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Melanoma

Oncology
Dermatology
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Introduction

Malignant Melanoma (MM) develops from melanocytes which are the cells responsible for pigmentation. Melanocytes are located in the skin, mucosa, central nervous system and the uveal tract of the eye. Skin cancers are the most commonly diagnosed cancers worldwide, with more than 1.5 million new cases estimated in 2020 [1].
Cutaneous MM (cMM) accounts for approximately 1 in 5 of these cancers, with approximately 325,000 cases estimated globally in 2020 [1]. The incidence of cMM has been rising over the past 50 years, particularly in fair-skinned populations of European ancestry [2, 3].
The risk of cMM generally increases with age, however cMM is among the most common cancers in young adults [4]. With the introduction of novel therapies including immunotherapies and targeted therapies, the prognosis of cMM has drastically changed and led to improved clinical outcomes.

Risk factors

Well-known risk factors for cMM include ultraviolet (UV) radiation (sun exposure, tanning beds), sunburn, multiple of dysplastic nevi, and a prior history of melanoma [5].
Inherited genetic mutations predisposing to the development of cMM are possible but rare. Inherited genetic conditions should be considered in a person with multiple cMM or history of cutaneous MM in multiple family members and/or in patients who suffer from hereditary conditions such as familial atypical multiple mole melanoma (FAMM) syndrome[6].
Approximately 35 to 40% of familial melanomas have been linked to mutations in the CDKN2A/p16 and CDK4 genes [7].

Screening

Screening for cMM includes skin examination for abnormal skin lesions or “moles”. Annual skin examinations are most important for those patients with risk factors for cMM.

Diagnosis

The “ABCD” characteristics of cMM have been traditionally used to identify a potentially suspicious mole that should be biopsied:
  • Asymmetry,
  • Border irregularities,
  • Color heterogeneity,
  • Diameter.

    However, the term Diameter more recently has been replaced by Dynamics, as today most primary melanomas have a diameter of <5mm [8].
Dynamics refers to evolution in color, elevation or size of the pigmented lesion as it can help to identify rapidly growing amelanotic melanomas.
Diagnosis of cMM should be based on a full thickness excisional biopsy. It is important to have the biopsy processed according to international guidelines and by an experienced pathologist. Subtypes of cMM include superficial spreading, lentigo maligna, acral lentiginous and nodular [9].

Staging

cMM is staged using the American Joint Committee on Cancer (AJCC) staging system [10].
This staging system incorporates Breslow tumor depth (T), node (N) and metastasis (M) as well as presence or absence of ulceration and mitotic index.
  • The tumor (T) stage is determined pathologically based on the biopsy specimen.
  • The nodal stage (N) is determined clinically if there are palpable lymph nodes, through imaging or pathologically at the time of surgery.
  • The metastasis (M) stage is generally determined through imaging investigations.

Treatment of local/locoregional disease

Surgical treatment for cMM involves wide local excision of the primary tumor site with margins of 0.5 cm for in situ melanomas, 1 cm for tumors with a thickness of up to 2 mm and 2 cm for thicker tumors [11]. Sentinel lymph node biopsy (SLNB) is recommended in patients who are clinically node negative for staging in cMM of AJCC eighth edition stage pT1b or higher, i.e. with tumor thickness >0.8 mm or with tumor thickness of <0.8 mm with ulceration [12].
SLNB involves injecting either a blue dye and/or radio-labelled tracer at the time of surgery to identify the first draining lymph nodes which are termed the sentinel lymph nodes. Completion lymph node dissection (CLND) in patients with positive sentinel nodes is no longer recommended based on studies which showed no impact on survival for early CLND compared with nodal observation with periodic ultrasound imaging of the SLN-positive basin [13, 14].
In the case of isolated locoregional clinically detectable lymph node metastases, therapeutic lymph node dissection is recommended after ruling out distant metastases through high resolution imaging techniques such as PET, CT or MRI.
Patients with resectable satellite or in transit disease may also be candidates for surgery. Those with unresectable satellite or in transit disease may benefit from local therapy with radiation or with newer injectable agents such as the oncolytic virus talimogene laherparepvec (T-VEC) [15]. However, use of such local injectable therapies should be restricted to centres experienced with their use.
Adjuvant radiation therapy may also be considered for local tumor control but is not routinely recommended given that it has no impact on recurrence-free survival (RFS) or overall survival in cMM [16].
Tumor testing for BRAFV600 mutations in patients with nodal involvement and in those with Stage IV disease is now considered standard of care and can be performed using routine immunohistochemical techniques or next-generation sequencing, depending on the experience of the centre [17].
These results are used to guide to use of systemic therapies. Testing for other gene mutations including in NRAS and c-kit is also often performed, as they are increasingly important to identify in order to select patients for clinical trials.
Adjuvant systemic therapy with either anti-PD-1 inhibitor or targeted therapy with BRAF/MEK inhibitors in BRAFV600-mutated cMM is now the standard of care in patients with SLN-positive melanoma. The anti-PD-1 inhibitor nivolumab has shown a significant recurrence-free survival benefit for stage IIB/C and IV (AJCC seventh edition) resected melanoma compared with adjuvant high-dose ipilimumab, with an RFS HR of 0.66 [18]. The anti-PD-1 inhibitor pembrolizumab has been compared to placebo in patients with stage IIIA (SN > 1 mm), B and C and is associated with significantly longer RFS than placebo with HR for recurrence or death of 0.57 [19].
In patients with BRAFV600-mutated melanoma, the combination of dabrafenib and trametinib targeted therapy in fully resected high-risk stage IIIA (LN metastases > 1 mm), IIB or IIIC cMM (AJCC seventh edition) was associated with a significantly improved RFS benefit versus placebo with HR for relapse or death of 0.57 [20].

Treatment of advanced /metastatic disease

Patients with resectable metastatic disease should be considered for surgical excision of the metastasis and adjuvant therapy with nivolumab [18].
Patients with BRAF– wildtype stage IV metastatic or unresectable melanoma can be considered for systemic therapy with either combination ipilimumab and nivolumab (preferred) or single agent nivolumab or pembrolizumab.
Those with BRAFV600-mutant melanoma can be offered combination BRAF/MEK inhibitors or immunotherapy with either combination ipilimumab and nivolumab or single agent nivolumab or pembrolizumab. However, two recent prospective studies, SECOMBIT (Ascierto et al presented at ESMO 2021 abstr LBA40) and DREAMSeq (Atkins et al presented at ASCO Plenary Series 2021 abstr 356154) support the use of combination immune checkpoint inhibitor over targeted therapies in the frontline setting for patients with untreated, metastatic BRAFV600-mutated melanoma.
In patients with CNS disease, combination immunotherapy with ipilimumab and nivolumab is preferred [21, 22] given its long duration of response and similar CNS and extracranial response rates. Targeted therapies with BRAF/MEK inhibitors are also an option in patients whose tumors harbor BRAFV600 mutations but duration of response in the CNS is suboptimal compared to extracranial sites [23].
Primary radiation therapy with stereotactic radiosurgery or palliative resection for patients with brain metastases should also be considered in addition to systemic therapy, especially for patients with symptomatic brain metastases.

Summary and Recommendations

Systemic therapy for cutaneous melanoma is a rapidly evolving field. There are many emerging options for the treatment of both early stage and advanced disease. Please refer to the National Comprehensive Cancer Network (NCCN) guidelines as well as guidelines from the American Society of Clinical Oncology (ASCO) and the European Society for Medical Oncology (ESMO) for the most up to date recommendations.

References

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  2. Erdmann F, Lortet-Tieulent J, Schuz J, Zeeb H, Greinert R, Breitbart EW, et al. International trends in the incidence of malignant melanoma 1953-2008–are recent generations at higher or lower risk? Int J Cancer. 2013;132(2):385-400.
  3. Arnold M, Holterhues C, Hollestein LM, Coebergh JW, Nijsten T, Pukkala E, et al. Trends in incidence and predictions of cutaneous melanoma across Europe up to 2015. J Eur Acad Dermatol Venereol. 2014;28(9):1170-8.
  4. Fidler MM, Gupta S, Soerjomataram I, Ferlay J, Steliarova-Foucher E, Bray F. Cancer incidence and mortality among young adults aged 20-39 years worldwide in 2012: a population-based study. Lancet Oncol. 2017;18(12):1579-89.
  5. Gandini S, Sera F, Cattaruzza MS, Pasquini P, Zanetti R, Masini C, et al. Meta-analysis of risk factors for cutaneous melanoma: III. Family history, actinic damage and phenotypic factors. Eur J Cancer. 2005;41(14):2040-59.
  6. Goldstein AM, Chan M, Harland M, Gillanders EM, Hayward NK, Avril MF, et al. High-risk melanoma susceptibility genes and pancreatic cancer, neural system tumors, and uveal melanoma across GenoMEL. Cancer Res. 2006;66(20):9818-28.
  7. Zuo L, Weger J, Yang Q, Goldstein AM, Tucker MA, Walker GJ, et al. Germline mutations in the p16INK4a binding domain of CDK4 in familial melanoma. Nat Genet. 1996;12(1):97-9.
  8. Bono A, Tolomio E, Trincone S, Bartoli C, Tomatis S, Carbone A, et al. Micro-melanoma detection: a clinical study on 206 consecutive cases of pigmented skin lesions with a diameter < or = 3 mm. Br J Dermatol. 2006;155(3):570-3.
  9. Whiteman DC, Pavan WJ, Bastian BC. The melanomas: a synthesis of epidemiological, clinical, histopathological, genetic, and biological aspects, supporting distinct subtypes, causal pathways, and cells of origin. Pigment Cell Melanoma Res. 2011;24(5):879-97.
  10. Gershenwald JE, Scolyer RA, Hess KR, Sondak VK, Long GV, Ross MI, et al. Melanoma staging: Evidence-based changes in the American Joint Committee on Cancer eighth edition cancer staging manual. CA Cancer J Clin. 2017;67(6):472-92.
  11. Thompson JF, Scolyer RA, Kefford RF. Cutaneous melanoma. Lancet. 2005;365(9460):687-701.
  12. Han D, Zager JS, Shyr Y, Chen H, Berry LD, Iyengar S, et al. Clinicopathologic predictors of sentinel lymph node metastasis in thin melanoma. J Clin Oncol. 2013;31(35):4387-93.
  13. Leiter U, Stadler R, Mauch C, Hohenberger W, Brockmeyer N, Berking C, et al. Complete lymph node dissection versus no dissection in patients with sentinel lymph node biopsy positive melanoma (DeCOG-SLT): a multicentre, randomised, phase 3 trial. Lancet Oncol. 2016;17(6):757-67.
  14. Faries MB, Thompson JF, Cochran AJ, Andtbacka RH, Mozzillo N, Zager JS, et al. Completion Dissection or Observation for Sentinel-Node Metastasis in Melanoma. N Engl J Med. 2017;376(23):2211-22.
  15. Andtbacka RH, Kaufman HL, Collichio F, Amatruda T, Senzer N, Chesney J, et al. Talimogene Laherparepvec Improves Durable Response Rate in Patients With Advanced Melanoma. J Clin Oncol. 2015;33(25):2780-8.
  16. Henderson MA, Burmeister BH, Ainslie J, Fisher R, Di Iulio J, Smithers BM, et al. Adjuvant lymph-node field radiotherapy versus observation only in patients with melanoma at high risk of further lymph-node field relapse after lymphadenectomy (ANZMTG 01.02/TROG 02.01): 6-year follow-up of a phase 3, randomised controlled trial. Lancet Oncol. 2015;16(9):1049-60.
  17. Michielin O, van Akkooi ACJ, Ascierto PA, Dummer R, Keilholz U, clinicalguidelines@esmo.org EGCEa. Cutaneous melanoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-updagger. Ann Oncol. 2019;30(12):1884-901.
  18. Weber J, Mandala M, Del Vecchio M, Gogas HJ, Arance AM, Cowey CL, et al. Adjuvant Nivolumab versus Ipilimumab in Resected Stage III or IV Melanoma. N Engl J Med. 2017;377(19):1824-35.
  19. Eggermont AMM, Robert C, Suciu S. Adjuvant Pembrolizumab in Resected Stage III Melanoma. N Engl J Med. 2018;379(6):593-5.
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  23. Davies MA, Saiag P, Robert C, Grob JJ, Flaherty KT, Arance A, et al. Dabrafenib plus trametinib in patients with BRAF(V600)-mutant melanoma brain metastases (COMBI-MB): a multicentre, multicohort, open-label, phase 2 trial. Lancet Oncol. 2017;18(7):863-73.