Key points

If I have seen a little further, it is by standing on the shoulders of giants.

Introduction

In 2014, an estimated 76,100 patients will develop new primary melanoma in the United States, and 9710 will die of this disease. In the United States, melanoma accounts for less than 5% of all skin cancers but is the leading cause of skin cancer mortality. The annual rate of increase of melanoma incidence is currently estimated at 3% compared with 6% in the 1970s to 1980s, but the overall mortality has been relatively stable since 1990. Worldwide the incidence of melanoma continues to increase; despite advances in local and systemic therapy, mortality continues to increase, with 80% of skin cancer-related deaths attributable to melanoma. Progress in the basic molecular biology and immunology of melanoma over the past 50 years has translated into improved outcomes for patients with localized disease as well as for those with systemic disease. The distribution of the burden of disease may be seen as inversely related to the opportunities to improve outcome. Advanced disease represents a smaller fraction of cases compared to earlier operable disease, associated with higher morbidity/mortality affording us greater opportunities for improved outcomes. Outcomes for patients with deeper primary lesions show a different picture. Those patients with deeper localized American Joint Committee on Cancer (AJCC) stage IIB/IIC disease have an increased risk of relapse and death, whereas patients with microscopic regional stage IIIA disease detectable with sentinel lymph node (SLN) mapping and biopsy have an intermediate risk. Recurrent nodal disease and bulky nodal IIIB-C disease have a relapse and mortality risk that approaches 70% or more at 5 years. Treatment and outcomes for advanced melanoma have improved over the past 20 years because of rapid advances in tumor cell biology, immunology, surgical techniques, radiosurgery, and imaging that are likely to further transform the field in the decade to come. This review reflects on the progress made in the past century and familiarizes the reader with the current state and management of melanoma.

Introduction

In 2014, an estimated 76,100 patients will develop new primary melanoma in the United States, and 9710 will die of this disease. In the United States, melanoma accounts for less than 5% of all skin cancers but is the leading cause of skin cancer mortality. The annual rate of increase of melanoma incidence is currently estimated at 3% compared with 6% in the 1970s to 1980s, but the overall mortality has been relatively stable since 1990. Worldwide the incidence of melanoma continues to increase; despite advances in local and systemic therapy, mortality continues to increase, with 80% of skin cancer-related deaths attributable to melanoma. Progress in the basic molecular biology and immunology of melanoma over the past 50 years has translated into improved outcomes for patients with localized disease as well as for those with systemic disease. The distribution of the burden of disease may be seen as inversely related to the opportunities to improve outcome. Advanced disease represents a smaller fraction of cases compared to earlier operable disease, associated with higher morbidity/mortality affording us greater opportunities for improved outcomes. Outcomes for patients with deeper primary lesions show a different picture. Those patients with deeper localized American Joint Committee on Cancer (AJCC) stage IIB/IIC disease have an increased risk of relapse and death, whereas patients with microscopic regional stage IIIA disease detectable with sentinel lymph node (SLN) mapping and biopsy have an intermediate risk. Recurrent nodal disease and bulky nodal IIIB-C disease have a relapse and mortality risk that approaches 70% or more at 5 years. Treatment and outcomes for advanced melanoma have improved over the past 20 years because of rapid advances in tumor cell biology, immunology, surgical techniques, radiosurgery, and imaging that are likely to further transform the field in the decade to come. This review reflects on the progress made in the past century and familiarizes the reader with the current state and management of melanoma.

Historical perspectives

Described in antiquity as a fatal black tumor , the term derived from Greek ( melas “dark” and oma “tumor”) was coined by Dr Robert Carswell in 1838. References to this fatal black tumor can be found in the writings of the Greek physician Hippocrates in the fifth century bc , whereas those of Rufus of Ephesus emanate from the first century ad . Hunter is credited with the first resection of melanoma in 1787. Renè Laennec described melanoma as a disease entity and coined the term melanose to describe the tumor in 1804. Dr William Norris noted the heterogeneous appearance of the tumor and its propensity to metastasize in 1820 and first noted the heritable nature of melanoma and familial atypical multiple melanoma. In further publications, he observed that most of his patients had fair skin with light colored hair and the futility of surgery and medical therapy in the setting of distant metastases. Thomas Fawdington described one of the first cases of uveal melanoma and despaired at the lack of knowledge of therapies for this “insidious” process in 1820. In 1844, British surgeon Samuel Cooper recognized the benefit of the early removal of tumors and the untreatable nature of advanced disease.

Pathogenesis

Melanocytes in the epidermis of the skin produce the pigment melanin, which occurs in several forms that variably protect the skin from UV radiation. Most melanoma is sporadic. Environmental insults followed by proto-oncogene activation coupled with the suppression of tumor suppressor genes and defects in the DNA repair mechanism further exacerbated by the inability of the immune system to contain these insults result in melanoma. William Norris presciently observed the hereditary nature of melanoma and light hair and complexion associated with melanoma in 1857. He proposed that nevi and environmental exposures predispose to melanoma, observations that were validated in the discovery of the Familial Atypical Multiple Mole and Melanoma (FAMM) syndrome and the sporadic dysplastic nevus syndrome. The connection between UV radiation exposure and increased risk of melanoma in the Australian Caucasian population was described by Henry Lancaster in 1956 whose later work demonstrated the importance of skin characteristics in the cause of melanoma. These observations gave impetus to efforts to understand the genetics of melanoma. The discovery of the melanocortin receptor 1 (MC1R) on skin/hair phenotype and its highly polymorphic nature helped make the association between pale skin/fair hair with poor tanning response (English/Celtic ancestry) and melanoma. Approximately 40% of familial melanomas were attributed to a heritable germline mutation in the cyclin-dependent kinase (CDK) gene CDKN2A. Defects in CDK4, xeroderma pigmentosum, and MC1R genes have been implicated in familial melanomas. The discovery of the role of the Ras oncogene family in the 1980s and their effects on downstream signaling were the first steps toward the identification of driver mutations in melanoma. NRAS was first identified in a melanoma cell line in 1984. The identification of the mitogen-activated protein kinase (MAPK)/ERK and PI3K/Akt pathways of melanoma tumorigenesis followed. The mutations termed rapidly accelerated fibrosarcoma (RAF) were initially identified in Ewing sarcoma. Systematic genetic typing identified the V600E variant to be frequent in cutaneous melanoma in 2002. This mutation and its constitutive activation of the MAPK pathway have become the target of multiple pharmaceutical trials of small molecule inhibitors resulting in several new therapies approved by the Food and Drug Administration (FDA). The evaluation of other histologic subtypes led to the discovery of cKIT in acral and mucosal melanomas. Uveal melanomas exhibit driver mutations in GNAQ, GNA11, and BAP1 with a low incidence of BRAF. The differing pattern of driver mutations in different histologic subtypes of melanoma and the numeric burden of mutations in different melanoma cell lines from single tumors and in tumor samples ex vivo reflect the genetic heterogeneity of melanoma and are likely to have profound implications for the molecular and immunologic therapy for melanoma.

Risk factors

Melanoma is a disease that afflicts Caucasian Americans 20 times more commonly than African Americans. The lifetime risk of melanoma is approximately 2.0% (1 in 50) for Caucasians, 0.1% (1 in 1000) for African Americans, and 0.5% (1 in 200) for Hispanics. The risk of melanoma increases with age. The average age at incidence is 61 years; but it is not uncommon among those younger than 30 years, especially young women. Men have a higher lifetime risk than women. Previous history of melanoma is associated with an approximately 7% chance of developing a second primary melanoma. Exposure to UV radiation is the predominant environmental risk factor leading to melanoma. Cumulative solar exposure and sunburn events (UV-B) are both suspected as causative. UV-A exposure from tanning beds has been implicated in the risk and incidence of melanoma, particularly among women younger than 35 years. This finding has led to the labeling of sun beds/lamps as human carcinogens by multiple health organizations, including the National Institutes of Health (NIH). Most melanomas arise as new lesions in the skin, although a significant fraction (25%–40%) seems to arise from preexisting nevi. The latter type, clinically described as atypical and pathologically identified as dysplastic nevi along with congenital nevi, has long been considered a risk marker and nonobligate precursor warranting surveillance. Giant congenital nevi (>20 cm) carry an increased risk of melanoma and are excised when possible. Family history of melanoma increases an individual’s risk of melanoma up to 8 fold. Population studies have shown an increased incidence of skin cancers, including melanoma, in patients with chronic lymphocytic leukemia. BRCA2 mutation carriers are noted to have a 2.58 times greater risk than noncarriers of developing melanoma.

Diagnosis

Patients may present with an unusual, new, or changing skin lesion to their primary care physician or dermatologist. Melanoma can present as amelanotic flesh-colored or nodular lesions. The ABCDEs of melanoma guide the decision to biopsy. The American Academy of Dermatology recommends an excisional biopsy with narrow margins as the preferred biopsy technique over shave and incisional biopsy. A deeper saucerization biopsy is acceptable, and incisional biopsy is appropriate for lesions suspicious for melanoma that are not suitable for excisional biopsy. If a punch biopsy is performed, it should be deep enough to encompass the base of the lesion. The stains traditionally used to identify melanoma include a combination of S100B (in some centers, this has been replaced with a pooled mixture of antibodies to Melan-A/MART1), HMB-45, and tyrosinase. Newer targets for IHC assessment include SOX10 and Mitf. Growth phase (radial vs vertical), morphotype (nodular or superficial spreading) mitotic rate, ulceration, and presence of tumor regression and tumor infiltration by lymphocytes are conventionally reported for their prognostic implications. Melanoma can be categorized morphologically and anatomically into the uveal, cutaneous, mucosal, and acral types, which have differing molecular patterns of driver oncogenes. Invasive cutaneous melanomas have historically been subdivided based on growth patterns into superficial spreading (most common), nodular (next most common), and acral lentiginous mucosal and lentigo maligna morphotypes, which have differing biologic behavior, prognosis, and molecular driver gene patterns.

Staging

The foundation for the current staging system was laid by the pioneering work of Wallace Clark and Alexander Breslow. In 1966, Clark proposed a system that derived from the assessment of the tissue level of invasion subsequently termed Clark level to assist in the pathologic assessment of the prognosis of melanoma. Invasion of the layers of skin reflect prognosis (Clark levels I–V representing the junction, upper papillary, full papillary, reticular, and subcutaneous zones of the skin) with decreasing survival rates associated with increased level of invasion. In 1970, Breslow observed that prognosis was affected by tumor thickness and worsened with increasing thickness measured from the granular layer of the epidermis. These systems were incorporated into clinical trial structure building the framework for surgical and medical management and serving as a common language for physicians to communicate and compare patients in clinical experiences. The AJCC Melanoma Staging Committee has periodically reassessed the staging of melanoma for prognostic assessment and last revised the staging system in 2009 (seventh edition), which was put it into practice after a period of commentary in 2010. The committee based its actions on a multivariate analysis of approximately 38,000 patients (7972 with stage IV disease) from North America, Europe, and Australia to revise/clarify the TNM classifications and overall stage grouping criteria. It incorporated key prognostic features, including Breslow thickness, ulceration, mitotic rate for thin melanomas (replaced Clark level), involvement of lymph nodes (LN) including manifestations of lymphatic spread (satellite lesions, in-transit disease), and the presence of distant metastatic disease (lung vs other). The system also integrated prognostic data for survival and risk of relapse within each stage. The staging system reflects excellent long-term survival for AJCC stage I and II melanoma, approaching 90% and 80%, respectively, at 20 years, whereas stages IIB and greater have an increased risk of relapse and death, with stage IIIB-C approaching 70% or greater relapse/mortality at 5 years.

Prognosis

The prognosis at diagnosis is largely defined by the stage of disease. Staging incorporates clinical and pathologic features and determines diagnostic and therapeutic pathways for a given individual. The extent of disease including the presence or absence of LN involvement and any distant metastases are the most important prognostic factors. The staging system also incorporates other important prognostic microstaging factors of the primary, such as Breslow thickness, presence or absence of ulceration, and mitotic rate of the primary tumor. Older patients have a worse prognosis regardless of the stage of disease compared with younger patients. Among the morphotypes of melanoma, nodular melanoma by virtue of its predominant vertical growth phase and more frequent presence of ulceration carries a worse prognosis. Acral lentiginous melanomas are more difficult to detect (inconspicuous location) and are generally first detected at more advanced stages. Lentigo maligna melanomas are generally often of longer gestation and may be detected and operated at lesser depths of invasion. Anatomically, extremity melanomas have better outcomes than truncal or head/neck melanomas. Women tend to do better than men. Ulceration serves as a marker for aggressive tumor biology and propensity to metastasize. In thin melanomas, a mitotic rate of 1 or more serves as an indication of higher risk and, therefore, warrants SLN evaluation. NRAS and BRAF mutations are also associated with differing patterns of disease aggressiveness. NRAS is associated with thicker primaries and higher mitotic rates. These markers seem to correlate with aggressive tumor biology reflecting a propensity for distant invasion.

Surgical treatment

Medical management

Most patients present with early stages of diseases, so skin examination for early detection is a mandate for all physicians in primary care as well as those who specialize in the management of melanoma from medical as well as surgical and dermatologic disciplines. Data from Germany, where the state of Schleswig Holstein adopted a program of screening among dermatologists, and many primary care practitioners now suggests that routine full-body skin examination significantly reduces the incident thickness of melanoma and the mortality attributable to the disease by up to 50% based on time trends for melanoma incidence and mortality in the state of Schleswig Holstein compared with surrounding German states and neighboring Denmark. These results have already led to the nationwide pursuit of regular skin screening for detection of melanoma across Germany—and health care systems elsewhere in the world are considering the role of screening and secondary prevention on this basis. Although the German model used a day-long training module, simpler Internet-based training modules that require only 1 to 2 hours for primary care physicians may provide more practicable current alternatives; one such primary care educational effort coupled with recommended annual total-body skin screening has been initiated in the University of Pittsburgh Medical Center Health System whereby incident melanoma thickness and melanoma mortality will be followed closely over the next several years. These measures, together with evidence that appropriate surgical management cures most patients with stage IA-IB melanoma, and many with stage IIA disease, are rapidly evolving at this time. The overall 5-year survival rates for early stage disease (AJCC IA-IIA) exceed 80%. The pattern of relapse for operable early melanoma suggests that data for such patients should be judged at longer horizons. The insidious nature of some melanoma relapses and the later distribution of relapses from early stage disease make the issues of surveillance of relapse particularly important. There are wide variations in the recommended frequency, and the utilization of radiologic and biomarker studies across the world. These lie beyond the scope of this overview, except to note that the economic and patient anxiety and overdiagnosis toll of surveillance have not always been factored into recommendations (eg, S3 German, Italian, and other high-intensity programs as compared with Australian, Dutch, British, and more minimalist recommendations). Sadly, there is little rigorous evidence to support the application of interval radiologic or biomarker studies in the follow-up of patients with melanoma. Closer interval follow-ups using imaging and blood testing for biomarkers, such as S1000B, which have been favored in Europe, have not been demonstrated to translate into improved survival outcomes when compared with clinical assessment at wider intervals. The data that are available generally do not account for the enormous fiscal costs and potential for patient and societal harms of the imaging assessments proposed. Because therapies for advanced melanoma are improving rapidly, the data on surveillance for earlier cohorts of patients will not be applicable to the present and future in which therapies may have increased potential for cure of the disease in the adjuvant as well as the metastatic settings. The need to develop evidence-based approaches to the surveillance of low-, intermediate-, and high-risk patients (stage IA-B, IIA-IIIA, and IIIB-C and other resectable disease) is pressing. Evidence that would guide us in regard to which patients are at risk of late relapse is critical to determine which patients are reasonable to consider for surveillance and, ultimately, for adjuvant therapy. The role of medical therapy in reducing the risk of relapse after surgery (ie, adjuvant therapy) has been compartmentalized in relation to low-, intermediate-, and high-risk populations of patients, with variable results. Research using more informative tissue assessment is ongoing to determine the efficacy of neoadjuvant therapy in melanoma. The agents in use today have fulfilled some of the criteria that Paul Ehrlich (1854–1915) articulated more than a century ago for the Magische Kugel or “magic bullet”; these will likely change our approach to surveillance for recurrence in intermediate- and high-risk operable disease, as well as inoperable disease, as therapies that can cure metastatic disease become more generally available.