Abstract
Background/Aim: Acral lentiginous melanoma (ALM) is the least common subtype of cutaneous melanoma and typically occurs on the palms, soles, and nails. Tumor characteristics and disease severity in the US population are not well understood. Our aim was to analyze the characteristics of ALM of the extremities. Patients and Methods: We queried the National Cancer Database to identify patients with the diagnosis of ALM and common malignant melanoma located in the extremities (CMME). We compared demographic, tumor, and treatment characteristics between patients with ALM and those with CMME. Statistical analysis was performed with chi-squared test and multivariate logistic regression models. Results: We identified 5,203 patients with ALM and 118,485 with CMME. When compared with patients with CMME, those with ALM were more likely to be older than 80. years at diagnosis [odds ratio (OR)=2.85, 95% confidence intervaI (CI)=2.12-3.82; p<0.001], have stage III disease (OR=4.22, 95% CI=1.47-12.16; p=0.01), and have ulceration (OR=1.52, 95% CI=1.33-1.74; p<0.001). Moreover, patients with ALM were less likely to have a mitotic count of 1/mm2 or greater (OR=0.57, 95% CI=0.48-0.67; p<0.001). No statistical difference was found for sex, lymph node involvement, regression, and use of surgery, radiotherapy, and immunotherapy between groups. Conclusion: Age, disease stage, ulceration, and mitotic count are independent factors associated with ALM. Knowledge of the disease characteristics may allow for better diagnosis and understanding of disease pathophysiology.
Acral lentiginous melanoma (ALM) is the rarest melanoma subtype with worst prognosis in the United States, accounting for approximately 1% to 7% of all melanomas in White persons (1). ALM primarily affects the glabrous skin of the palms and soles, including the nails of the upper and lower extremities (2). It is characterized by proliferation of atypical melanocytes in the dermoepidermal junctions and extension into deeper structures when invasive (3).
ALM is challenging to diagnose with the classic ABCDE criteria (asymmetry, border irregularity, color variation, diameter greater than 6 mm, and evolving characteristics). The pigmentation of a benign melanocytic nevus located in an acral site extends along the skin markings of the palms and soles, therefore mimicking malignant lesions (1). Moreover, an ALM lesion can be technically difficult to biopsy because of its location (2).
Regarding prognostic factors, only age, ulceration and tumor thickness were found to be associated with ALM in Brazilian and German patients (4). Improved understanding of the prognostic factors of ALM in the US population will allow healthcare providers to determine the disease status and improve management. The aims of this study were to analyze the characteristics of ALM and to compare them with those of common malignant melanoma located in the extremities (CMME).
Patients and Methods
We performed a retrospective analysis of ALM and CMME cases that were registered in the National Cancer Database (NCDB) from January 1, 2004, through December 31, 2015. We included patients with a confirmed histopathological diagnosis of ALM or CMME. Although CMME was classified as melanoma of the extremities with the histologic characteristics of “malignant melanoma not otherwise specified”, this definition included patients with melanoma not specified at diagnosis and located in the upper and lower extremities. Patients with melanoma classified as other histological types or located in sites other than the extremities were excluded from the study. Patients with missing data were also excluded from the analysis.
Statistical analysis. We compared demographic and tumor characteristics by using the chi-squared test. After adjustment for age and sex, multivariate logistic regression was performed to compare the risks of tumor characteristics in patients with ALM with those with CMME. Odds ratios (ORs) and confidence intervaIs (CIs) were calculated to compare the groups, and p<0.05 was considered statistically significant. All analyses were performed with SPSS software version 25 (IBM, Armonk, NY, USA).
Results
A total of 5,203 patients had ALM, and 118,485 had CMME. Mean age (±SD) at diagnosis of ALM was 64.3 ± 15.41 years. Most patients were White (84%) and women (54.9%), and almost half were between 61 and 80 years old (45.6%) (Table I). The most common severity of ALM was stage I (36.6%). Common tumor characteristics included Breslow depth of 1 mm or less (32.3%), absence of ulceration (60.7%), mitotic count of 1/mm2 or greater (32.7%), positive lymph node status (66%), and absence of regression (40.7%). In addition, 98.8% of patients with ALM underwent surgical procedures, without radiotherapy (97.3%) or immunotherapy (91.7%) (Table I).
Compared with those with CMME, patients with ALM were more likely to be older than 80 years at diagnosis (OR=2.85, 95% CI=2.12-3.82; p<0.001), have stage III disease (OR=4.22, 95% CI=1.47-12.16; p=0.01), and have ulceration (OR=1.52, 95% CI=1.33-1.74; p<0.001). However, compared with patients with CMME, those with ALM were less likely to have a mitotic count of 1/mm2 or greater (OR=0.57, 95% CI=0.48-0.67; p<0.001). No statistical difference was found for sex, lymph node involvement, regression, and use of surgery, radiotherapy, and immunotherapy between groups (Table II).
Discussion
To our knowledge, this study analyzed the largest number of patients with ALM (n=5,203) in the United States. In 1976, Reed defined ALM for the first time as pigmented lesions on the extremities, particularly on the palms and soles, characterized by a radial (i.e., lentiginous) growth pattern that evolves over months or years to a vertical invasive stage (5). Classic risk factors for melanoma, including sun exposure, fair skin, and preexisting melanocytic nevi, do not seem to apply to ALM (6). Previous trauma (6), pressure (7), and distinct genomic mutations (8) may promote the development of ALM. Compared with other subtypes, ALM has the worst prognosis because of its inherent biological behavior and the difficulty in identifying lesions (9). Melanocytes in acral skin lack hair follicles; therefore, they do not contain melanocytic stem cells and are more susceptible to replicative stress and genomic aberrations (2). Knowledge of clinical factors is useful for clinical suspicion and diagnosis of melanotic lesions in acral areas. Previous studies have shown that being male (6), and having a more advanced pathological stage (10, 11), greater Breslow thickness (12), the presence of ulceration (12), more than 15 mitoses/mm2 (11), and sentinel lymph node positivity (12) are independent prognostic factors for patients with ALM.
In our study, more than one-half of all patients with ALM received the diagnosis of stage II disease or greater. In addition, almost one-third had a Breslow depth greater than 1 mm, ulceration, and a mitotic count of 1/mm2 or greater. These findings suggest that many patients had advanced disease at the time of diagnosis and thus had a higher risk of death. Lino-Silva et al. analyzed the characteristics of 715 patients with ALM and reported that the 5-year disease-specific survival decreased as disease stage increased: 53.5% for patients with stage I ALM, 52.7% for those with stage II, and 40.8% for those with stage III (13). Bradford et al. reported similar results for 10-year survival, and they reported that patients with ALM had a 10.% to 15% lower survival rate than patients with CMM (10). Patients diagnosed with ALM were also more likely to be older; this was most likely attributable to misdiagnosis, which occurs in approximately 40.% of patients (14).
We found a high percentage of patients with ALM (66%) had a positive sentinel lymph node at diagnosis, although this was not a factor associated with ALM. These findings highlight the importance of performing lymph node biopsy during initial management and serial physical examinations during follow-up. In a series of 281 patients, Bello et al. demonstrated that a more advanced disease stage, the presence of ulceration, a greater Breslow thickness, and a positive sentinel lymph node were prognostic factors associated with poor survival, and patients with ALM had worse survival than patients with nonacral cutaneous melanoma (12). Ulcerations in patients with CMM were related to a biological phenomenon resulting from proliferative cell activity and overexpression of c-MYC; in comparison, ALM may be related to previous trauma (15).
Interestingly, patients with ALM had a lower likelihood of having a mitotic count of 1/mm2 or greater. Although whether the mitotic count is a prognostic factor for patients with ALM remains controversial, our results are consistent with those of other studies that did not find any statistical difference in the association with survival (12, 16). In contrast, Lv et al. identified a higher mitotic rate of greater than 15/mm2 as an independent prognostic factor for ALM (11). These differences may be related to variance in the mitotic rates calculated in these studies.
This study has limitations. We collected data from the NCDB, and thus our results were limited by the accuracy of data provided nationally. To obtain the most reliable results, we excluded patients with missing data, which might have affected the models. Furthermore, the NCDB likely misrepresents ALM owing to under-reporting by health care providers and hospitals. However, we are reassured that the results obtained from this study are concordant with those of similar studies.
Conclusion
We determined that being older, with a more advanced disease stage, a greater Breslow depth, presence of ulceration, and absence of mitosis are factors independently associated with ALM compared with CMME. Knowledge of these factors may help improve the diagnosis and treatment of this aggressive cancer. Nevertheless, further prospective studies are needed to better understand the pathophysiology and other potential risk factors of ALM.
Acknowledgements
This study was supported in part by the Mayo Clinic Center for Individualized Medicine and by the Plastic Surgery Foundation.
Footnotes
Authors' Contributions
MTH, DJR and AJF had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: MTH, AJF, SPB, ACS. Acquisition, analysis, or interpretation of data: ACS, MTH, AJF. Drafting of the article: MTH, DJR, DB, RAV. Critical revision of the article for important intellectual content: SPB, ACS, BDR and AJF. Study supervision: BDR, AJF
Conflicts of Interest
The Authors have no conflicts of interest to declare regarding this study.
- Received April 13, 2020.
- Revision received April 18, 2020.
- Accepted April 22, 2020.
- Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved