Analysis of Recurrence Patterns in Acral Versus Nonacral Melanoma: Should Histologic Subtype Influence Treatment Guidelines?

Current surgical treatment of primary melanoma is uniform for all histosubtypes, although certain types of melanoma, such as acral lentiginous melanoma (ALM), have a worse prognosis. No study has explored the effectiveness of standard melanoma treatment guidelines for managing ALM compared with nonacral melanoma (NAM). Study subjects were identified from a prospectively enrolled database of patients with primary melanoma at New York University. Patients with ALM were matched to those with NAM (1:3) by gender and melanoma stage, including substage (ALM, 61; NAM, 183). All patients received standard-of-care treatment. Recurrence and survival outcomes in both cohorts were compared. ALM histologic subtype was an independent negative predictor of recurrence-free survival (hazard ratio [HR], 2.24; P=.001) and melanoma-specific survival (HR, 2.58; P=.001) compared with NAM. Recurrence was significantly more common in patients with ALM than in those with NAM (49% vs 30%; P=.007). For tumors less than 2 mm in thickness, a significantly higher recurrence rate was seen with ALM versus NAM (P=.048). No significant difference was seen in recurrence for tumors greater than 2 mm (P=.12). Notably, the rate of locoregional recurrence was nearly double for ALM compared with NAM (P=.001). The data presented herein reveal a high rate of locoregional failure in ALM compared with NAM when controlling for AJCC stage. These results raise the question of whether ALM may require more aggressive surgical treatment than nonacral cutaneous melanomas of equal thickness, particularly in tumors less than 2 mm thick. Larger multicenter trials are necessary for further conclusions.

Abstract

Current surgical treatment of primary melanoma is uniform for all histosubtypes, although certain types of melanoma, such as acral lentiginous melanoma (ALM), have a worse prognosis. No study has explored the effectiveness of standard melanoma treatment guidelines for managing ALM compared with nonacral melanoma (NAM). Study subjects were identified from a prospectively enrolled database of patients with primary melanoma at New York University. Patients with ALM were matched to those with NAM (1:3) by gender and melanoma stage, including substage (ALM, 61; NAM, 183). All patients received standard-of-care treatment. Recurrence and survival outcomes in both cohorts were compared. ALM histologic subtype was an independent negative predictor of recurrence-free survival (hazard ratio [HR], 2.24; P=.001) and melanoma-specific survival (HR, 2.58; P=.001) compared with NAM. Recurrence was significantly more common in patients with ALM than in those with NAM (49% vs 30%; P=.007). For tumors less than 2 mm in thickness, a significantly higher recurrence rate was seen with ALM versus NAM (P=.048). No significant difference was seen in recurrence for tumors greater than 2 mm (P=.12). Notably, the rate of locoregional recurrence was nearly double for ALM compared with NAM (P=.001). The data presented herein reveal a high rate of locoregional failure in ALM compared with NAM when controlling for AJCC stage. These results raise the question of whether ALM may require more aggressive surgical treatment than nonacral cutaneous melanomas of equal thickness, particularly in tumors less than 2 mm thick. Larger multicenter trials are necessary for further conclusions.

Acral lentiginous melanoma (ALM), which occurs on the palms, soles, or nail apparatus, accounts for approximately 1% to 15% of melanomas in the United States, depending on the predominant ethnic background.1 Although the incidence of ALM is similar across racial and ethnic groups, it represents a disproportionately high percentage of melanomas among patients with skin of color.2 Despite its relatively low incidence, ALM is particularly important because it carries a worse prognosis than other main melanoma subtypes.2 The cause of this finding is controversial.215 In previous studies, poor outcomes in ALM have been explained by a delay in diagnosis8,10,1618 because of its unusual and uncommon presentation. Several more recent studies, however, have shown that ALM has worse survival outcomes than nonacral melanoma (NAM), even after controlling for melanoma stage.2,19 This suggests that inherent molecular/biologic differences2022 in ALM may also contribute to poor outcomes.

One major limitation of these studies is a lack of data on recurrent disease because of inadequate patient follow-up. Because recurrence is a critical predictive factor of patient survival, poor outcomes in ALM may be explained by differences in recurrence patterns between ALM and NAM. No studies have compared recurrence in ALM versus NAM. However, 2 studies analyzing recurrence exclusively in ALM reported recurrence rates of 25% to 30%, with most patients presenting with a local or regional recurrence in the involved extremity.5,7 Possible explanations for this observation, other than standard risk factors for recurrence, such as an elevated Breslow thickness, ulceration, mitoses, and sentinel lymph node involvement, include inadequate surgical margins. Margins less than 2 cm, however, were not associated with an increased risk of locoregional recurrence in a retrospective study.5

To date, no study has explored the effectiveness of standard melanoma treatment guidelines in the management of ALM compared with NAM. In particular, although ALM carries a poor prognosis, it is treated with the same surgical resection margins as NAM; current surgical treatment guidelines are uniform for all melanoma histosubtypes. This study compares recurrence patterns and survival outcomes in ALM versus NAM in a stage-matched cohort of patients prospectively enrolled in the New York University (NYU) Interdisciplinary Melanoma Cooperative Group (IMCG) database. The investigators aim to integrate data on primary treatment, recurrence, and survival to raise the question of whether ALM tumors should require more aggressive surgical treatment than NAM tumors of equal thickness.

Materials and Methods

Study Population

Patients who presented for treatment of primary invasive melanoma at NYU from September 2002 to August 2013 and provided written informed consent were prospectively enrolled in the IMCG database. Study subjects were accrued within 2 months of primary melanoma treatment. All patients underwent wide local excisions with standard margins and a sentinel node biopsy if indicated by NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Melanoma. The Institutional Review Board at NYU approved this study.

Clinical and demographic data, including gender, race, age at first melanoma diagnosis, anatomic site of melanoma, and AJCC stage at diagnosis, were recorded for each patient. The initial biopsy date of the primary tumor was used as the date of diagnosis; it was also used to calculate age at diagnosis, time to recurrence, and follow-up time. Surgical margin width, lymph node status, and histologic tumor characteristics, including melanoma subtype, Breslow thickness, ulceration, and mitotic index, were extracted from medical records. The IMCG pathologist, Farbod Darvishian, MD, confirmed all tumor characteristics after review of slides to standardize all histologic information in the database. Active prospective follow-up of all patients enrolled in the database was conducted every 6 months by IMCG staff. Recurrence and survival information was recorded for each patient.

Statistical Methods

Each patient with ALM (n=61) in the IMCG database was matched to 3 patients with NAM (n=183) by gender and melanoma stage, including substage.19 ALM cases included melanomas arising from volar surfaces of the hands and feet, and subungual melanoma. The NAM cohort was restricted to superficial spreading and nodular melanoma. Standard demographic variables (mean age at diagnosis and race) and prognostic indicators (Breslow thickness, sentinel lymph node status, ulceration, and mitosis) were compared between both groups to confirm an adequate match. A Fisher exact/Chi-square test was used for categorical variables, and an independent sample t test was used for continuous variables.

Melanoma-specific and recurrence-free survivals were calculated for both cohorts using a Kaplan-Meier analysis. Survival was measured from the time of enrollment until a specified end point: death from melanoma in melanoma-specific survival and any type of recurrence (local, regional, or distant) in recurrence-free survival. A log-rank test was used to determine statistical significance. A multivariate Cox regression model was used to calculate adjusted hazard ratios (HRs) of ALM versus NAM for melanoma-specific and recurrence-free survivals. HRs were adjusted for unmatched risk factors, such as race/ethnicity, Breslow thickness, mitotic index, ulceration, and sentinel lymph node status.

Recurrence rates in ALM and NAM were compared using a Fisher exact/Chi-square test, and subgroups were stratified by tumor thickness. When stratifying this cohort, patient demographic and tumor characteristics were reexamined to ensure no significant differences between the groups.

Location of first recurrence in each group was compared using a Fisher exact test. The rate of locoregional versus distant recurrence was compared between ALM and NAM. A locoregional recurrence was defined to include local recurrences, satellite or in-transit metastases, and regional lymph node involvement. A distant recurrence was defined as metastases to distant skin, lymph nodes, or viscera. In patients who experienced a locoregional recurrence and distant recurrence simultaneously, each recurrence was tabulated as a separate event.

IBM SPSS Statistics 21 was used for all statistical analyses. A P value of less than .05 (2-tailed analysis) was used as the metric for statistical significance.

Results

Clinical and pathologic characteristics of this study cohort are illustrated in Table 1. Each patient with ALM (n=61) was matched to 3 patients with NAM (n=183) by gender and melanoma stage, including substage. Women constituted 56% of the study cohort. Patients in this series ranged from AJCC clinical stage I through III (I, 34%; II, 33%; III, 33%). The mean Breslow thickness in the ALM and NAM groups was similar (2.52 vs 2.51 mm, respectively; P=.278). No significant difference was seen in mean age at diagnosis (61.7 and 62.9 years, respectively; P=.252) and standard prognostic indicators (mitoses, P=.60; ulceration, P=.55; and sentinel lymph node positivity, P=.68) between both cohorts. The only demographic that was not adequately matched was ethnicity. Most patients in both cohorts were white, non-Hispanic (ALM, 75%; NAM, 96%). Significantly more Black, Hispanic, and Asian patients were in the ALM group (P<.0001).

Patients in this series received standard-of-care treatment and were treated by the same medical and surgical oncology team. All patients underwent surgical excision of their primary melanoma, with a sentinel lymph node biopsy if indicated by standard guidelines. Treatment at the time of first recurrence varied based on recurrence site. Most patients with locoregional recurrences were treated with surgery or surgery and radiation. Most patients with distant metastases were treated with systemic therapy, often combined with surgery or radiation when appropriate. It is noteworthy that most patients in this series were treated before the development of immunotherapy and BRAF-inhibitors for melanoma. Of 16 patients with ALM who received systemic therapy, 5 (31%) were treated with ipilimumab after a first recurrence. Of the 29 patients with NAM who received systemic therapy after an initial recurrence, 1 (3%) was treated with ipilimumab and 1 (3%) with vemurafenib.

Poor Survival Outcomes in ALM versus NAM

Kaplan-Meier analysis was used to determine melanoma-specific survival. The median follow-up time for the ALM and NAM cohorts were 33 and 58 months, respectively. A statistically significant decrease in melanoma-specific survival was seen in ALM compared with NAM (Figure 1). The ALM cohort demonstrated a lower median melanoma-specific survival time (82.1 months) compared with the NAM group (>200 months; P=.004). In the NAM group, the median melanoma-specific survival time has not yet been reached.

A multivariate Cox regression model was used to evaluate whether ALM histologic subtype was an independent predictor of melanoma-specific survival. After adjusting for race/ethnicity and unmatched prognostic indicators, such as Breslow thickness, mitotic index, sentinel lymph node status, and ulceration, results showed that ALM was an independent negative predictor of melanoma-specific survival (HR, 2.58; P=.001) compared with NAM.

Recurrence is More Common in ALM, Particularly in Tumors <2 mm Thick

Recurrence data for the cohort are shown in Table 2. Recurrence was significantly more common in patients with ALM than in those with NAM (49% vs 30%; P=.007; odds ratio [OR], 2.25; 95% CI, 1.24–4.08). Additionally, recurrence rates in subgroups stratified by tumor thickness were compared in both cohorts because surgical treatment of primary melanoma is based on tumor thickness: for tumors greater than 2 mm in thickness, a 2-cm surgical margin is recommended, whereas for tumors less than 2 mm, a surgical margin between 1 and 2 cm is acceptable.23 When stratifying the cohort by tumor thickness, patient demographic and tumor characteristics in the ALM and NAM groups were reexamined to ensure that both groups were not significantly different. For tumors 2 mm or less in thickness (ALM, n=25; NAM, n=86), a significantly higher recurrence rate was seen in ALM versus NAM (28% vs 10%, respectively; P=.048; OR, 3.33; 95% CI, 1.09–10.13). For tumors greater than 2 mm (ALM, n=36; NAM, n=97), the recurrence rate was elevated, although nonsignificant, in ALM compared with NAM, (ALM, 64%; NAM, 47%; P=.12; OR, 1.96; 95% CI, 0.89–4.31).

Recurrence-free survival in both groups was calculated using a Kaplan-Meier analysis to determine median time to recurrence. The median recurrence-free survival time in ALM was 47.1 months compared with 213.5 months in NAM (P<.001; Figure 2). After performing a multivariate analysis, the data revealed that ALM histologic subtype was an independent negative predictor of recurrence-free survival compared with NAM (HR, 2.24; P=.001).

No significant differences were seen between patients with ALM and NAM who experienced a recurrence in terms of demographic and primary lesion

Table 1

Patient Demographic and Histologic/Clinical Tumor Characteristics

Table 1
clinical parameters. The mean age of recurrence in patients with ALM was 61.0 years compared with 66.3 years in those with NAM (P=.06). The mean primary tumor thickness in patients experiencing recurrence in both groups was also similar (ALM, 3.28 mm; NAM, 3.95 mm; P=.201). No significant difference in mitoses (P=.2), ulceration (P=.82), or lymph node status (P=.82) was seen between both groups. Additionally, when analyzing only the subset of patients experiencing recurrence, no significant difference in melanoma-specific survival time was seen between the groups (ALM vs NAM adjusted HR, 1.14; P=.67).

Locoregional Failure Rate Nearly Double in ALM Compared With NAM

Location of first recurrence was examined by comparing locoregional recurrence to distant recurrence in both cohorts (Table 2). In patients who presented with a locoregional recurrence and distant recurrence simultaneously (eg, regional skin and distant lymph

Figure 1
Figure 1

Kaplan-Meier curve of melanoma-specific survival in acral lentiginous melanoma (ALM) and nonacral melanoma (NAM). Melanoma-specific survival time was decreased in ALM compared with NAM. The ALM cohort demonstrated a lower median melanoma-specific survival (82.1 mo) compared with the NAM group (>200 mo; P=.004).

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 12, 12; 10.6004/jnccn.2014.0172

node involvement), each recurrence was tabulated as a separate event. The data showed that the rate of locoregional recurrence was nearly double in ALM than in NAM (39% vs 19%, respectively; P=.001; Figure 3). The rate of distant metastasis was similar in both groups (16% vs 15%, respectively; P=.84).

Discussion

Results of this study showed that ALM has higher recurrence rates and poor survival outcomes than NAM after controlling for melanoma stage. Poor outcomes in ALM have been explained by several hypotheses, including a delay in diagnosis. This would lead to diagnosis at an advanced stage, with thicker primary tumors and delayed treatment.24,25 The investigators have shown that even after accounting for these factors, patients with ALM experienced worse outcomes than their NAM counterparts. In this series, patients with ALM were significantly more likely to experience a recurrence than those with NAM (49% vs 30%, respectively; P=.007; OR, 2.25; 95% CI, 1.24–4.08). Additionally, ALM histologic subtype was an independent negative predictor of recurrence-free survival (HR, 2.24; P=.001) and melanoma-specific survival (HR, 2.58; P=.001) compared with NAM. Although several studies have shown that ALM has

Table 2

Recurrence and Survival Data

Table 2
poor survival outcomes compared with NAM,2,4,19 recurrence patterns between both groups have not been compared. To date, this study is the first to integrate data on primary treatment, recurrence, and survival in ALM versus NAM.

A high rate of locoregional failure in ALM compared with NAM when controlling for AJCC stage is a unique finding in this study. The results are concordant with those of previous studies analyzing recurrence exclusively in ALM that reported rates of 25% to 30%, with most patients presenting with a locoregional failure.5,7 Interestingly, in this series, the rate of distant metastases was similar in ALM and NAM, despite the fact that patients with ALM experienced worse survival outcomes. To further elucidate the role of recurrence in survival in ALM, the investigators compared melanoma-specific survival in patients who experienced a recurrence in both cohorts and showed that survival was similar. Overall, these results suggest that recurrence rate, not location of first recurrence, contributes to worse survival outcomes in ALM. According to this logic, decreasing locoregional recurrence would decrease the overall recurrence rate in ALM, which may improve survival.

The high rate of locoregional failure in this series raises the question of whether ALM may require wider surgical margins than nonacral cutaneous melanomas of equal thickness. Widening surgical margins in ALM may not be beneficial for thicker tumors, but may decrease recurrence in tumors less than 2 mm in thickness, because these tumors had a significantly elevated recurrence rate compared with NAM in this series. Current NCCN Guidelines are uniform for all melanoma subtypes. A 1-cm surgical margin is recommended for tumors 1 mm or less in thickness. For tumors between 1 and 2 mm, a surgical margin between 1 and 2 cm is acceptable. For

Figure 2
Figure 2

Kaplan-Meier curve of recurrence-free survival in acral lentiginous melanoma (ALM) and nonacral melanoma (NAM). Patients with ALM experienced a decreased recurrence-free survival compared with NAM. Median recurrence-free survival time was 47.1 months in ALM compared with 213.5 months in NAM (P<.001).

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 12, 12; 10.6004/jnccn.2014.0172

lesions 2 mm or greater, a 2-cm margin is recommended.23 Several previous studies have shown that widening surgical margins in melanomas between 1 and 4 mm in thickness decreases the rate of locoregional failure but does not impact survival.26,27 Other clinical trials have shown that widening surgical margins does not improve local control of primary invasive melanoma.2833 All of these studies, however, exclude ALM. Although one
Figure 3
Figure 3

Recurrence rates in acral lentiginous melanoma (ALM) and nonacral melanoma (NAM). Recurrence was significantly more common in ALM compared with NAM (49% vs 30%; P=.007). The rate of locoregional recurrence was nearly double in ALM (39%) compared with NAM (19%; P=.001).

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 12, 12; 10.6004/jnccn.2014.0172

retrospective study investigated the association between locoregional recurrence and surgical margins less than 2 cm in ALM, no association was reported, probably because of inadequate sample size.17 In light of the current findings, the role of surgical resection margins in ALM prognosis is an important question for future investigation.

ALM tumors have been shown to demonstrate unique genomic aberrations,2022 suggesting that ALM invasion and progression may be biologically distinct from other cutaneous melanomas. Although the rate of distant metastases was similar in ALM and NAM, distant metastases comprised a higher proportion of recurrences within the NAM group. This suggests that improved local control with a more extensive surgical resection may not have a major impact on survival. Targeted systemic therapy might be more beneficial in these patients. For ALM, in which most recurrences were locoregional, patients might benefit from a more extensive surgical resection. Arguments against widening surgical margins include increased morbidity in a sensitive site where achieving even appropriate margins may be difficult. However, wider surgical margins may prevent subsequent reexcisions from recurrences, thereby decreasing long-term morbidity.

In summary, these data revealed a high rate of locoregional failure in ALM compared with NAM when controlling for all standard prognostic indicators. These results suggest that ALM is a uniquely aggressive melanoma subtype that may require specially tailored treatment. These results also question whether current surgical treatment guidelines are adequate for the management of ALM, although no recommendations can be made without further investigation. Larger multicenter trials are necessary for further conclusions. Furthermore, independent validation in a different subset of patients is needed to confirm the findings. This study was conducted in a tertiary care center with a large number of patients with advanced disease; a wider sampling of patients may be necessary to better reflect outcomes in the general population. Nonetheless, the results highlight pronounced differences in recurrence and survival between ALM and NAM and identify key areas for future research.

Conclusions

Overall, these data show that a high rate of locoregional failure in patients with ALM may contribute to a decrease in melanoma-specific survival. ALM is an aggressive melanoma variant that may require uniquely tailored therapy. Surgical resection margins may be one factor that explains higher recurrence rates and poor survival outcomes in ALM, although further studies are necessary to best delineate the impact of surgical margins in ALM prognosis.

Ms. Gumaste, Mr. Fleming, and Drs. Silva, Shapiro, Berman, Zhong, Osman, and Stein participated in the drafting of the manuscript and critical revision of the manuscript for important intellectual content. NCI Cancer Center Support Grant (5 P30 CA 016087-27) to the Perlmutter Cancer Center at New York University and the Marc Jacobs Campaign to support melanoma research were funding sources for this paper. Dr. Stein was supported by the Irwin I. Lubowe Fellowship in Dermatology. Data presented in this paper were submitted for presentation at the 2014 ASCO Annual Meeting, May 30–June 3, 2014.

References

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Correspondence: Jennifer A. Stein, MD, PhD, New York University School of Medicine, 530 First Ave, Skirball 7R, New York, NY 10016. E-mail: Jennifer.Stein@nyumc.org
  • View in gallery

    Kaplan-Meier curve of melanoma-specific survival in acral lentiginous melanoma (ALM) and nonacral melanoma (NAM). Melanoma-specific survival time was decreased in ALM compared with NAM. The ALM cohort demonstrated a lower median melanoma-specific survival (82.1 mo) compared with the NAM group (>200 mo; P=.004).

  • View in gallery

    Kaplan-Meier curve of recurrence-free survival in acral lentiginous melanoma (ALM) and nonacral melanoma (NAM). Patients with ALM experienced a decreased recurrence-free survival compared with NAM. Median recurrence-free survival time was 47.1 months in ALM compared with 213.5 months in NAM (P<.001).

  • View in gallery

    Recurrence rates in acral lentiginous melanoma (ALM) and nonacral melanoma (NAM). Recurrence was significantly more common in ALM compared with NAM (49% vs 30%; P=.007). The rate of locoregional recurrence was nearly double in ALM (39%) compared with NAM (19%; P=.001).

  • 1

    WuXCEideMJKingJ. Racial and ethnic variations in incidence and survival of cutaneous melanoma in the United States, 1999-2006. J Am Acad Dermatol2011;65:S2637.

    • Search Google Scholar
    • Export Citation
  • 2

    BradfordPTGoldsteinAMMcMasterMLTuckerMA. Acral lentiginous melanoma: incidence and survival patterns in the United States, 1986-2005. Arch Dermatol2009;145:427434.

    • Search Google Scholar
    • Export Citation
  • 3

    KuchelmeisterCSchaumburg-LeverGGarbeC. Acral cutaneous melanoma in caucasians: clinical features, histopathology and prognosis in 112 patients. Br J Dermatol2000;143:275280.

    • Search Google Scholar
    • Export Citation
  • 4

    SlingluffCLJrVollmerRSeiglerHF. Acral melanoma: a review of 185 patients with identification of prognostic variables. J Surg Oncol1990;45:9198.

    • Search Google Scholar
    • Export Citation
  • 5

    EggerMEMcMastersKMCallenderGG. Unique prognostic factors in acral lentiginous melanoma. Am J Surg2012;204:874879; discussion 879–880.

    • Search Google Scholar
    • Export Citation
  • 6

    PhanATouzetSDalleS. Acral lentiginous melanoma: histopathological prognostic features of 121 cases. Br J Dermatol2007;157:311318.

  • 7

    PhanATouzetSDalleS. Acral lentiginous melanoma: a clinicoprognostic study of 126 cases. Br J Dermatol2006;155:561569.

  • 8

    ChangAEKarnellLHMenckHR. The National Cancer Data Base report on cutaneous and noncutaneous melanoma: a summary of 84,836 cases from the past decade. The American College of Surgeons Commission on Cancer and the American Cancer Society. Cancer1998;83:16641678.

    • Search Google Scholar
    • Export Citation
  • 9

    PaladuguRRWinbergCDYonemotoRH. Acral lentiginous melanoma. A clinicopathologic study of 36 patients. Cancer1983;52:161168.

  • 10

    RidgewayCAHiekenTJRonanSG. Acral lentiginous melanoma. Arch Surg1995;130:8892.

  • 11

    SondergaardK. Histological type and biological behavior of primary cutaneous malignant melanoma. 2. An analysis of 86 cases located on so-called acral regions as plantar, palmar, and sub-/parungual areas. Virchows Arch A Pathol Anat Histopathol1983;401:333343.

    • Search Google Scholar
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