/African American and Hispanic/Latino patients (p = 0.016) and presented with greater median Breslow depth (1.1 mm vs. 0.55 mm, p = 0.050). Notably, HL tumors were predominantly managed via wide local excision (77.8%), while low-load (LL) tumors were significantly more likely to undergo amputation (29.1%, p < 0.001). Patient characteristics were largely complete, with missing variables limited to insurance status (n = 5; 3 LL, 2 HL), race (n = 13; 9 LL, 4 HL) and pathologic staging (n = 2; 1 LL, 1 HL).
| Patients, n (%) | |||
|---|---|---|---|
| Low Load (Weight) Bearing Acral Melanomas N= 145 | High Load (Weight) Bearing Acral Melanomas N= 138 | p-value | |
| Basic Demographics | |||
| Age, median (IQR) | 64 (51–74) | 63 (54–73) | 0.982 |
| Gender (Male), n(%) | 66 (45.5%) | 60 (43.5%) | 0.811 |
| Race/Ethnicity, n (%) | 0.016*** | ||
| Non-Hispanic White | 107 (78.7%) | 85 (63.4%) | |
| Hispanic/Latino | 13 (9.6%) | 24 (17.9%) | |
| Black/African American | 2 (1.5%) | 8 (6.0%) | |
| Asian | 14 (10.3%) | 17 (12.7%) | |
| Insurance, n (%) | 0.085 | ||
| Private | 68 (47.9%) | 56 (40.6%) | |
| Medicare | 56 (39.4%) | 51 (37.0%) | |
| Medicaid | 9 (6.3%) | 22 (15.9%) | |
| Uninsured | 9 (6.3%) | 7 (5.1%) | |
| Tumor Characteristics | |||
| Breslow Depth, mm (IQR) | 0.55 (0–1.8) | 1.1 (0–2.6) | 0.050*** |
| Recurrence | 41 (28.3%) | 51 (37.0%) | 0.129 |
| Tumor Staging | 0.427 | ||
| Stage Tis | 50 (34.7%) | 42 (30.7%) | |
| Stage T1 | 40 (27.8%) | 33 (24.1%) | |
| Stage T2 | 22 (15.3%) | 29 (21.2%) | |
| Stage T3 | 24 (16.7%) | 29 (21.2%) | |
| Stage T4 | 8 (5.6%) | 4 (2.9%) | |
| Ulceration | 32 (23.2%) | 32 (22.2%) | 0.887 |
| Surgical Management | |||
| Wide Local Excision (WLE) | 47(41.2%) | 91 (77.8%) | <0.001*** |
| Amputation | 39 (29.1%) | 1 (0.7%) | <0.001*** |
| Mohs Micrographic Surgery | 20 (16.1%) | 14 (10.4%) | 0.199 |
| Clinical Course | |||
| Immunotherapy | 28 (22.6%) | 41 (30.4%) | 0.163 |
| Time to 1st Treatment (Days) (IQR) | 24 (0–54) | 8.5 (0–55) | 0.621 |
| Follow-up duration [days], median (IQR) | 516 (85–1442) | 753 (111–1771) | 0.159 |
Among 185 invasive cases (95 HL and 90 LL), HL AM showed a greater median Breslow depth (2.1 mm, interquartile range (IQR) 1.1–4.1 mm) versus LL (1.45 mm, IQR 0.6–2.6 mm) AM.
Patients aged ≥ 65 with invasive HL AM experienced a 33% reduction in 5-year overall survival (log-rank p = 0.018). Immunotherapy-treated invasive HL AM experienced a 38% reduction in 5-year overall survival versus 20% in LL AM (log-rank p = 0.0043).
Multivariate analysis showed an 8% increase in hazard ratio (HR) per year of life (HL × age: p = 0.016; HR = 1.08), with a hazard inflection point at approximately age 70 (age 45: HR = 0.19, p = 0.042; age 87: HR = 3.90, p = 0.046). (Table 2)
Table 2. Multivariate Cox Proportional Hazards Model for Overall Survival.
Interaction analysis between age and weight-bearing status in invasive acral melanoma (n=185). After adjusting for clinical stage, Breslow depth, and patient demographics, the interaction between age and high-load (HL) status was a significant independent predictor of mortality. For patients with HL tumors, each additional year of age was associated with an 8% increase in mortality hazard (HR 1.08; 95% CI [1.02–1.14]; p = 0.016). Age was centered at 65 years to ensure interpretability of the interaction term. A significant age × load-bearing site interaction was also observed (unadjusted: HR 0.93, 95%, CI 0.87–0.99, p=0.0147; multivariate: HR 0.93, 95%, CI 0.88–0.99, p=0.016). Separately, among patients who underwent sentinel lymph node biopsy, nodal invasion did not differ significantly by load-bearing status (p=0.22). While not the focus of this work, the implications of these findings for younger patients, low-load-bearing acral melanomas, and regional spread patterns warrant further study.
| Variable | Unadjusted HR (95% CI) | P-value | Fully Adjusted HR (95% CI) | P-value |
|---|---|---|---|---|
| Interaction Term | ||||
| Age × High-Load Interaction | 1.08 (1.01–1.15) | 0.0147* | 1.08 (1.01–1.14) | 0.016* |
| Covariates | ||||
| Breslow Depth (per mm) | 1.24 (1.12–1.37) | <0.001* | 1.25 (1.12–1.38) | <0.001* |
| Age (per year, centered at 65) | 1.05 (1.02–1.08) | <0.001* | 1.02 (0.98–1.06) | 0.335 |
| High-Load (Weight-Bearing) Site | 1.02 (0.48–2.16) | 0.953 | 0.79 (0.34–1.83) | 0.587 |
Surgical management differs significantly, yet WLE alone may be inadequate for older patients with HL AM given the 8% annual mortality hazard increase. Mechanical stress at weight-bearing sites, coupled with AM’s immunosuppressive microenvironment, immunosenescence, and inherently poor immunogenicity, may drive the observed mortality gradient4
The disproportionate presentation of HL AM in Black and Hispanic patients (p = 0.016) reflects structural barriers, systemic screening biases, and lack of disease awareness justifying investigation into multi-tiered, culturally tailored interventions.5
Weight-bearing status is an age-dependent risk modifier in AM. The increased mortality hazard in older patients with HL AM, coupled with demographic disparities, warrants closer clinical monitoring and targeted therapeutic evaluation in patients over age 70. Limitations include the retrospective design, cohort size and confounding by indication in immunotherapy-treated patients. Additionally, we utilized all-cause rather than melanoma-specific mortality due to low disease-specific death counts. Future studies should investigate these trends and develop targeted interventions to improve AM survival.
Supplementary Material
The supplemental figures for this article are available at Mendeley Data: Yonas, Noah (2026), “Weight Bearing Acral Melanoma Supplementary Figures”, Mendeley Data, V1, doi: 10.17632/rtx5wz8j6k.1
Funding Source:
Dr. Chang reports support from the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health under award No. K23AR082918 during the conduct of this study. This project was supported by the National Center for Advancing Translational Sciences, National Institutes of Health, through UCSF-CTSI Grant Number UL1 TR001872. The National Institutes of Health had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH.
Abbreviations:
- AM
Acral melanoma
- HR
Hazard ratio
- HL
High Load
- IQR
Interquartile range
- LL
Low Load
- ORR
Overall response rate
- PFS
Progression-free survival
- WLE
Wide local excision
- YAP
Yes-associated protein
Footnotes
Conflicts of Interest: There are no relevant financial or personal conflicts of interest associated with this manuscript. MTT has performed central pathology review and advisory board for Merck (money paid to UCSF); MTT reports relationships with Philogen (advisory board and central pathology review) and Regeneron (advisory board).
IRB: UCSF 20-33109
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