Acral Lentiginous Melanoma Patients Research Articles

Adjuvant nivolumab therapy may not improve disease-free survival in resected acral lentiginous melanoma patients: A retrospective case series.

Adjuvant nivolumab therapy has been reported to improve the survival of melanoma patients. Acral lentiginous melanoma (ALM) has been reported to be less likely to respond to immune checkpoint inhibitors (ICIs) than other subtypes. However, the efficacy of adjuvant nivolumab therapy for ALM patients remains uncertain due to the low number of cases. In this single-center retrospective case series, we analyzed the clinical data of patients with resected stage III/IV ALM who were referred to our department between April 1, 2004 and March 31, 2022. The analyzed clinical data included age, sex, TNM stage, treatments, adverse events and disease-free survival (DFS). Enrolled patients were divided into a nivolumab group and a non-ICI group according to the adjuvant therapy they received. In total, 27 patients were included. The nivolumab and non-ICI groups had 5 and 22 patients, respectively. There were no significant differences in patient characteristics between the two groups. There were no serious treatment-related adverse events in the non-ICI group, but one patient in the nivolumab group developed type 1 diabetes. In the survival analysis, the DFS for the nivolumab group did not exceed that of the non-ICI group in postoperative adjuvant therapy for ALM patients. Given that adjuvant nivolumab therapy sometimes results in serious adverse effects, the administration of the therapy may need to be carefully considered, especially for ALM patients.

Influencing factors associated with lymph node status in patients with cutaneous melanoma: An Asian population study.

Sentinel lymph node (SLN) status is the predominant prognostic factor in patients diagnosed with clinically localized melanoma. The significance of completion lymph node dissection in patients with SLN metastasis is debatable. Not many studies have been conducted on acrallentiginous melanoma (ALM). This study aimed to characterize the prognostic factors of nodal positive ALM and confirm whether ALM patients can undergo the same treatment strategy as non-ALM patients in the Asian population. This is a retrospective review of patients who underwent surgery for cutaneous melanoma (CM) at Taipei Veterans General Hospital between January 1993 and December 2019. We investigated the risk factors for lymph node status. The association between clinicopathological factors and lymph node status of ALM and non-ALM patients was analyzed. Outcomes of completion lymph node dissection (CLND) performed following sentinel lymph node biopsy (SLNB) in the CM and ALM groups were compared. A total of 197 patients were included in this study. ALM was the most common histological subtype, accounting for 66.5% of all the cases. Patients in the CM and ALM subgroups with metastatic SLN ( p = 0.012) or lymph nodes ( p < 0.001 and p = 0.001) exhibited higher mortality rate. Multivariate analysis showed that patients with clinical presentation of T4 category tumor ( p = 0.012) and lymphovascular invasion ( p = 0.012) had a significantly higher risk of positive lymph nodes. The overall survival of patients with lymph nodes metastasis was not associated with the performance of CLND. Patients in the CM or ALM subgroups with metastatic SLNs or lymph nodes exhibited significantly poorer overall survival. Advanced Breslow thickness and lymphovascular invasion were independent predictive factors for CM and ALM patients with positive lymph node status. There was no significant difference in survival between CM and ALM patients following SLNB, regardless of CLND being performed.

Clinicopathological characteristics and prognosis in significantly thick acral lentiginous melanoma in Taiwan

This retrospective cohort study enrolled 385 patients diagnosed with cutaneous melanoma from 1980 to 2021 in National Taiwan University Hospital (NTUH). The aim of this study was to investigate the relationship between thickness of primary melanoma lesions and disease outcome of melanoma patients, in particular, those diagnosed with acral lentiginous melanoma (ALM). The association between important clinicopathological characteristics other than tumor thickness and disease outcome was also analyzed. Survival analyses with the Kaplan-Meier method were utilized to investigate the prognoses of patients with different lesion thickness. The male-to-female ratio was 1.12:1. The median age at diagnosis was 63 years old (mean: 62.2 years). There were 283 cases (73.5%) of acral lentiginous melanoma (ALM) with a male-to-female ratio of 1.04:1. Between patients with primary ALM lesions 4.1 millimeters (mm) to 8.0 mm thick and those with lesions over 8.0 mm thick, significant differences in prognostic outcomes including incidence of second recurrences within 1 year (raw p = 0.003, Bonferroni corrected p = 0.009) and distant metastases within 1 year (raw p = 0.003, Bonferroni corrected p = 0.008), were observed. Significantly worse 1-year (raw p = 0.01, Bonferroni corrected p=0.03) and 2-year survival (raw p = 0.006, Bonferroni corrected p = 0.02) were found in ALM patients with lesions of over 8 mm thick than those with lesions 4.1 mm to 8.0 mm at diagnosis. Vigilant short-term follow-up is warranted in ALM patients with lesions of over 8.0 mm thick at diagnosis due to higher risks of adverse outcome.

Risk factors of recurrence and distant metastasis in primary cutaneous melanoma in Taiwan

Risk factors of recurrence and distant metastasis of acral lentiginous melanoma (ALM) are of great interest for the high percentage of ALM in cutaneous melanoma in Asian populations. This single-center retrospective cohort including 177 patients with localized melanoma diagnosed from 2004 to 2020 aims to identify adverse predictors in cutaneous melanoma in Taiwan, with a focus on ALM. The relationship between clinicopathological features and outcomes, including incidences of recurrence and distant metastasis in 5 years from diagnosis, was analyzed. This study included 124 patients (70.1%) with ALM and 53 (29.9%) with non-ALM melanoma. Regarding clinicopathological characteristics, ALM patients were diagnosed at an older age and received sentinel lymph node biopsies (SLNBs) more often, while adjacent melanocytic nevi were more prevalent in non-ALM patients. With respect to prognostic implications of clinicopathological features, in ALM, implementation of SLNB was associated with a lower 5-year distant metastasis rate. Thickness of melanoma lesions over 4 mm, ulceration, and neurotropism, were related to both higher 5-year recurrence and distant metastasis rates. With regard to non-ALM patients, diagnoses made at or over 65 years old was linked to a higher 5-year recurrence rate, whereas ulceration was associated with both higher 5-year recurrence and distant metastasis rates. In conclusion, several clinicopathological characteristics have been identified to be associated with poor prognosis of cutaneous melanoma, especially ALM.

Effect of changes in Breslow thickness between the initial punch biopsy results and final pathology reports in acral lentiginous melanoma patients

Acral lentiginous melanoma (ALM) is the most common subtype of cutaneous melanoma among Asians; punch biopsy is widely performed for its diagnosis. However, the pathologic parameters evaluated via punch biopsy may not be sufficient for predicting disease prognosis compared to the parameters evaluated via excisional biopsy. We investigated whether changes in Breslow thickness (BT) between initial punch biopsy results and final pathology reports can affect the prognosis of ALM. Pathologic parameters were recorded from specimens acquired through the initial punch biopsy and wide excision. Patients were classified into two groups based on a change in Breslow depth: the BT increased or decreased on comparing the samples from the initial punch biopsy and final wide excision. We compared clinical characteristics, and a Cox regression model was used to identify independent prognostic factors influencing melanoma-specific death (MSD). Changes in BT did not affect MSD (hazard ratio [HR]: 0.55, P = 0.447). In multivariate analysis, a higher BT (> 2 mm) (HR: 9.93, P = 0.046) and nodal metastasis (HR: 5.66, P = 0.041) were significantly associated with an increased MSD risk. The use of punch biopsy did not affect MSD despite the inaccuracy of BT measurement as long as ALM was accurately diagnosed.

Acral lentiginous melanoma-Population, treatment, and survival using the NCDB from 2004 to 2015.

Acral lentiginous melanoma (ALM) is a rare histological subtype of cutaneous malignant melanoma that typically presents on the palms and soles. To characterize the demographic and treatment characteristics of ALM, we used the National Cancer Database (NCDB) to describe a large multi-institutional cohort of ALM patients, consisting of 4,796 ALM patients from 2004 to 2015. ALM was more likely to be diagnosed at a later stage overall compared with non-ALM cutaneous melanomas, and more likely to be thicker, ulcerated, lymph node positive, and have lymphovascular invasion and positive margins. When stratified by stage, ALM had worse survival compared with non-ALM patients, most notably in stage III patients with 5-year survival of 47.5% versus 56.7%, respectively (p<.001). In ALM patients, older age, male sex, higher comorbidity burden, increased tumor thickness and ulceration, positive lymph nodes, and positive metastasis were independently associated with lower 5-year survival. Multimodality therapy, defined as surgery in addition to systemic therapy and/or radiation therapy, was associated with higher survival in stage III patients but not in other stages. These results call for further investigation into possible treatment intensification in the ALM population in the future.

Clinical characteristics and prognosis of acral lentiginous melanoma: a single-center series of 211 cases in China.

Acral lentiginous melanoma (ALM) is common in China with poor prognosis. However, there are only a few studies of ALM in the Asian population. We aimed to summarize and analyze the clinical characteristics, treatment strategy, treatment effect, and prognostic factors of ALM in a Chinese population. We included a total of 249 ALM patients (211 with follow-up data) from a single institution. Demographic, laboratory data, treatment strategy, and prognosis were analyzed. The ratio of male and female was 1.3 ∶ 1.0. The median age was 58 years old. The majority of patients (70.3%) had lesions on the sole. Trauma history and irritation were associated with lesion size increase in some patients. The prognosis of patients in stage II-III undergoing standard operation was significantly better compared with those without surgical treatment. Patients who did not receive postoperative adjuvant treatment had shorter time to distant metastasis. In multivariable analysis, distant metastasis, duration of disease, LDH level, and Ki67 index were independently associated with survival. Prognosis for ALM patients was poor in our study. Distant metastasis, duration of disease, LDH level, and Ki67 index were independently associated with prognosis.

Subtyping Cutaneous Melanoma Matters.

BackgroundOur aim was to investigate the role of melanoma subtype on survival and focus on the effects stratified by Breslow thickness and ulceration status.MethodsPatients with cutaneous melanoma stage I, II, or III diagnosed between 2000 and 2014 were derived from the Dutch Nationwide Pathology Registry and overall survival data from the Netherlands Cancer Registry. Patients were followed until 2018. Using multivariable Cox proportional hazards models, hazard ratios were calculated for each melanoma subtype, per Breslow thickness category and ulceration status, and adjusted for age, sex, stage, and localization.ResultsA total of 48 361 patients were included: 79.3% had superficial spreading melanoma (SSM), 14.6% nodular melanoma (NM), 5.2% lentigo maligna melanoma, and 0.9% acral lentiginous melanoma (ALM). In the total patient group, using SSM as the reference category, adjusted hazard ratios were 1.06 (95% confidence interval [CI] = 1.01 to 1.12) for NM, 1.02 (95% CI = 0.93 to 1.13) for lentigo maligna melanoma, and 1.26 (95% = CI 1.06 to 1.50) for ALM. Among patients with 1.0 mm or less Breslow thickness and no ulceration, NM showed a twofold increased risk (hazard ratio = 1.96, 95% CI = 1.58 to 2.45) compared with SSM. Compared with 1.0 mm or less SSM without ulceration, the hazard ratio for 1.0 mm or less SSM with ulceration was 1.94 (95% CI = 1.55 to 2.44), and the hazard ratio for 1.0 mm or less NM with ulceration was 3.46 (95% CI = 2.17 to 5.50). NM patients with tumors greater than 1.0 mm did not show worse survival than SSM patients with tumors greater than 1.0 mm.ConclusionsIn this large nationwide study, ALM patients showed worse survival than SSM patients. Among patients with melanomas that were thin (1.0 mm or less), NM subtype patients also showed worse survival than SSM patients.

Prognostic significance of acral lentiginous histologic type in T1 melanoma.

Acral lentiginous melanoma (ALM) is a rare type of cutaneous melanoma with a poor prognosis. It is unclear whether the poor outcome of ALM is due to its inherent disease characteristics or advanced stage at initial diagnosis. To address this question, we retrospectively analyzed the clinicopathologic factors of 828 thin (T1; Breslow thickness ≤1.0 mm) melanomas [129 (15.6%) ALMs and 699 (84.4%) non-ALMs] and their nodal and distance metastases and local recurrence rates and determined their relationship with the disease-specific (DSS), overall (OS), and recurrence-free survivals (RFS) at the pathologic stages T1, T1a, and T1b with a median follow-up time of 84.5 months. With the exception of OS at T1b stage, ALM patients showed significantly lower 5- and 10-year DSS, OS, and RFS rates at every pathologic stage when compared with non-ALM. In multivariable analysis, ALM histologic type, SLN positivity, age, and the use of systemic therapy were detected as independent poor prognostic factors associated with significantly lower survival rates. ALM histologic type was associated with lower DSS and OS rates at T1 and T1a stages and lower RFS rates at T1b stage. SLN positivity was associated with lower DSS, OS, and RFS rates at T1, T1a, and T1b stages. Age was associated with lower OS rates at T1 and T1b stages. Whereas the use of systemic therapy was associated with lower DSS rates at T1a stage and RFS rates at T1b stage. In addition, the ALM group showed significantly older median age patients and higher rates of female sex, Hispanic ethnicity, nevoid cytology, non-brisk tumor-infiltrating lymphocytes, nodal metastasis, and local recurrence at every pathologic stage of thin melanoma. Our findings suggest that ALM is inherently more aggressive than other types of cutaneous melanoma. This information may be useful for prognostic stratification of patients with thin melanomas, especially to help guide the clinical decision-making for SLN biopsy and patients entering clinical trials.

Acral lentiginous melanoma: Clinicopathologic and survival differences according to tumour location.

Acral lentiginous melanoma (ALM) is a melanoma subtype associated with atypical locations on the hands and feet and advanced disease at diagnosis. There is a limited understanding of whether the survival is similar for nail, non-nail, lower limb and upper limb ALM patients. We therefore explored clinicopathologic characteristics and melanoma-specific survival of ALM patients according to tumour location. A prospectively collected cohort study was performed of all primary invasive cutaneous acral lentiginous melanomas with known thickness and tumour location reviewed at a tertiary referral centre over 21years. A total of 101 ALM patients were reviewed from 1994 until 2016. The majority of cases (82/101) occurred on the feet. Hand ALMs were thicker and more likely to be ulcerated than feet ALMs (P=0.05 and 0.02, respectively); however, survival was not statistically different between these two groups (univariate HR 0.48 P=0.11, 95% CI, 0.20-1.17; multivariate HR 0.67 P=0.40, 95% CI, 0.27-1.69, respectively). Non-nail ALM patients had longer survival when compared to nail ALM on univariate analysis (HR 0.40, 95% CI, 0.17 to 0.90) which was accounted for by Breslow thickness and ulceration (multivariate HR 0.56, 95% CI, 0.24 to 1.34). The reduced melanoma-specific survival in nail ALM patients was likely due to their greater thickness and ulceration. Although hand ALMs are thicker and more frequently ulcerated, this is likely due to the higher proportion of nail ALMs present in this location.

Acral Lentiginous Melanoma: Do Surgical Approach and Sentinel Lymph Node Biopsy Matter?

Background:Management of acral lentiginous melanoma (ALM) remains controversial. Traditionally, ALM was managed with digit amputation (DA), resulting in significant morbidity, but recent evidence has advocated for digit sparing management. Furthermore, the significance of nodal metastasis for ALM is not well reported. The aims of this study were to determine if surgical approach for primary ALM impacts outcomes and to evaluate the predictive value of nodal status for ALM.Methods:Patients with localized ALM diagnosed from 1982 to 2017 were retrospectively identified. Clinicopathologic characteristics were correlated with surgical approach, nodal metastasis, overall survival, and recurrence-free survival.Results:There were 47 patients with ALM. Median age was 59 years, and median thickness was 3 mm. 51% of patients underwent wide local excision (WLE), 27.9% underwent DA, and 20.9% underwent partial digit amputation (PDA). ALM on the hand versus foot (OR: 12.7, 95%, confidence interval (CI), 2.0–80.1; P = 0.007) and subungual versus nonsubungual location (OR: 28.0, 95% confidence interval, 2.7–295.7; P = 0.006) were significantly associated with surgical approach (DA and PDA versus WLE). There were no significant differences in overall survival or recurrence-free survival between DA, PDA, or WLE cases (P = 0.481 and P = 0.778, respectively). There were no significant differences in overall survival or recurrence-free survival based on nodal status (P = 0.562 and P = 0.136, respectively).Conclusions:No significant differences in overall survival or recurrence-free survival were seen between ALM patients treated with DA, PDA, and WLE. Given these results, PDA or WLE may be options in select patients with digital ALM; however, careful consideration must be taken when deciding on the surgical approach.

Metastatic acral lentiginous melanoma in a tertiary referral center in Switzerland: a systematic analysis

Acral lentiginous melanoma (ALM) is a unique histopathological subtype of melanoma with a poorer prognosis than other cutaneous melanomas. This study aims to evaluate the clinicopathological characteristics, metastatic pattern, prognostic factors, response to systemic therapy, and overall survival (OS) of ALM in a White population. This is a retrospective study of patients who were diagnosed and/or treated for ALM at the Department of Dermatology of the University Hospital Zurich, Switzerland, from January 2005 to December 2015. Overall, 172 patients with histologically confirmed ALM were included in the study. In univariate Cox regression, Breslow thickness (P<0.001), age (P=0.003), status of sentinel lymph node (P=0.005), and ulceration (P=0.008) were identified as significant prognostic factors for OS in ALM. In multivariate analysis, only Breslow thickness (P=0.0003) showed statistical significance. The median OS (mOS) was 155.7 months in the entire cohort (n=172) and 11.2 months for stage IV patients (n=36), irrespective of treatment. When first treatment was considered (n=35), mOS for stage IV patients was 8.9, 16.6, 21.7, and 3.7 months, for patients who had received chemotherapy (ChT) (n=17), immunotherapy (n=9), targeted therapy (TT) (n=3), and no therapy (n=6), respectively. The overall response rate was 44% (7/16 patients) to ChT, 100% to TT (3/3), and 25% to ipilimumab (2/8). In our study, Breslow thickness represents the best prognostic factor for OS. In stage IV ALM patients treated with either immunotherapy or TT, there is a trend for extended mOS compared with ChT.

Acral Lentiginous Melanoma: Survival Analysis of 715 Cases

Acral lentiginous melanoma (ALM) is an aggressive variant of melanoma; the incidence, prevalence, and prognosis differ among populations. We analyzed clinicopathological features and survival in Hispanics, a population with high ALM prevalence. From 1144 patients with melanoma, we analyzed 715 ALMs and 429 non-ALMs from the National Referral Cancer Centre and compared survival. Of the ALM group, 62.8% were female; the median age was 58 years. The mean Breslow thickness was 3.56 ± 7.16 mm. ALM patients showed an estimated 5-year disease-specific survival (DSS) of 53.3%, 52.7%, and 40.8% for stage I, II, and III, respectively. For non-ALM patients, the DSS rates were 66%, 60.8%, and 48.4% for stage I, II, and III disease, respectively. Overall, the 1-, 3-, and 5-year DSS rates for patients with ALM were 85.1%, 59.4%, and 46.3%, respectively; for non-ALM patients, they were 81.3%, 64.8%, and 55.7%, respectively ( P = .168). In the multivariate analysis, factors associated with decreased DSS were high Breslow thickness, recurrence, ulceration, male sex, and advanced stage. The 1-, 3-, and 5-year DSS rates of patients with ALM were not statistically different from those of non-ALM patients. In addition to known adverse prognostic factors, male sex was also associated with worse survival.

Use of immune checkpoint inhibitors prolonged overall survival in a Japanese population of advanced malignant melanoma patients: Retrospective single institutional study.

Although recent clinical trials have revealed that immune checkpoint inhibitors significantly improved the overall survival (OS) of patients with advanced melanoma, these previous studies comprised mainly white populations, in which superficial spreading melanoma (SSM) and lentigo maligna melanoma are the major clinical types of melanoma. In contrast, Asians manifest a distinct clinicopathological type of melanoma from that of whites and show much higher frequencies of acral lentiginous melanoma (ALM) and mucosal melanoma, which have been shown to be less susceptible to immune checkpoint inhibitors. Because no comparative studies have been published showing improvement of OS by immune checkpoint inhibitors in Asian melanoma patients, we retrospectively collected the data for 45 melanoma patients treated with checkpoint inhibitors and 24 melanoma patients treated with chemotherapy alone before immune checkpoint inhibitors became available, and compared their OS. The results showed that the patients treated with immune checkpoint inhibitors had significantly better OS than did those treated with chemotherapy alone (P < 0.0001). Improved OS was observed in both the SSM and the ALM patients. In addition, multivariate Cox regression analyses revealed that use of immune checkpoint inhibitors was associated with favorable prognosis (P = 0.0001), indicating that use of immune checkpoint inhibitors is an independent factor for favorable survival. Our study showed that immune checkpoint inhibitors may also improve the prognosis of Asian melanoma patients.

Diagnosis and Management of Acral Lentiginous Melanoma.

Melanoma is one of the most aggressive malignant skin tumors and its incidence has been increasing worldwide in recent decades. Among the four subtypes, acral lentiginous melanoma (ALM) shows the highest incidence in Asian countries, whereas ALM comprises only 1% of all melanomas in white populations. Early clinical diagnosis of ALM is essential, but early ALM lesions are often difficult to diagnose because the pigmentation of the lesions sometimes follows the skin marking of the palms and soles, resulting in an asymmetrical appearance and an irregular border in both ALM and benign melanocytic nevus. To overcome this difficulty, dermoscopy was introduced, and determination of the patterns by this method is essential for accurate clinical diagnosis of ALM. Although recent clinical trials have demonstrated that immune checkpoint inhibitors and BRAF/MEK inhibitors showed significantly improved overall survival of patients with advanced melanoma, ALM may be less susceptible to immune checkpoint inhibitors because of the poor immune response to the tumor. Therefore, strategies for enhancing the immune response to the tumor cells may be required when we apply immune checkpoint inhibitors in advanced ALM. In this context, imiquimod, dacarbazine, or interferon are possible therapies that may enhance the effectiveness of the immune checkpoint inhibitors. In addition to being known to have poor immunogenicity, ALM is also known to have infrequent BRAF mutation. Therefore, the majority of ALM patients may not benefit from therapy with BRAF/MEK inhibitors. However, some ALMs have mutations such as KIT and NRAS mutations, and therefore, targeted therapies may improve the survival of ALM patients in the future.

Abstract 3389: Integrated genomic analyses reveal frequent TERT aberrations in acral melanoma

Abstract Genomic analyses of cutaneous melanoma (CM) have yielded biological and therapeutic insights, but understanding of non-ultraviolet (UV)-derived CMs remains limited. Deeper analysis of acral lentiginous melanoma (ALM), a rare sun-shielded melanoma subtype associated with worse survival than CM, is needed to delineate non-UV oncogenic mechanisms. We thus performed comprehensive genomic and transcriptomic analysis of 34 ALM patients. Unlike CM, somatic alterations were dominated by structural variation and absence of UV-derived mutation signatures. Only 38% of patients demonstrated driver BRAF/NRAS/NF1 mutations. Contrasting with CM, we observed PAK1 copy gains in 15% of patients, and somatic TERT translocations, copy gains, and missense and promoter mutations, or germline events, in 41% of patients. We further show that in vitro TERT inhibition has cytotoxic effects on primary ALM cells. These findings provide insight into the role of TERT in ALM tumorigenesis, and reveal preliminary evidence that TERT inhibition represents a potential therapeutic strategy in ALM. Citation Format: Winnie S. Liang, William Hendricks, Jeffrey Kiefer, Jessica Schmidt, Shobana Sekar, John Carpten, David W. Craig, Jonathan Adkins, Lori Cuyugan, Zarko Manojlovic, Rebecca F. Halperin, Adrienne Helland, Sara Nasser, Christophe Legendre, Laurence H. Hurley, Karthigayini Sivaprakasam, Douglas B. Johnson, Holly Crandall, Klaus J. Busam, Victoria Zismann, Valerie De Luca, Jeeyun Lee, Aleksandar Sekulic, Charlotte E. Ariyan, Jeffrey Sosman, Jeffrey Trent. Integrated genomic analyses reveal frequent TERT aberrations in acral melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3389. doi:10.1158/1538-7445.AM2017-3389

Integrated genomic analyses reveal frequent TERT aberrations in acral melanoma.

Genomic analyses of cutaneous melanoma (CM) have yielded biological and therapeutic insights, but understanding of non-ultraviolet (UV)-derived CMs remains limited. Deeper analysis of acral lentiginous melanoma (ALM), a rare sun-shielded melanoma subtype associated with worse survival than CM, is needed to delineate non-UV oncogenic mechanisms. We thus performed comprehensive genomic and transcriptomic analysis of 34 ALM patients. Unlike CM, somatic alterations were dominated by structural variation and absence of UV-derived mutation signatures. Only 38% of patients demonstrated driver BRAF/NRAS/NF1 mutations. In contrast with CM, we observed PAK1 copy gains in 15% of patients, and somatic TERT translocations, copy gains, and missense and promoter mutations, or germline events, in 41% of patients. We further show that in vitro TERT inhibition has cytotoxic effects on primary ALM cells. These findings provide insight into the role of TERT in ALM tumorigenesis and reveal preliminary evidence that TERT inhibition represents a potential therapeutic strategy in ALM.

Abstract 3591: Triple negative (c-KIT, BRAF, NRAS) acral lentiginous melanoma in Hawaii: Molecular profiling in a multi-ethnic population

Abstract Background: Acral lentiginous melanoma (ALM) is the least common subtype among patients with melanoma. There is a higher preponderance in the minority population. A different pathogenesis has been proposed for ALM. Previous studies have profiled the importance of c-KIT, BRAF and NRAS mutations in melanoma treatment and prognosis. However, characterization of these somatic mutations in a specific non-Caucasian ALM population has not been reported. The Pacific Basin provides a unique opportunity to study diseases in diverse ethnic groups, including Pacific Islanders and Filipinos. We sought to determine the frequency of a “triple negative” genotype in our multi-ethnic cohort. Methods: IRB approval was obtained for this molecular analysis. From 1999 to 2011, 12 non-Caucasian patients (8-Filipino, 3-Pacific Islander and 1-Vietnamese) histologically confirmed to have ALM were evaluated at a tertiary institution. Data including age, gender, tumor location, Breslow thickness, Clark level, ulceration, regression, and mitoses per mm squared were compiled. Direct sequencing (c-KIT [Exons 8,9,11,13,17,18], NRAS [Exons 2,3]) and real-time PCR (BRAF [Exon 15]) was performed on formalin-fixed/ paraffin-embedded archived biospecimens (primary lesions). Results: Our findings demonstrated that 7/12 (58%) patients exhibited the “triple negative” genotype. Mutually exclusive somatic mutations (4 c-KIT and 1 BRAF) were identified in the remaining 5/12 (42%) patients. Those in the “triple negative” group trended toward a deeper Breslow thickness, when compared to those with a mutation (depth 4.73 mm vs. 3.07 mm). Demographics of the entire non-Caucasian cohort included a mean age of 72.0 years old (range 52-87) and male gender 6/12 (50%). Tumor location principally involved the foot 10/12 (83%); mean Breslow thickness was 4.04 mm (range 2.20-7.75), Clark IV or higher 11/12 (92%), ulceration 8/12 (67%), regression 12/12 (100%), and mean mitoses per mm squared was 5.71 (range 0-30). Conclusions: Non-Caucasian patients with ALM were found to have a high prevalence of the “triple negative” genotype. Those within that group appeared to have thicker tumors. Nearly half of our cohort had thick primary lesions with a high propensity for ulceration. This is the first study to our knowledge that has profiled somatic mutations (c-KIT, BRAF, NRAS) in a multi-ethnic population of ALM patients and examined the histologic correlates of a “triple negative” genotype. This novel concept highlights the relevance of alternate pathways and molecular targets, such as PI3KCA in prognosis and therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3591. doi:1538-7445.AM2012-3591

Acral lentiginous melanoma in Hawaii: Characterization of the mTOR pathway in the non-Caucasian population.

8592 Background: Although, acral lentiginous melanoma (ALM) is the least common subtype among patients with melanoma, there is a higher preponderance in the non-Caucasian population. ALM has been proposed to have a different pathogenesis. Recent studies have profiled the importance of the mTOR (mammalian target of rapamycin) pathway in carcinogenesis. However, characterization of this pathway in a multi-ethnic ALM population has not been reported. The Pacific Basin provides a unique opportunity to study diseases in non-Caucasian patients. We elected to determine the frequency of mTOR pathway involvement in ALM. Methods: IRB approval was obtained for this retrospective analysis. From 1992 to 2010, 20 non-Caucasian patients (9-Filipino, 4-Micronesian, 4-Samoan, 1-Thai, 1-unspecified Pacific Islander and 1-Vietnamese) histologically confirmed to have ALM were evaluated at a tertiary institution. Data including age, gender, tumor location, Breslow thickness, Clark level, ulceration, regression, and mitoses per mm squared were compiled. Immunohistochemical expression for mTOR and eIF4E (eukaryotic initiation factor 4E) proteins was performed on formalin-fixed/ paraffin-embedded archived biospecimens (primary lesions). Both m-TOR and eIF4e expression were graded on a scale from 0 (absent) to 2 (high). Results: Our results demonstrated that the mTOR protein 14/20 (70%) and eIF4E protein 9/20 (45%) were highly expressed. Demographics of the non-Caucasian cohort include mean age of 69.6 years old (range 48-89) and male gender 10/20 (50%). Tumor location principally involved the foot 19/20 (95%); mean Breslow thickness was 4.36 mm (range 1.6-10.0), Clark IV or higher 16/20 (80%), ulceration 16/20 (80%), regression 20/20 (100%), and mean mitoses per mm squared was 8.5 (range 1-30). Conclusions: Non-Caucasian patients with ALM were found to have a high prevalence of effectors involving the mTOR pathway. Nearly half of our cohort had thick primary lesions with a high propensity for ulceration. This is the first study to our knowledge that has examined the mTOR pathway in a non-Caucasian population of ALM patients. This is compelling data that may be applied to the metastatic phenotype in future trials.

Putative linkage between HLA class I polymorphism and the susceptibility to malignant melanoma.

Human leukocyte antigen (HLA) frequencies in 67 melanoma patients were compared to 120 controls in Japan. The frequency of HLA-B13 was increased in melanoma patients compared to controls and was particularly common in nodular melanoma HLA-B61 was decreased in melanoma patients. Almost 50% of acral lentiginous melanoma patients expressed HLA-B51 compared to 0% of nodular melanomas.