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Diagnosis and Management of Acral Lentiginous Melanoma

  • Skin Cancer (T Ito, Section Editor)
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Opinion statement

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.

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References and Recommended Reading

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Abbasi NR, Shaw HM, Rigel DS, et al. Early diagnosis of cutaneous melanoma: revisiting the ABCD criteria. JAMA. 2004;292(22):2771–6.

    Article  PubMed  CAS  Google Scholar 

  2. Cascinelli N, Zurrida S, Galimberti V, et al. Acral lentiginous melanoma. A histological type without prognostic significance. J Dermatol Surg Oncol. 1994;20(12):817–22.

    Article  PubMed  CAS  Google Scholar 

  3. Cress RD, Holly EA. Incidence of cutaneous melanoma among non-Hispanic whites, Hispanics, Asians, and blacks: an analysis of california cancer registry data, 1988–93. Cancer Causes Control. 1997;8(2):246–52.

    Article  PubMed  CAS  Google Scholar 

  4. Chang JW, Yeh KY, Wang CH, et al. Malignant melanoma in Taiwan: a prognostic study of 181 cases. Melanoma Res. 2004;14(6):537–41.

    Article  PubMed  Google Scholar 

  5. Wada M, Ito T, Tsuji G, et al. Acral lentiginous melanoma versus other melanoma: A single-center analysis in Japan. J Dermatol. 2017;44(8):932–8.

    Article  PubMed  CAS  Google Scholar 

  6. Lv J, Dai B, Kong Y, Shen X, Kong J. Acral Melanoma in Chinese: A Clinicopathological and Prognostic Study of 142 cases. Sci Rep. 2016;6(31):432.

    Google Scholar 

  7. Phan A, Dalle S, Touzet S, Ronger-Savle S, Balme B, Thomas L. Dermoscopic features of acral lentiginous melanoma in a large series of 110 cases in a white population. Br J Dermatol. 2010;162(4):765–71.

    Article  PubMed  CAS  Google Scholar 

  8. Somach SC, Taira JW, Pitha JV, Everett MA. Pigmented lesions in actinically damaged skin. Histopathologic comparison of biopsy and excisional specimens. Arch Dermatol. 1996;132(11):1297–302.

    Article  PubMed  CAS  Google Scholar 

  9. Kilinc Karaarslan I, Akalin T, Unal I, Ozdemir F. Atypical melanosis of the foot showing a dermoscopic feature of the parallel ridge pattern. J Dermatol. 2007;34(1):56–9.

    Article  PubMed  Google Scholar 

  10. Saida T, Miyazaki A, Oguchi S, et al. Significance of dermoscopic patterns in detecting malignant melanoma on acral volar skin: results of a multicenter study in Japan. Arch Dermatol. 2004;140(10):1233–8.

    Article  PubMed  Google Scholar 

  11. Merkel EA, Gerami P. Malignant melanoma of sun-protected sites: a review of clinical, histological, and molecular features. Lab Investig. 2017;97(6):630–5.

    Article  PubMed  CAS  Google Scholar 

  12. Bravo Puccio F, Chian C. Acral junctional nevus versus acral lentiginous melanoma in situ: a differential diagnosis that should be based on clinicopathologic correlation. Arch Pathol Lab Med. 2011;135(7):847–52.

    PubMed  Google Scholar 

  13. Fernandez-Flores A, Cassarino DS. Histopathological diagnosis of acral lentiginous melanoma in early stages. Ann Diagn Pathol. 2017;26:64–9.

    Article  PubMed  Google Scholar 

  14. Felton S, Taylor RS, Srivastava D. Excision Margins for Melanoma In Situ on the Head and Neck. Dermatol Surg. 2016;42(3):327–34.

    Article  PubMed  CAS  Google Scholar 

  15. Khayat D, Rixe O, Martin G, et al. Surgical margins in cutaneous melanoma (2 cm versus 5 cm for lesions measuring less than 2.1-mm thick). Cancer. 2003;97(8):1941–6.

    Article  PubMed  Google Scholar 

  16. Balch CM, Urist MM, Karakousis CP, et al. Efficacy of 2-cm surgical margins for intermediate-thickness melanomas (1 to 4 mm). Results of a multi-institutional randomized surgical trial. Ann Surg. 1993;218(3):262–7. discussion 67–9

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. McKinnon JG, Starritt EC, Scolyer RA, McCarthy WH, Thompson JF. Histopathologic excision margin affects local recurrence rate: analysis of 2681 patients with melanomas < or = 2 mm thick. Ann Surg. 2005;241(2):326–33.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Bichakjian CK, Halpern AC, Johnson TM, et al. Guidelines of care for the management of primary cutaneous melanoma. American Academy of Dermatology. J Am Acad Dermatol. 2011;65(5):1032–47.

    Article  PubMed  Google Scholar 

  19. Lee KT, Kim EJ, Lee DY, Kim JH, Jang KT, Mun GH. Surgical excision margin for primary acral melanoma. J Surg Oncol. 2016;114(8):933–9.

    Article  PubMed  Google Scholar 

  20. Bartoli C, Bono A, Clemente C, Del Prato ID, Zurrida S, Cascinelli N. Clinical diagnosis and therapy of cutaneous melanoma in situ. Cancer. 1996;77(5):888–92.

    Article  PubMed  CAS  Google Scholar 

  21. Kunishige JH, Brodland DG, Zitelli JA. Surgical margins for melanoma in situ. J Am Acad Dermatol. 2012;66(3):438–44.

    Article  PubMed  Google Scholar 

  22. Llanos S, Danilla S, Barraza C, et al. Effectiveness of negative pressure closure in the integration of split thickness skin grafts: a randomized, double-masked, controlled trial. Ann Surg. 2006;244(5):700–5.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Jung JY, Roh HJ, Lee SH, Nam K, Chung KY. Comparison of secondary intention healing and full-thickness skin graft after excision of acral lentiginous melanoma on foot. Dermatol Surg. 2011;37(9):1245–51.

    Article  PubMed  CAS  Google Scholar 

  24. Oh BH, Lee SH, Nam KA, Lee HB, Chung KY. Comparison of negative pressure wound therapy and secondary intention healing after excision of acral lentiginous melanoma on the foot. Br J Dermatol. 2013;168(2):333–8.

    Article  PubMed  CAS  Google Scholar 

  25. Nakamura Y, Fujisawa Y, Okiyama N, et al. Surgical damage to the lymphatic system promotes tumor growth via impaired adaptive immune response. J Dermatol Sci. 2018;90(1):46–51.

    Article  PubMed  CAS  Google Scholar 

  26. Duarte AF, Correia O, Barros AM, Ventura F, Haneke E. Nail melanoma in situ: clinical, dermoscopic, pathologic clues, and steps for minimally invasive treatment. Dermatol Surg. 2015;41(1):59–68.

    Article  PubMed  CAS  Google Scholar 

  27. Coit DG, Thompson JA, Algazi A, et al. Melanoma, Version 2.2016, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Cancer Netw. 2016;14(4):450–73.

    Article  Google Scholar 

  28. Ito T, Wada M, Nagae K, et al. Acral lentiginous melanoma: who benefits from sentinel lymph node biopsy? J Am Acad Dermatol. 2015;72(1):71–7.

    Article  PubMed  Google Scholar 

  29. Marek AJ, Ming ME, Bartlett EK, Karakousis GC, Chu EY. Acral Lentiginous Histologic Subtype and Sentinel Lymph Node Positivity in Thin Melanoma. JAMA Dermatol. 2016;152(7):836–7.

    Article  PubMed  PubMed Central  Google Scholar 

  30. •• Faries MB, Thompson JF, Cochran AJ, et al. Completion Dissection or Observation for Sentinel-Node Metastasis in Melanoma. N Engl J Med. 2017;376(23):2211–22. A randamized crinical trial showing immediate ELDN for positive SLN patients did not improve melanoma-specific survival.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Manzano JL, Layos L, Buges C, et al. Resistant mechanisms to BRAF inhibitors in melanoma. Ann Transl Med. 2016;4(12):237.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. McCubrey JA, Steelman LS, Chappell WH, et al. Roles of the Raf/MEK/ERK pathway in cell growth, malignant transformation and drug resistance. Biochim Biophys Acta. 2007;1773(8):1263–84.

    Article  PubMed  CAS  Google Scholar 

  33. Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011;364(26):2507–16.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. Hauschild A, Grob JJ, Demidov LV, et al. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomized controlled trial. Lancet. 2012;380(9839):358–65.

    Article  PubMed  CAS  Google Scholar 

  35. Flaherty KT, Robert C, Hersey P, et al. Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med. 2012;367(2):107–14.

    Article  PubMed  CAS  Google Scholar 

  36. • Long GV, Flaherty KT, Stroyakovskiy D, et al. Dabrafenib plus trametinib versus dabrafenib monotherapy in patients with metastatic BRAF V600E/K-mutant melanoma: long-term survival and safety analysis of a phase 3 study. Ann Oncol. 2017;28(7):1631–9. A randomized clinical trial showing a combination therpy of dabrafenib and trametinib improved response rate and prolonged progression-free and overall survival compared with dabrafenib alone.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. Russo I, Zorzetto L, Frigo AC, Chiarion Sileni V. Alaibac M. A comparative study of the cutaneous side effects between BRAF monotherapy and BRAF/MEK inhibitor combination therapy in patients with advanced melanoma: a single-centre experience. Eur J Dermatol. 2017;27(5):482–6.

    PubMed  Google Scholar 

  38. Coit DG, Thompson JA, Algazi A, et al. NCCN Guidelines Insights: Melanoma, Version 3.2016. J Natl Compr Cancer Netw. 2016;14(8):945–58.

    Article  Google Scholar 

  39. Zebary A, Omholt K, Vassilaki I, et al. KIT, NRAS, BRAF and PTEN mutations in a sample of Swedish patients with acral lentiginous melanoma. J Dermatol Sci. 2013;72(3):284–9.

    Article  PubMed  CAS  Google Scholar 

  40. Curtin JA, Fridlyand J, Kageshita T, et al. Distinct sets of genetic alterations in melanoma. N Engl J Med. 2005;353(20):2135–47.

    Article  PubMed  CAS  Google Scholar 

  41. Beadling C, Jacobson-Dunlop E, Hodi FS, et al. KIT gene mutations and copy number in melanoma subtypes. Clin Cancer Res. 2008;14(21):6821–8.

    Article  PubMed  CAS  Google Scholar 

  42. Greaves WO, Verma S, Patel KP, et al. Frequency and spectrum of BRAF mutations in a retrospective, single-institution study of 1112 cases of melanoma. J Mol Diagn. 2013;15(2):220–6.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  43. Yamazaki N, Tanaka R, Tsutsumida A, et al. BRAF V600 mutations and pathological features in Japanese melanoma patients. Melanoma Res. 2015;25(1):9–14.

    Article  PubMed  CAS  Google Scholar 

  44. Kim SY, Kim SN, Hahn HJ, Lee YW, Choe YB, Ahn KJ. Metaanalysis of BRAF mutations and clinicopathologic characteristics in primary melanoma. J Am Acad Dermatol. 2015;72(6):1036–46 e2.

    Article  PubMed  CAS  Google Scholar 

  45. Curtin JA, Busam K, Pinkel D, Bastian BC. Somatic activation of KIT in distinct subtypes of melanoma. J Clin Oncol. 2006;24(26):4340–6.

    Article  PubMed  CAS  Google Scholar 

  46. Omholt K, Grafstrom E, Kanter-Lewensohn L, Hansson J. Ragnarsson-Olding BK. KIT pathway alterations in mucosal melanomas of the vulva and other sites. Clin Cancer Res. 2011;17(12):3933–42.

    Article  PubMed  CAS  Google Scholar 

  47. Woodman SE, Davies MA. Targeting KIT in melanoma: a paradigm of molecular medicine and targeted therapeutics. Biochem Pharmacol. 2010;80(5):568–74.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  48. Lee JH, Choi JW, Kim YS. Frequencies of BRAF and NRAS mutations are different in histological types and sites of origin of cutaneous melanoma: a meta-analysis. Br J Dermatol. 2011;164(4):776–84.

    Article  PubMed  CAS  Google Scholar 

  49. Ascierto PA, Schadendorf D, Berking C, et al. MEK162 for patients with advanced melanoma harboring NRAS or Val600 BRAF mutations: a non-randomized, open-label phase 2 study. Lancet Oncol. 2013;14(3):249–56.

    Article  PubMed  CAS  Google Scholar 

  50. Sharpe AH, Wherry EJ, Ahmed R, Freeman GJ. The function of programmed cell death 1 and its ligands in regulating autoimmunity and infection. Nat Immunol. 2007;8(3):239–45.

    Article  PubMed  CAS  Google Scholar 

  51. Arasanz H, Gato-Canas M, Zuazo M, et al. PD1 signal transduction pathways in T cells. Oncotarget. 2017;8(31):51936–45.

    Article  PubMed  PubMed Central  Google Scholar 

  52. Linsley PS, Bradshaw J, Greene J, Peach R, Bennett KL, Mittler RS. Intracellular trafficking of CTLA-4 and focal localization toward sites of TCR engagement. Immunity. 1996;4(6):535–43.

    Article  PubMed  CAS  Google Scholar 

  53. Robert C, Long GV, Brady B, et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med. 2015;372(4):320–30.

    Article  PubMed  CAS  Google Scholar 

  54. Robert C, Thomas L, Bondarenko I, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med. 2011;364(26):2517–26.

    Article  PubMed  CAS  Google Scholar 

  55. Hamid O, Puzanov I, Dummer R, et al. Final analysis of a randomized trial comparing pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory advanced melanoma. Eur J Cancer. 2017;86:37–45.

    Article  PubMed  CAS  Google Scholar 

  56. Kaunitz GJ, Cottrell TR, Lilo M, et al. Melanoma subtypes demonstrate distinct PD-L1 expression profiles. Lab Investig. 2017;97(9):1063–71.

    Article  PubMed  CAS  Google Scholar 

  57. Castaneda CA, Torres-Cabala C, Castillo M, et al. Tumor infiltrating lymphocytes in acral lentiginous melanoma: a study of a large cohort of cases from Latin America. Clin Transl Oncol. 2017;19(12):1478–88.

    Article  PubMed  CAS  Google Scholar 

  58. Savarese I, Papi F, D’Errico A, et al. Acral lentiginous melanoma treated with topical imiquimod cream: possible cooperation between drug and tumor cells. Clin Exp Dermatol. 2015;40(1):27–30.

    Article  PubMed  CAS  Google Scholar 

  59. Swetter SM, Chen FW, Kim DD, Egbert BM. Imiquimod 5% cream as primary or adjuvant therapy for melanoma in situ, lentigo maligna type. J Am Acad Dermatol. 2015;72(6):1047–53.

    Article  PubMed  CAS  Google Scholar 

  60. Fan Q, Cohen S, John B, Riker AI. Melanoma in Situ Treated with Topical Imiquimod for Management of Persistently Positive Margins: A Review of Treatment Methods. Ochsner J. 2015;15(4):443–7.

    PubMed  PubMed Central  Google Scholar 

  61. Ocampo-Garza J, Gioia Di Chiacchio N, Haneke E, le Voci F, Paschoal FM. Subungual Melanoma In Situ Treated With Imiquimod 5% Cream After Conservative Surgery Recurrence. J Drugs Dermatol. 2017;16(3):268–70.

    PubMed  Google Scholar 

  62. Joseph RW, Cappel M, Tzou K, et al. Treatment of in-transit and metastatic melanoma in two patients treated with ipilimumab and topical imiquimod. Melanoma Res. 2016;26(4):409–12.

    Article  PubMed  Google Scholar 

  63. Fujimura T, Kambayashi Y, Sato Y, et al. Successful Treatment of Nivolumab-Resistant Multiple In-Transit Melanomas with Ipilimumab and Topical Imiquimod. Case Rep Oncol. 2018;11(1):1–5.

    Article  PubMed  PubMed Central  Google Scholar 

  64. Hervieu A, Rebe C, Vegran F, et al. Dacarbazine-mediated upregulation of NKG2D ligands on tumor cells activates NK and CD8 T cells and restrains melanoma growth. J Invest Dermatol. 2013;133(2):499–508.

    Article  PubMed  CAS  Google Scholar 

  65. Kirkwood JM, Richards T, Zarour HM, et al. Immunomodulatory effects of high-dose and low-dose interferon alpha2b in patients with high-risk resected melanoma: the E2690 laboratory corollary of intergroup adjuvant trial E1690. Cancer. 2002;95(5):1101–12.

    Article  PubMed  CAS  Google Scholar 

  66. Wang W, Edington HD, Rao UN, et al. Modulation of signal transducers and activators of transcription 1 and 3 signaling in melanoma by high-dose IFNalpha2b. Clin Cancer Res. 2007;13(5):1523–31.

    Article  PubMed  CAS  Google Scholar 

  67. Parlato S, Santini SM, Lapenta C, et al. Expression of CCR-7, MIP-3beta, and Th-1 chemokines in type I IFN-induced monocyte-derived dendritic cells: importance for the rapid acquisition of potent migratory and functional activities. Blood. 2001;98(10):3022–9.

    Article  PubMed  CAS  Google Scholar 

  68. Brinkmann V, Geiger T, Alkan S, Heusser CH. Interferon alpha increases the frequency of interferon gamma-producing human CD4+ T cells. J Exp Med. 1993;178(5):1655–63.

    Article  PubMed  CAS  Google Scholar 

  69. Rafique I, Kirkwood JM, Tarhini AA. Immune checkpoint blockade and interferon-alpha in melanoma. Semin Oncol. 2015;42(3):436–47.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  70. Eggermont AMM, Blank CU, Mandala M et al. Adjuvant Pembrolizumab versus Placebo in Resected Stage III Melanoma. N Engl J Med. 2018;378(19):1789–1801.

  71. Long GV, Hauschild A, Santinami M, et al. Adjuvant Dabrafenib plus Trametinib in Stage III BRAF-Mutated Melanoma. N Engl J Med. 2017;377(19):1813–23.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

We thank Flaminia Miyamasu of the University of Tsukuba Medical English Communication Center for English editing of this manuscript.

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  1. Department of Dermatology, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8575, Japan

    Yoshiyuki Nakamura MD, PhD & Yasuhiro Fujisawa MD, PhD

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  1. Yoshiyuki Nakamura MD, PhD
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Correspondence to Yoshiyuki Nakamura MD, PhD.

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Nakamura, Y., Fujisawa, Y. Diagnosis and Management of Acral Lentiginous Melanoma. Curr. Treat. Options in Oncol. 19, 42 (2018). https://doi.org/10.1007/s11864-018-0560-y

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