Melanoma and Other Skin Cancers

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Skin cancer is the single most common form of cancer, accounting for more than 75% of all cancer diagnoses. More than 1 million cases of squamous cell and basal cell carcinomas are diagnosed annually, with a lifetime risk of more than one in five.

Overview

Skin cancer is the most common form of malignancy, accounting for more than 75% of all cancer diagnoses. More than 3 million cases of squamous cell carcinomas, basal cell carcinomas, and melanomas are diagnosed annually in the US, with one in five Americans developing skin cancer. The vast majority of skin cancers can be cured via localized therapies including topical therapy, radiation therapy, and simple surgical interventions. Resection with wide surgical margins remains the mainstay of therapy for melanoma.

The interaction of genes and the environment is responsible for most skin cancers. Exposure to ultraviolet radiation is the best-known and best-studied environmental risk factor for squamous cell and basal cell skin cancer, and is the only known environmental risk factor for melanoma. Genetic predisposition to skin cancer, which may be expressed by phenotypic traits such as red hair or the presence of many nevi, also plays a significant role. Genetic susceptibility to melanoma clearly varies across the population and correlates to a large degree with light skin, hair, and eye color. Melanoma contributes to 75% of deaths from skin cancer. An estimated 73,870 new cases of melanoma of the skin will be diagnosed in the United States in 2015, with approximately 9,940 deaths. The overall death rate from melanoma increased by 5.8% in the United States between 1990 and 2005; this increase was the result of a significant rise in melanoma deaths in men. The mortality rate in women over the same period of time actually showed a slight decrease. The lifetime risk of melanoma for Caucasians is 1 in 35 for men and 1 in 54 for women in the United States. The 5-year survival was 92% of patients diagnosed with melanoma in the United States between 1996 and 2004, an increase of 10% compared with the years 1975 through 1977. This is almost certainly due to an increase in early detection.

The knowledge that melanoma and other skin cancers begin their growth within the superficial layers of the skin supports campaigns to raise public awareness and healthcare provider expertise in detecting skin cancers at the earliest possible stage. High-risk groups, for whom screening efforts might make the largest impact, are older men, individuals with many nevi, those with a personal or family history of skin cancer, and families with numerous cases of melanoma, just to mention a few of the high-risk groups.

Melanoma

Epidemiology

The vast majority of melanomas arise from cutaneous sites. Most arise from intermittently sun-exposed skin. A small percentage arise on acral surfaces of the hands and feet. Melanoma can arise from melanocytes adjacent to the retina or within mucosal surfaces in the oropharynx, sinuses, rectum, or vulva. These noncutaneous melanomas have distinct clinical and biological features when compared to cutaneous melanoma.

The relationship between the incidence of melanoma and age is unusual in comparison to other common cancers. There is not an exponential increase in risk with age but rather a more even distribution across age groups. The median age at diagnosis of melanoma is 53 years, almost 10 years younger than the median age of diagnosis of most common cancers. Forty-two percent of cases present in people younger than age 55, contributing to the third highest number of years of life lost across all cancers. In contrast, the incidence of squamous cell and basal cell carcinomas increases exponentially with age.

Men are more likely than women to develop melanoma (67% higher incidence), and their prognosis is worse (136% higher risk of death from melanoma). The reasons for this are unclear.

Caucasians are by far the most susceptible race for all skin cancers. Hispanics have a lower incidence but represent the group at next-highest risk. Asians and African Americans have the lowest rates of skin cancer. For those populations, cutaneous melanomas arising from sun-exposed sites are uncommon but not unseen. The most common type of primary melanoma in low-risk groups is the acral subtype, occurring on the hands and feet.

The rates of melanoma and other skin cancers are highest in countries where fair-skinned Caucasians migrated to lower latitudes, with annual sun exposure that is substantially higher than their historically native climates. Australia, New Zealand, South Africa, and Israel bear a disproportionate burden of skin cancer. In Australia, melanoma is the third most common cancer. In the United States, Hawaii and the desert Southwest have the highest rates of skin cancer of all kinds, including melanoma.

Skin cancers that are confined to the skin at presentation and with adequate staging evaluation have a high rate of cure. The 10-year survival of patients with invasive melanomas that are 1 mm or less in thickness and that lack ulceration is 97%. Melanoma that is microscopically present in regional lymph nodes is associated with a 10-year survival of 50% to 60%; when macroscopic or clinically apparent lymph nodes are detected, the 10-year survival is only 30% to 40%. The presence of more distant metastatic disease is associated with only a 5% possibility of survival 10 years from initial recognition.

Etiology

Although there are families in which melanoma can occur with high likelihood, an underlying genetic predisposition can only be found in only a small percentage of patients. These pedigrees have been identified because of their high likelihood of a mutation carrier developing melanoma. Lower-penetrance genotypes remain to be elucidated. Nonetheless, identification of the genes responsible for familial melanoma has greatly contributed to the understanding of the molecular pathophysiology of the disease.

The clinical observation that patients with multiple dysplastic nevi were at greater risk for melanoma and that many such patients came from families with multiple affected individuals provided the first insight into a melanoma progression model that might be accelerated based on inborn genetic abnormalities. Two highly related genes were discovered in roughly 50% of melanoma pedigrees: CDKN2A and CDK4. CDKN2A encodes two products via alternate splicing of messenger RNA: p16INK4A and p14ARF. Each of these tumor suppressor genes exerts an inhibitory effect on cell cycle progression.

Xeroderma pigmentosum (XP) is a rare inherited disorder in which DNA repair following UV damage is impaired. Mutations in XP genes A through G have been identified as the underlying molecular event. Squamous cell and basal cell carcinomas and melanoma are prevalent in this population at a young age. The near-complete penetrance of melanoma in these patients emphasizes the critical balance between UV-induced DNA damage and repair in risk for skin cancer. As DNA damage repair is mediated by a complex network of sensor and effector proteins, variability in the function of this system almost certainly underlies the variability in risk among the fair-skinned population.

Genetic variability in the melanocortin-1 receptor (MC1R) has been clearly implicated in pigmentation of skin and hair and, more recently, in melanoma predisposition. It has been known for decades that melanoma is more prevalent among fair-skinned individuals with red or blond hair. Furthermore, blondes with an inability to tan are at substantially greater risk of developing melanoma than those who tan readily. Polymorphisms, distinct from mutations, in MC1R appear to account for skin and hair color differences among Caucasians. It appears that individuals with melanocortin receptors that have a muted response to increased melanocortin expression following sun exposure suffer the greatest UV-induced genetic damage, leading to a greater risk of melanoma.

Risk Factors

History of melanoma

The single greatest clinical risk factor for melanoma is a personal history of melanoma. In addition to having surveillance for local and distant recurrence related to their prior melanoma, these individuals require lifelong observation for the emergence of a new primary melanoma; their risk is 10 times greater than that of the general Caucasian population.

UV exposure

Even the inheritance of CDKN2A and CDK4 mutations is insufficient to lead to melanoma in all carriers. It is clear that multiple genetic changes are required to give rise to invasive disease. UV damage is the best-described modifiable risk factor for melanoma, as well as squamous cell and basal cell skin cancers. It is believed that the acquired or somatic genetic changes that give rise to melanoma occur as a consequence of UV-induced genetic damage.

Epidemiologic data relate the risk of melanoma most closely to a connection between cumulative sun exposure, severe sunburns, or sun exposure during childhood, depending on the study. The disagreement between studies likely stems from methodologic differences in obtaining a sun exposure history, a heterogeneous effect of sun exposure and risk depending on the underlying genetic composition of the study population, or both. It has been clarified that melanoma arising on intermittently sun-exposed skin (such as the trunk) has its peak incidence among younger individuals and declines severely with increasing age. On the other hand, melanoma arising from chronically sun-damaged skin (such as the face, neck, and upper extremities) has the highest incidence in older individuals. With the rise in popularity of indoor tanning salons, data indicate that those who use them are at higher risk of melanoma. This may account for the recent rise in melanoma incidence observed in young women in the United States. There is little dispute regarding the causal link between sun exposure or tanning salon use and risk of melanoma; however, there is disagreement regarding the constituents of light (UV-A or UV-B) that contribute most to genetic damage. Laboratory studies support a connection for both and suggest that prevention strategies must take the entire UV light spectrum into account.

Nevi

Patients with numerous benign nevi (small, regularly shaped, and uniformly pigmented moles) are at increased risk of melanoma, as are patients with relatively few dysplastic nevi (large, irregularly shaped, and heterogeneously pigmented moles). Patients in either group may have a fivefold increased risk of developing melanoma compared to those with few benign nevi or without dysplastic nevi.

Atypical, or dysplastic, nevi represent a risk factor for melanoma in that individual lesions can occasionally progress to invasive melanoma. More commonly, the presence of dysplastic nevi suggests an individual at risk for melanoma formation at other sites. The clinical definition of atypical nevi has never been formally established but generally refers to the presence of one or two of the ABCD features (see Signs and Symptoms section). Cutaneous photography has been routinely incorporated in the follow-up of patients with multiple clinically dysplastic nevi in specialized pigmented lesion clinics. Full-body cutaneous photography is increasingly available to patients and provides an objective baseline from which to judge change of pre-existing lesions or the appearance of new lesions. The vast majority of dysplastic nevi do not give rise to melanoma. There seems to be little value in resecting every nevus that appears dysplastic on clinical grounds and does not adequately address the risk that patients face of developing melanoma in sites where no precursor lesion is found. Surveying the skin regularly for new or changing moles has been the most widely adopted strategy for educating patients and healthcare providers. In patients older than 25 to 30 years, new mole formation warrants examination by a provider who is comfortable making the diagnosis of melanoma.

Congenital nevi are relatively rare compared with acquired nevi. In general, they do not suggest a predisposition to melanoma. A small number of children are born with so-called giant congenital nevi, also referred to as bathing trunk nevi. Melanoma arising from within a giant congenital nevus is a well-described phenomenon and is one reason that staged resection of such lesions is recommended for many children and adolescents.

Immunosuppression

Although there is incontrovertible evidence linking immunosuppression and squamous cell skin cancer, the risk of developing primary melanoma in the setting of immunosuppression is less well established. There is some evidence that patients who have a history of melanoma are more likely to develop disease recurrence in the setting of immunosuppression.

Prevention

With the incidence of melanoma still rising, it is clear that primary prevention efforts have not yet taken hold. The only approach firmly rooted in evidence is to minimize sun exposure. The use of sun-protective clothing appears to be the next best strategy. There are conflicting data regarding the protective effect of sunscreens for melanoma, although there is no controversy regarding their ability to prevent squamous cell and basal cell carcinomas. Protection against UV-A has been a long-standing feature of widely available suncreens, whereas UV-B protection has more recently been engineered into all mainstream products. It is possible that the more widespread of these wide-spectrum sunscreens will provide more meaningful protective effects over the coming decades.

Signs and Symptoms

The diagnosis of melanoma is based on complete pathologic evaluation of a clinically suspicious lesion. A growing or changing skin lesion is the easiest description that a patient can provide a physician to assist in determining which skin lesions should be biopsied.

The “ABCDEs” is a simple method for identifying lesions that should be brought to medical attention and referral for consideration of biopsy (see the color atlas in this chapter). This system, which is based on asymmetry of the skin lesion, irregular edges, color variegation, and diameter, can be helpful to patients, but it does not describe all lesions that are ultimately diagnosed as melanoma upon pathologic review. This algorithm has not proved to be a particularly effective method of educating the general population. “A” indicates gross asymmetry of a pigmented lesion. “B” refers to irregular or indistinct borders. “C” denotes color variegation, which, in the case of melanoma, refers to various combinations of black, dark brown, red/pink/purple or blue color developing in a pigmented lesion. In the case of pre-existing moles, the loss of pigmentation in a portion of the lesion can indicate regression, which is worrisome for melanoma. Additionally, a focus of darker pigmentation within a pre-existing mole is grounds for concern. “D,” or diameter of 6 mm or greater, raises concern for melanoma, whereas smaller lesions are rarely indicative of invasive lesions (with the exception of nodular melanoma). “E” refers to “evolution,” or “change,” and it is perhaps the most accurate single feature to guide biopsy of a melanocytic lesion. Lesions that satisfy multiple criteria warrant either close observation or biopsy of the most abnormal portion. Not included in the ABCD system is the papular or nodular characteristic of most melanomas. If melanoma arises within a pre-existing mole, the raised element of an otherwise flat or macular lesion should be considered suspicious for melanoma. Some primary melanomas do not produce melanin and therefore lack the classic appearance.

In general, asymptomatic, physician-detected melanomas tend to be early lesions. Patients who present with more signs or symptoms, namely those who present with lesions that have changed in size, shape, or color, or which have bled or itched, tend to have more advanced disease at presentation. Amelanotic melanoma and Merkel cell carcinoma can be very difficult diagnostically. These are often quite innocuous in appearance and resemble low-grade skin cancers or benign lesions. Subungual melanomas (arising beneath the nail bed) are commonly presumed to be oncomycosis, leading to more advanced disease at eventual diagnosis.

Diagnosis

Physical examination

Examination of the entire body should be performed for any patient who presents with numerous benign-appearing nevi, any dysplastic nevi, or a history of even a single melanoma. The entire skin is at risk in these individuals and must be investigated for the appearance of new or changing lesions. Patients who fit into any of these risk groups should be instructed to perform monthly skin self-examination. Two mirrors are required to adequately examine the back if a partner is not available to assist in examining the back longitudinally.

Skin examination should be performed in a well-lit room with the patient completely disrobed. For patients with numerous moles, full-body cutaneous photography is extremely helpful to provide an objective baseline from which to judge change. For patients with only a few atypical moles, close-up photographs of those lesions may facilitate their careful evaluation while the remainder of the skin is surveyed for new lesions.

Dermoscopy, a focused method for examining individual lesions, employs low-level magnification of the epidermis with tangential light applied to a liquid-skin interface. Examination of pigmented lesions with dermoscopy allows more precise visualization of patterns of pigmentation than is possible with the unaided eye. This method requires some degree of training and the availability of appropriate equipment. When regression of part or all of a pre-existing mole is suspected, a Wood’s lamp can be helpful in bringing out the contrast in pigmentation between normally pigmented surrounding skin and an area where immunologic destruction of melanocytes has occurred.

Nodular melanomas represent the most difficult subset of melanoma to diagnose at an early stage. These lesions are more rapidly proliferative than typical melanomas and are generally not pigmented. Furthermore, they are generally raised early in their development and have symmetric and well-demarcated boundaries. Thus, they do not meet the ABCD criteria. Nodular melanomas account for approximately 10% of melanoma cases, but account for a disproportionate percentage of fatalities. The most useful clinical rule to apply in the assessment of lesions that have these features is that the de novo appearance of such lesions over a short time (months) warrants consideration of biopsy. As the features of nodular melanoma are common to some benign skin lesions, as well as basal cell carcinoma, the yield of biopsies for such lesions may be relatively low. Nonetheless, heightened awareness of this small but lethal subset of melanoma is needed.

Lymph node examination

This should be performed in all patients who are suspected of having invasive melanoma or large squamous cell or basal cell carcinomas. The closest lymph node basin is the most essential area to examine; however, all potentially involved basins should initially be examined as part of a thorough history and physical examination. The presence of a palpable lymph node mandates biopsy of the suspicious node, generally with fine needle aspiration (FNA). If the node is small or difficult to access with FNA, an open lymph node biopsy should be pursued.

Biopsy techniques

A biopsy is recommended for any lesion that is suspected of being melanoma, squamous cell cancer, or basal cell carcinoma. An excisional biopsy is appropriate for lesions that can be entirely excised without concern over causing an unacceptable cosmetic result. Local anesthesia is generally all that is required. Narrow margins of 1 to 2 mm are sufficient when making an initial diagnosis of skin cancer. The biopsy should extend to the subcutaneous tissue to provide an adequate estimate of the depth of invasion, particularly for melanoma. Biopsy specimens should be placed in formalin and submitted for expert pathologic preparation including embedding in paraffin. Careful attention to documenting the site of the biopsy is essential to subsequent care.

Incisional biopsy is an acceptable alterative for large lesions, especially when located on the face, neck, or distal extremities. In the case of possible melanoma, the most abnormal-appearing area should be biopsied. As with excisional biopsies, the biopsy should include subcutaneous tissue to allow an estimation of thickness. Either punch biopsy of sufficient diameter to encompass the most abnormal-appearing area or a shave biopsy is reasonable for the purpose of diagnosis. Should the biopsy identify a melanocytic lesion with dysplasia or atypia, the entire lesion should be removed, when possible, with radial margins of 1 to 2 mm.

For lesions that are suspicious for melanoma, every attempt should be made to preserve the ability to assess involvement of margins and to perform immunohistochemistry of the primary tumor. The latter is critically important in borderline cases, for which the diagnosis of melanoma is uncertain. Thus, serial thin section techniques (such as Mohs surgery) are strictly contraindicated. Frozen biopsy assessment is inadequate for the diagnosis of melanoma and does not allow adequate material for review in pathologically difficult cases.

Melanoma of unknown primary

Melanoma of unknown primary occurs in up to 5% of patients who present to tertiary cancer referral centers. Lymphadenopathy is the most common clinical presentation, followed by identification of visceral metastases and presentation with a cutaneous nodule(s). Patients should be evaluated by a dermatologist and should undergo a complete physical examination, including an anorectal and genital evaluation. In the absence of symptoms, an ophthalmologic consultation is probably not warranted unless liver metastases are the only site of disease, given the propensity for ocular melanoma to metastasize to this site.

Staging of Melanoma

A great deal of information is available regarding factors that correlate with clinical outcome in patients with melanoma. In patients with clinically localized disease, the most important prognostic factors are Breslow’s thickness, mitotic rate, ulceration, and SLN status. Overall, 85% of patients with invasive melanoma present with clinically normal lymph nodes. In clinically node-negative patients, most investigators have found the microscopic degree of invasion of the melanoma, or microstaging, to be of critical importance in predicting outcome (Tables 1 and 2; Figure 1).

The melanoma staging committee of the American Joint Committe on Cancer (AJCC) revised the TNM staging system to reflect more accurately the impact of statistically significant prognostic factors that were validated in a multi-institution sample of 38,918 melanoma patients. The AJCC 2010 Staging System is shown in Tables 1, 2, and 3. Survival curves from the AJCC Melanoma Staging Database comparing different T categories and stage groupings for stages I and II melanoma are shown in Figure 1; in addition, for patients with stage III disease, survival curves in this figure compare the different N categories and the stage groupings. For patients with stage IV disease (distant metastases), there are few long-term survivors, but more favorable survival is associated with soft-tissue sites (vs lung or visceral sites) and normal lactate dehydrogenase.

Changes in the staging system are summarized in Table 3. The most significant change to the 2010 AJCC staging classification is the replacement of Clark’s level by presence of mitoses in the stage I group. This involves the use of mitotic rate in the staging of patients with clinically localized melanoma ≤ 1 mm. Primary lesions without ulceration and a mitosis < 1/mm2 are categorized as T1a, whereas those with either feature > 1/mm2 are T1b.

Three microscopic characteristics of primary melanoma are now incorporated into the new AJCC staging system for melanoma, as each contributes significantly to predicting risk of regional lymph node involvement and long-term risk of metastatic disease and death.

Breslow thickness

First described by Alexander Breslow, this method of describing tumor thickness measures from the top of the granular layer of the epidermis to the deepest contiguous tumor cell at the base of the lesion using a micrometer in the microscope eyepiece. It is the primary determinant of T staging and has the highest prognostic value of any primary tumor characteristic.

TABLE 1: TNM staging for cutaneous melanoma

TABLE 2: Anatomic stage groupings for cutaneous melanoma

FIGURE 1: Survival curves from the American Joint Committee on Cancer Melanoma Staging Database comparing (A) the different T categories and (B) the stage groupings for stages I and II melanoma. For patients with stage III disease, survival curves are shown comparing (C) the different N categories and (D) the stage groupings.

Ulceration

The presence of ulceration in a primary melanoma is one of the strongest negative predictive factors for long-term survival. Ulceration is defined as the lack of a complete epidermal layer overlying the melanocytic lesion. The presence of ulceration essentially upstages affected patients to the next highest T level. In other words, a patient with a 1.1- to 2-mm melanoma that is ulcerated will carry the same long-term prognosis as a patient with a 2.1- to 4-mm melanoma that does not have ulceration. The likelihood of finding ulceration is directly related to tumor depth: Patients with thin melanomas (≤ 1 mm) have a 6% incidence of ulceration, whereas those with > 4-mm melanomas have a 63% incidence of ulceration. Along with tumor depth, ulceration is integral to determining a patient’s long-term prognosis and is an independent predictor of patient outcome.

Mitoses

The presence of mitotic figures in the dermal component of a primary melanoma has been shown in several institutional series to confer poor prognosis.

In the 2010 AJCC staging system, the mitotic rate was identified as an independent predictor of survival for primary melanoma < 1 mm in Breslow thickness. It is defined as the number of dividing cells identified within 1 mm2. The most powerful cutoff was < 1/mm2 vs > 1/mm2. Indeed, in more than 10,000 patients with early melanoma, mitotic rate was second only to Breslow thickness as a survival determinant.

Clark’s level

Wallace Clark and associates devised a system to classify melanomas according to the level of invasion relative to histologically defined landmarks in the skin. Although Clark’s levels correlate with prognosis (lesions with deeper levels of invasion have a greater propensity for recurrence), the inherent problem with Clark’s system is that the thickness of the skin and hence the distance between the various landmark dermal layers varies greatly in different parts of the body. When initially described, the Clark’s level was a standard way to stage patients with melanoma and predict outcome. Over the years, it has proven much less reliable than Breslow thickness, and the 2002 AJCC staging system was used only for lesions < 1 mm. In the 2010 AJCC staging system, the mitotic index has replaced the Clark’s level in staging lesions < 1 mm. The Clark’s level is only used when mitotic index is unavailable for lesions < 1 mm, as it is not predictive of outcome when the three cardinal features are considered.

Regional lymph node involvement

In patients with intermediate-risk melanoma (1 to 4 mm in thickness), lymph node involvement is the strongest prognostic indicator in the staging of melanoma. Patients with nodal involvement at the time of their diagnosis have significantly decreased survival compared with node-negative patients. There is a direct relationship between the depth of invasion of the primary lesion and the potential for lymph node involvement.

Among node-positive patients, the prognosis is more favorable in those with microscopic as opposed to macroscopic or clinically apparent disease. In addition, the increased number of nodes involved is associated with decreased survival in both microscopically detected and clinically apparent regional nodal metastasis. The worst prognosis occurs in patients with large, matted regional lymph nodes, whose outcome is similar to that of patients with stage IV disease.

In the 2010 version of the AJCC staging system, there was no change in nodal basin staging. Importantly, despite reports from some centers that a low burden of disease in the regional node predicts no additional nodal metastasis, the current staging system does not identify a minimal nodal tumor burden that would be considered essentially negative.

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TABLE 3: Differences between the 6th edition (2002) and the 7th edition (2010) of the AJCC melanoma staging system

Additional Melanoma Prognostic Factors

Age

Patients who are ≥ 65 years old have a survival rate that is decreased by 10% to 15% compared with their younger counterparts. This trend has been demonstrated in numerous studies. A different relationship between age and risk of lymph node involvement is emerging, however. Paradoxically, data from the prospective Sunbelt Melanoma Trial and other retrospective studies reveal that younger patients are significantly more likely to have a positive SLN biopsy than older patients with similar lesions.

Anatomic location

There is a correlation between anatomic location and prognosis of primary melanoma. Those with lesions on the back, upper arms, neck, and scalp (BANS area) have a worse prognosis than those with lesions on the extremities.

Gender

Many studies have identified improved survival in women vs men with melanoma, when stratified by stage. The reasons for this are unclear. Men are more likely to develop truncal melanomas, whereas women are most likely to develop melanoma on their extremities, but the prognostic advantage of female gender appears not to be attributed to the melanoma site alone.

Angiolymphatic invasion

Defined as invasion of tumor cells into the wall and/or lumen of vessels or lymphatics of the dermis or deeper structures, angiolymphatic invasion is uncommon in melanoma. However, this finding is clearly associated with more aggressive tumors. Multiple large studies have shown worsened long-term survival and more frequent lymph node involvement in patients with angioinvasive melanomas. Patients with vascular invasion in their primary melanoma have a threefold risk of lymph node involvement and a reduction in 5-year survival by as much as 50% compared with matched patients without vascular invasion.

Regression

The finding of regression represents a host immune response to invasive melanoma. Areas where invasive cells may have once existed are replaced by inflammatory reaction and fibrosis, which may make it impossible to determine the precise depth of the initial lesion histologically. There is continuing debate regarding the prognostic importance of regression; however, many clinicians believe that thin lesions that show signs of regression should be given higher consideration for surgical nodal staging, given the fact that the initial lesion may have originally been more deeply invasive. Although some studies have shown that regressed lesions have a higher propensity for lymph node metastases than nonregressed primary tumors of the same thickness, this finding has not been universally observed. Indeed, a recent retrospective single-institution study demonstrated no increased risk of SLN metastasis in patients with regressed melanoma, suggesting that SLNB should not be performed for lesions that would otherwise not be considered for the procedure based on the presence of regression.

Tumor-infiltrating lymphocytes

Variable numbers of tumor-infiltrating lymphocytes (TILs) are observed in melanoma. Many studies have shown that tumors with a high number of TILs carry an improved prognosis, presumably because of the active host response to tumor. The absence of TILs in the primary melanoma has been associated with a higher risk of positive SLNs in a large, single-institution study. In addition, as Azimi et al reported (J Clin Oncol 2012), the quantification of TIL within the primary tumor can predict survival in patients with clinically localized disease, with high-grade TIL infiltration associated with improved survival.

Surgical Management of Cutaneous Melanoma

Surgical management of primary melanomas

It was recognized over a century ago that tumor cells could extend within the skin for several centimeters beyond the visible borders of a melanoma. Thus, the risk of local recurrence relates to the width of normal skin excised around the primary tumor. Only much more recently was it realized that the thickness of the primary tumor influenced the likelihood of contiguous spread and that not all melanomas require the same excision margin. This realization prompted a number of randomized trials to determine the optimal excision margins for melanomas of different Breslow thicknesses.

Initially, a “one-size-fits-all” approach of taking a 5-cm margin around all invasive melanomas was adopted. With such wide margins, skin grafts were usually required for reconstruction. Modern melanoma surgical care is based on level I medical evidence, and many large, prospective randomized trials have been conducted to determine the appropriate radial margin for cutaneous melanoma based on Breslow thickness.

A randomized trial conducted by the World Health Organization found that when a 1-cm margin of normal skin was taken around a melanoma ≤ 1 mm thick, the local recurrence rate was exceedingly low (< 1%), and patient survival was just as good as when 3-cm margins were taken. For melanomas 1 to 2 mm in thickness, patient survival was the same for both margins of excision, but the local recurrence rate was higher with the 1-cm margin (3.3% after 10-year follow-up).

The Intergroup Melanoma Trial compared 2- vs 4-cm margins for all cutaneous melanomas of the trunk or proximal extremity between 1 and 4 mm in thickness. Most patients in this trial had melanomas ≤ 2 mm in thickness. In this trial both local recurrence and survival were the same regardless of whether 2- or 4-cm margins were obtained. Skin grafts were less frequent and hospital stays shorter with the narrower margin.

A trial conducted in the United Kingdom addressed patients with primary melanoma ≥ 2 mm in depth. Patients who underwent a 1-cm radial margin of excision had a higher risk of local/regional recurrence than those who underwent excision with 3-cm margins.

Based on these important studies, it is possible to make rational recommendations for excision margins for melanoma patients.

• Patients with melanoma ≤ 1 mm should undergo excision of skin and subcutaneous tissue, for a radial margin of 1 cm.

• Patients with melanoma between 1 and 2 mm should undergo excision of skin and subcutaneous tissue, for a radial margin of 1 to 2 cm.

• Patients with melanoma > 2 mm in depth should undergo a wide excision of skin and subcutaneous tissue of 2 to 3 cm.

• When the anatomic location of the primary tumor precludes excision of the margin (eg, on the face), at least 1 cm should be taken when feasible.

Surgical management of the draining lymph node basins

The identification and management of regional nodal disease have evolved significantly over the past 20 years. Historically, regional lymph node dissections were performed on all patients with intermediate-thickness melanomas in the belief that doing so would lead to a survival benefit. This was based on the observation that there was an approximately 20% survival advantage to patients found to have microscopic involvement of lymph nodes at “elective” lymph node dissection (ELND) when compared with patients who had clinically apparent nodal metastasis and underwent a “therapeutic” lymph node dissection (TLND). With ELND, however, most (80% to 85%) patients had pathologically negative lymph nodes. More importantly, a series of prospective randomized clinical trials failed to demonstrate a survival advantage for patients undergoing ELND over wide excision only. For this reason, the standard approach prior to the development of SLN mapping was wide excision alone and clinical observation of the nodal basin.

The surgical management of clinically normal nodes is currently determined by the characteristics of the primary lesion. A direct relationship between thickness of the primary lesion and nodal involvement has long been recognized. When the depth of the primary is unknown because of the biopsy technique or other factors, consideration should be given to SLN mapping as a staging procedure.

SLN mapping is performed by injecting radiolabeled colloid into the dermis surrounding the primary melanoma. The radiotracer migrates via the lymphatics to the regional nodal basin(s), which is visualized with a gamma camera. The patient is then taken to the operating room, where a hand-held gamma probe is used to identify the sentinel node(s). This technique, in combination with the use of vital blue dye, has led to a success rate of SLN identification exceeding 97% at experienced centers.

Patients with thin melanoma (< 1 mm Breslow depth) generally have a low risk of occult nodal involvement (< 5%). Some patients with melanomas 0.76 to 1 mm have a high enough risk of lymph node involvement to justify consideration of SLNB in addition to wide excision.

For instance, when ulceration is present, consideration should be given to SLNB. In addition, a mitotic count ≥ 1 should prompt consideration of regional nodal basin staging in the appropriate patient.

Risk of nodal metastasis rises significantly with increasing depth of invasion. Patients with a 1-mm thick melanoma have approximately a 10% chance of nodal involvement, whereas those with a 4-mm melanoma have a 35% to 40% risk of nodal metastases. For these reasons, wide excision of the primary tumor is generally accompanied by SLNB for staging of the nodal basin in this patient population. This may, however, be inappropriate in certain clinical scenarios. For example, the presence of satellitosis surrounding a primary melanoma is such a poor prognostic sign for recurrence that no additional prognostic information is to be gained by SLN mapping.

Patients who have evidence of metastasis in the SLN are offered completion lymphadenectomy (CLND) as a “standard” approach, although nodal basin observation should also be discussed, as there is no level 1 medical evidence supporting CLND. Indeed, the hypothesis that SLN mapping and biopsy followed by CLND would result in improved survival was disproven by the Multicenter Selective Lymphadenectomy Trial I. In addition, a CLND for those at high risk of local and regional recurrence may subject the patients to undue morbidity. The lymphedema associated with complete node dissection may complicate treatment of subsequent recurrences in patients with deep melanoma of the extremity. A prospective clinical trial evaluating the role of CLND in SLN+ patients is ongoing (Multicenter Selective Lymphadenectomy Trial II).

Importantly, melanoma patients with clinically enlarged nodes and no evidence of distant disease (AJCC stage IIIB) should undergo pathologic evaluation of the nodes by FNA or open biopsy, followed by complete lymphadenectomy in the event of a positive frozen section or by touch-prep cytologic determination of metastasis.

Surgical Management of Uncommon Melanoma Subtypes

Desmoplastic melanoma

Desmoplastic melanomas represent a less common but clinically distinct spindle cell variant of melanoma with dense fibrosis and frequent neurotropism. Clinically, they present as raised, firm nodules that are amelanotic in up to 40% of patients, commonly leading to a delay in diagnosis. They are usually deep lesions, but have a more favorable prognosis than do conventional melanomas of similar Breslow thickness. The association of desmoplastic melanoma with local recurrence may be due to the fact that many of these lesions are misdiagnosed and undertreated with regard to an appropriate radial margin of excision.

Although many desmoplastic melanomas are deeply invasive at the time of diagnosis, they are less likely to involve regional lymph node basins than similarly staged conventional melanomas. Patients with “pure” desmoplastic melanoma are extremely unlikely to harbor regional nodal metastasis, and SLN biopsy is unlikely to provide useful information. Patients with “mixed” desmoplastic melanoma, containing a component of conventional melanoma, have a risk of regional nodal metastasis that is approximately half that of patients with conventional melanoma, and SLN mapping should be considered in these patients.

Despite the fact that these lesions are often relatively thick at presentation, patients with desmoplastic melanomas have survival rates that are favorable compared with patients who have conventional melanomas of a similar depth.

Uveal melanoma

Uveal melanomas generally do not have access to lymphatic channels, so the surgical principles outlined previously do not apply. These lesions have a unique propensity to metastasize hematogenously, often to the liver and not infrequently after a long relapse-free interval.

A diagnosis of ocular melanoma with no evidence of distant disease signifies that a decision must be made as to whether or not the eye can be spared. Some small melanomas situated peripherally in the retina can be excised with minimal loss of vision, but most cannot. For larger lesions, treatment options are enucleation (total removal of the eye), implanted radiotherapy with a radioactive gold plaque fitted to the back of the eyeball immediately behind the tumor, or proton beam radiotherapy. A multi-institution, randomized trial comparing implanted radiotherapy with enucleation was completed by the Collaborative Ocular Melanoma Study Group and demonstrated similar outcomes for medium-sized tumors.

Mucosal melanoma

These most commonly arise from the mucosal surfaces of the sinonasal, oral cavity, vulvovaginal, and anorectal regions. Mucosal melanomas are notoriously difficult to cure and are almost always associated with a poor outcome.

Melanomas arising in the mucosal surfaces of the head and neck should be widely excised to include adjacent bony structures, if needed. Node dissection is generally reserved for patients who have proven nodal involvement; however, given the greater incidence of nodal metastases from oral cavity mucosal melanoma, routine SLN biopsy in this subset of disease could be considered. Radiotherapy should be considered for patients whose primary tumor cannot be fully removed with adequate margins or as adjuvant therapy in patients unlikely to achieve disease control with surgical resection alone.

The surgical management of anal melanoma is controversial, but most surgeons prefer a wide excision, when possible, over an abdominoperineal resection (APR). In the past, an APR was more commonly used for patients with less-advanced disease who were viewed as potentially curable. This almost certainly explains the reported association of APR with long-term survivors. More recently, APR is reserved for patients with bulky disease or recurrent disease that is not amenable to wide excision, which is favored for patients with more localized/potentially curable disease. Not surprisingly, more recent studies demonstrate no survival advantage to APR, which appears to be equivalent to wide excision.

Radical resection is also less commonly performed for patients with vulvovaginal melanoma, who also have a high risk of relapse and death. Function-preserving resection and nodal basin staging in the setting of relatively early disease are appropriate, but, as in patients with anal primaries, preemptive nodal staging in patients with advanced primary tumors is unlikely to impart a benefit to those whose nodal basin can be followed clinically and radiologically.

Melanoma of unknown primary

Melanoma of unknown primary occurs in up to 5% of patients who present to tertiary cancer referral centers. Lymphadenopathy is the most common clinical presentation, followed by identification of visceral metastases and cutaneous nodules. Patients should be evaluated by a dermatologist and should undergo a complete physical examination, including an anorectal and genital evaluation. In the absence of symptoms, an ophthalmologic consultation is probably not warranted unless liver metastases are the only site of disease, given the propensity for ocular melanoma to metastasize to this site.

A CT scan of the chest, abdomen, and pelvis and/or a whole-body PET scan can be useful for staging patients with melanoma of unknown primary. In the absence of other sites of disease, surgical resection of the metastatic lesion (or complete regional lymphadenectomy) is appropriate.

Single dermal nodules with no identifiable primary lesion are typically treated in a fashion similar to that of primary melanomas, with wide local excision and regional nodal evaluation by SLNB if appropriate. The prognosis for patients who present with MUP is similar to that for somewhat more favorable patients with metastatic disease from a known primary (those who are M1a by AJCC staging).

Adjuvant Radiation and Systemic Therapy for Melanoma

Adjuvant radiotherapy

Radiation treatment has been increasingly employed in the postoperative setting to improve locoregional tumor control in a select group of patients at “high risk” for local or regional recurrence. “High risk” has been variably defined, but includes patients with large, matted nodes, extranodal extension of tumor, inadequate margins due to anatomic constraints, head and neck site, and multiple local/regional recurrences. The 5-year regional control has ranged from 87% to 94%, and the 5-year overall survival has ranged from 36% to 46% with the addition of radiation to surgery. Single institutions have reported that local recurrence is reduced to 6% to 11% when postoperative radiotherapy is used for high-risk lesions. Serious complication rates after radiation therapy were low, which is likely secondary to the superficial nature of the treated volumes.

A prospective randomized trial (ANZMTG 01.02/Trans-Tasman Radiation Oncology Group [TROG] 02.01) evaluated the role of adjuvant radiation treatment after therapeutic lymphadenectomy in patients with melanoma at high risk of lymph-node-field and distant recurrence. Patients were randomized to observation after surgery or to adjuvant RT (48 Gy in 20 fractions). This study showed that the use of adjuvant nodal basin radiation in these patients following surgery improved lymph-node relapse rates, but had no effect on disease-free survival or overall survival. High-risk patients were those with ≥ 1 parotid, ≥ 2 cervical or axillary, or ≥ 3 groin nodes; extranodal spread of tumor; or maximum metastatic node diameter ≥ 3 cm in the neck or axilla or ≥ 4 cm in the groin. At a median follow-up of 40 months, adjuvant RT improved regional control in melanoma patients at high risk for relapse after lymphadenectomy (hazard ratio [HR] = 0.56; 95% CI, 0.32–0.98; P = .041), but did not improve relapse-free survival (70 vs 73 events, HR = 0.91; 95% CI, 0.65–1.26; P = .56) or overall survival (59 vs 47 deaths, HR = 1.37; 95% CI, 0.94–2.01; P = .12). The RT compliance rate was 79%. There was a higher rate of acute toxicity (dermatitis and pain) with RT, but no grade 4 toxicity was seen. In the final analysis, updated in abstract form, adjuvant radiation continued to be associated with a reduction in local recurrence (HR = 0.52; 95% CI, 0.31–0.88; P = .023), with no difference in survival (HR = 1.13; 95% CI, 0.82–1.55; P = .21) at a mean follow-up of 73 months. Regional symptoms (P = .035) and grade 2–4 long-term toxicity were higher in the RT arm. Quality of life was similar in both groups.

The risk of long-term lymphedema following adjuvant radiation therapy is known to be significant in patients with inguinal lymph node metastases; it is greater following radiotherapy to the inguinal region than to the axilla or neck. This risk should be discussed when considering treatment of these patients with adjuvant radiotherapy. In a review on the use of RT in melanoma, Stevens and McKay offered the following recommendations for postoperative RT after regional lymph node dissection, indicating it should be performed in cases of:

Multiple involved nodes (more than one for parotid, three to four in other regions)

Any involved node greater than 3 to 4 cm in maximum diameter

Extranodal spread

Incomplete dissection

Recurrence after previous lymph node dissection (no previous RT)

Preclinical studies suggest the presence of a biologic interaction between radiation therapy and immunotherapy, with cases of dramatic abscopal effects with concurrent therapy now reported (Postow et al, NEJM 2012). Based on the lack of prospective clinical data, multiple ongoing phase I and II trials are evaluating the safety and efficacy of combined radiation therapy and immunotherapy in the management of melanoma.

The Florida Melanoma Trial I, a prospective multicenter phase I/II trial, evaluated the feasibility and toxicity of postoperative hypofractionated RT concurrent with systemic interferon alpha-2b in patients with high-risk stage III melanoma. This designation was based on more than four pathologically involved nodes, nodes > 4-cm, extracapsular extension (> 10% of capsule circumference), or recurrent disease following previous lymphadenectomy. Adjuvant therapy consisted of high-dose interferon followed by concurrent intermediate-dose interferon and hypofractionated radiation therapy to the dissected nodal bed (30 Gy in 5 fractions) over 2.5 weeks, with maintenance interferon for up to an additional year. Of the 29 patients enrolled, only 23 (80%) received the full therapy, with 6 patients unable to receive RT. At a median follow-up of 80 months among 10 survivors (43%), the median overall survival time was 34.5 months, with a median failure-free survival time of 19.9 months. Regional disease-free survival was 78% at 5 years and 10 years, with overall survival and disease-free survival at 3 years reported as 48% and 43%, respectively. Concurrent therapy was well-tolerated, with limited late toxicity.

Adjuvant systemic therapy

Single-agent chemotherapy or combination chemotherapy regimens have not been systematically evaluated for the adjuvant treatment of melanoma because of the low response rates seen in patients with advanced disease. The largest randomized trial evaluated an IV administered regimen of carmustine (BiCNU; 80 mg/m2) every 4 weeks, and dactinomycin (10 μg/kg/day, days 1 to 5) and vincristine (1 mg/m2) every 2 weeks, for 6 months as compared with observation among patients with resected stage III or IV melanoma. A significant improvement in relapse-free survival, but not overall survival, was observed in this small study. A randomized trial comparing dacarbazine vs observation failed to demonstrate an improvement in either relapse-free survival or overall survival.

Interferon α-2b (IFN-α) was approved for use in patients with deep primary melanoma or resected stage III or IV melanoma in 1995. In the Eastern Cooperative Oncology Group (ECOG) 1684 trial that led to its FDA approval, interferon α-2b was administered intravenously at 20 mU/m2 for 5 consecutive days every 7 days for 4 weeks, during the “induction” phase. For a subsequent 48 weeks, 10 mU/m2 was administered by subcutaneous injection on alternate days for a total of three doses every 7 days in the “maintenance” phase.

This “high-dose” regimen was compared with observation. A statistically significant improvement in overall survival was demonstrated with interferon, compared with the observation arm; relapse-free survival was also improved. Three-quarters of the interferon patients experienced severe toxicities, most commonly fatigue, asthenia, fever, depression, and elevated liver transaminase levels. A quality-of-life analysis found that the toxicity associated with this regimen was largely compensated for by the prevention of disease relapse.

Due to uncertainty regarding the optimal dose and schedule of interferon, the ECOG trial E1690 was initiated; this trial compared patients randomized to a high-dose regimen vs a low-dose regimen (3 mU by subcutaneous injection three times weekly for 24 months) vs observation. No significant improvement in overall survival for either the high-dose or low-dose arm was observed compared with observation; relapse-free survival was improved by 22% in the high-dose arm compared with observation. A pooled analysis of E1684 and E1690, with longer follow-up for both trials, revealed a continued, statistically significant impact of high-dose interferon on relapse-free survival but not on overall survival.

High-dose interferon has been consistently shown to improve relapse-free survival compared with either observation or ganglioside GM2/keyhole limpet hemocyanin (GM2-KLH) vaccination but does not reproducibly confer an overall survival advantage. A prospective randomized trial conducted by the Hellenic Cooperative Oncology Group compared outcomes in patients treated with high-dose interferon as an adjuvant for 1 month vs 1 year and found no difference in overall survival or disease-free survival; however, this trial was of insufficient size for the investigators to firmly conclude that 1 month of interferon therapy is truly equivalent to the full-year regimen with regard to relapse-free survival.

Intermediate-dose regimens with interferon have been evaluated in several trials; they have less consistently demonstrated a relapse-free survival advantage compared with observation but have never resulted in a survival advantage. A recent trial conducted by the European Organisation for Research and Treatment of Cancer (EORTC) demonstrated no survival advantage for patients undergoing 13 months or 25 months of intermediate-dose adjuvant interferon after resection of stage IIB (deep primary melanoma) or stage III nodal disease when compared with observation.

The EORTC reported the results of a prospective randomized trial of observation vs pegylated interferon-α for 5 years. Again, there was an advantage to treatment in terms of relapse-free survival, but no overall survival advantage for patients with high-risk resected melanoma. Nearly one-third of the patients in the treated arm discontinued therapy due to toxicity. This regimen has received FDA approval. Induction therapy consists of 6 μg/kg weekly for 2 months, followed by 3 μg/kg weekly provided that patients can maintain good performance status. If performance is compromised, then the dose is reduced to 2 μg/kg, and again to 1 μg/kg as needed.

Due to the significant toxicity associated with interferon and the lack of a reproducible overall survival advantage, consensus is lacking regarding the use of interferon in the adjuvant setting. A recent meta-analysis confirmed the relapse-free survival observed in individual trials, yet the overall survival benefit was extremely small, and of unclear clinical relevance. For this reason, expectant observation remains a reasonable option for patients in this setting.

Given the efficacy of immunologic checkpoint blockade for patients with metastatic melanoma, there is great interest in the evaluation of these agents in the adjuvant setting. EORTC 18071 is a phase III trial that randomized 951 patients with resected stage III disease to either ipilimumab at 10 mg/kg or placebo. The results were presented at ASCO 2014. On this trial, patients received therapy every 3 weeks for 4 doses and then every 3 months for up to 3 years until completion, disease recurrence, or unacceptable toxicity. The study met its primary endpoint of recurrence-free survival, with a median recurrence-free survival time of 17.1 vs 26.1 months in favor of ipilimumab (HR = 0.75; P = .0013); however, 52% of patients randomized to ipilimumab discontinued therapy due to adverse events, with 1.1% dying due to toxicity. Survival data were not mature at the time of presentation.

Treatment of Advanced Melanoma

Surgical management of advanced melanoma

Surgical resection is a reasonable approach to treatment of select patients with limited metastastic melanoma. Surgical resection is associated with better outcome than no treatment or treatment with traditional chemotherapeutic regimens, although patient selection and the clinical impact of the newer and more effective systemic therapies make conclusions about these reports difficult. All studies to date are retrospective reviews. A number of retrospective studies have shown the validity of resecting pulmonary metastases in patients with melanoma. Further, more recent studies have shown similar survival rates for patients undergoing resection of a limited number of lesions and sites of disease (usually up to four) for metastases to distant lymph nodes, skin and subcutaneous tissue, and lungs. Patients with isolated metastases in the liver, adrenal gland, brain, and gastrointestinal tract may undergo resection, but the survival of these patients appears to be less favorable.

Surgical resection may also be an important component of palliation. Bleeding or obstruction from small-intestine metastases may be managed by resection. Although palliative resection can provide short-term effective relief of patient symptoms, numerous studies have shown that incomplete resection does nothing to enhance the length of survival.

Palliative radiotherapy

In vitro data from the 1970s demonstrated radiation resistance among melanoma cell lines and led to the reluctance to use radiation therapy in the treatment of melanoma. More recent data have shown that many melanomas are sensitive to radiation; however, the proper fraction size to use in melanoma is unclear. In a large series of patients studied by Overgaard and colleagues, the investigators found that the response rate of metastatic melanoma lesions was dependent on the fraction size. The complete response rate was 57% when fractions greater than 4 Gy were used, compared with 24% for fractions less than 4 Gy. Radiation Therapy Oncology Group (RTOG) 83-05 is the only randomized trial that compared hypofractionated (8 Gy for 4 fractions) vs conventional (2.5 Gy for 20 fractions) schedules of radiation therapy. In this study, they noted no difference in the complete and partial responses, emphasizing the need for more research to better understand and create an effective fractionation schedule.

Patients with recurrent disease or metastasis at multiple sites may require palliative radiation therapy. Common examples include skin metastases that have bleeding and fungation, painful bony metastases or soft tissue metastases, lesions that cause neurologic compromise, and vertebral metastasis that cause spinal cord compression. These patients may benefit from an improvement in quality of life with a short course of RT.

Stereotactic body radiation therapy (SBRT) has been more commonly used to treat both metastatic and definitive disease sites. Recently there has been further investigation into the use of spinal SBRT (sSBRT) for spinal metastatic disease (sMET). As characteristics of patients being treated for sMET with sSBRT can be widely varied, a recursive partitioning analysis (RPA) has been performed for patients with metastatic disease. RPA, initially described by RTOG, is a decision-making tool that can be used to divide patients into groups based on the predicted length of survival. The investigators analyzed survival based on histologies: median overall survival for favorable, radioresistant (renal cell carcinoma, melanoma, sarcoma), and other histologies were 14 months, 11.2 months, and 7.3 months, respectively (P = .02). In the study, they performed an RPA resulting in three classes of patients. RPA Class 1 is defined as time from primary diagnosis (TPD) > 30 months and KPS > 70; Class 2 is defined as TPD > 30 months and KPS ≤ 70 or a TPD ≤ 30 months and age < 70 years; and Class 3 is TPD ≤ 30 months and age ≥ 70 years. With this RPA, the researchers found that the median overall survival for Class 1 was 21.1 months, for Class 2 was 8.7 months, and for Class 3 was 2.4 months. Use of this RPA may help to direct which metastatic patients may benefit from sSBRT.

Unfortunately, many patients with malignant melanoma will present with CNS metastases. These patients can be symptomatic, with complaints of headache, seizures, motor loss, or impaired mentation. These symptoms can be relieved with the use of whole-brain radiation therapy (WBRT). WBRT has been used with multiple different fractionation schemes, although none has been found to be superior to standard fractionation (300 cGy × 10). These patients have a median survival of 2.2 to 4.9 months; however, the impact of WBRT upon survival is unclear (de la Fuente et al CNS Oncol 2014).

Stereotactic radiosurgery (SRS) involves the use of a large, single fraction of radiation to a limited target volume and rapid dose falloff outside the target. A standard linear accelerator is used to deliver one dose, usually between 15 and 24 Gy. Most centers that perform SRS have an upper size limit for the metastatic lesion (approximately 4 cm). Proponents of this treatment have shown less cognitive decline, due to the limited area of radiation. There has been a small prospective series of patients with one to three brain metastases from melanoma, renal cell carcinoma, and sarcoma treated with SRS alone; they were found to have a 32 intracranial recurrence rate outside the SRS volume, suggesting there is a need for WBRT.

The RTOG 95-08 trial was a randomized study evaluating addition of SRS to WBRT in patients with one to three brain metastases (including those with metastatic melanoma). Both treatment modalities produced an improvement in Karnofsky Performance Status (KPS) at 6-month follow-up, with no difference in mental status or neurologic death. Patients with only one brain metastasis who underwent WBRT and SRS had a survival advantage (median survival time, 6.5 vs 4.9 months; P = .0393).

There is a randomized phase III trial currently undergoing accrual for WBRT after local treatment of brain metastases in melanoma patients (trial registration Australia and New Zealand Clinic Trial Registry [ANZCTR] #ACTRN12607000512426). The primary endpoint is the proportion of patients with distant intracranial failure, as determined by MRI assessment at 12 months. Secondary endpoints include survival, quality of life, performance status, and neurocognitive function. The results of this trial should provide evidence that will aid in treatment decision-making.

Clinical observations and preclinical data indicate that exposure of cancer cells to high-dose radiation therapy results in the release of tumor antigens, alteration of the tumor microenvironment, and enhancement of the immunomodulatory effects of IL-2. A pilot study assessed the safety of delivering SBRT to one to three metastatic lesions followed by high-dose IL-2. The study included 12 patients with metastatic melanoma or renal cell carcinoma without history of prior medical therapy for metastatic disease. Patients were assigned to three cohorts and received one, two, or three doses of SBRT (20 Gy per fraction), with the last fraction delivered 3 days prior to initiation of high-dose IL-2 (dose to central lesions in the thorax was reduced to 16 Gy per fraction). No dose-limiting toxicity of radiation therapy was identified, and the maximum tolerated dose was not reached. All irradiated metastases demonstrated regression without recurrence or evidence of fluorodeoxyglucose (FDG)-avidity on positron emission tomography (PET). Of the seven patients with melanoma, five demonstrated a response in the nonirradiated target lesions based on RECIST (Response Evaluation Criteria in Solid Tumors); there were four PRs and one CR, for an overall response rate of 71% (95% CI, 29%–96%). The study suggests SBRT and IL-2 can be safely administered with a higher response rate compared with historical data on monotherapy alone.

Systemic treatment options for patients with advanced melanoma

In the setting of metastatic melanoma, eight agents have been approved for use by the US FDA: dacarbazine (DTIC), interleukin-2, ipilumumab, vemurafenib, dabrafenib, trametinib, pembrolizumab, and nivolumab. These agents can be broadly classified as chemotherapeutic agents, targeted therapy, and immunotherapeutic agents.

Chemotherapeutic agents

Melanoma is regarded as a relatively chemotherapy-refractory tumor. Durable objective responses have been observed in a small minority of patients with metastatic melanoma treated with chemotherapy.

TABLE 4: Selected chemotherapy agents–Results from phase II and phase III trials in melanoma

Dacarbazine, or DTIC, is an alkylating agent that has received FDA approval for use in patients with metastatic melanoma. In the majority of trials of this agent, dacarbazine was administered IV at daily doses of 200 mg/m2 for 5 days every 3 or 4 weeks; however, doses of 1,000 mg/m2 given once every 3 or 4 weeks have been studied in recent trials. The most common toxicities are myelosuppression and nausea. The severity of myelosuppression rarely requires the use of growth factor support, and the advent of potent antiemetics in recent years has significantly improved the tolerability of this agent. In the largest phase III trial that included a single-agent dacarbazine arm, the objective response rate was 3.5%, and the median progression-free survival time was 1.5 months. Overall survival for dacarbazine-treated patients is 6 to 9 months.

The highest response rates have been observed with alkylating agents, platinum-analog, and mictrotubule-interactive drugs (Table 4). Fotemustine, a nitrosourea with modestly superior activity compared with dacarbazine, is available for clinical use in Europe but not in the United States.

Combinations of agents with some measurable single-agent activity in melanoma have been empirically developed. Clinical trials combining chemotherapy have produced promising response rates in single-arm, single-institution studies, but have never demonstrated an improvement in overall survival compared with single-agent chemotherapy in multicenter, randomized trials. Given the increased toxicity associated with such regimens, the absence of a survival advantage limits their consideration as standard therapies. These treatments include a regimen of cisplatin, vinblastine, and dacarbazine (CVD) and the Dartmouth regimen (cisplatin, carmustine, dacarbazine, and tamoxifen). The severity of myelosuppression often requires growth factor support, which is not needed for patients receiving single-agent chemotherapies.

Targeted agents

The discovery of somatic genetic mutations in melanoma, underlying aberrant signal transduction in melanoma cells, has provided leads for the development of molecularly targeted therapy. The MAP kinase pathway, which is activated in the vast majority of melanomas due to mutations in BRAF, NRAS, c-kit, GNAQ, and GNA11, has been the focus of most clinical investigations of signal transduction (kinase) inhibitors.

BRAF inhibition is an appealing strategy in patients with cutaneous melanoma, as 50% to 65% of patients have tumors with an activating mutation. In August 2011, the BRAF kinase inhibitor vemurafenib became the first FDA-approved treatment for patients with BRAF V600E mutation–positive metastatic melanoma. Vemurafenib is a specific inhibitor of activated BRAF, and response rates in phase I, II and III clinical trials have ranged from 50% to 80%. Results of the pivotal phase III BRIM-3 trial (Chapman et al, NEJM 2011) led to approval of vemurafenib. In this study, 675 patients with BRAF-mutated metastatic melanoma that had not previously been treated in the metastatic setting were randomized to receive vemurafenib or dacarbazine. The primary endpoint of overall survival was reached, with an HR of 0.37 in favor of the vemurafenib group. This improvement in survival, in addition to the high early response rate, established BRAF inhibition as an additional standard therapy in the treatment of metastatic melanoma. BRAF mutation testing is now commercially available and can be conducted using paraffin-embedded tumor tissue. Two other agents targeting the MAPK pathway, dabrafenib (Hauschild et al, Lancet 2012) and trametinib (Flaherty et al, NEJM 2012), were approved for BRAF-mutant melanoma in 2013, also based upon randomized trials demonstrating improved overall survival in this patient population.

The combination of BRAF and MEK inhibition has been demonstrated to achieve clinical outcomes superior to BRAF inhibition alone in three separate phase III trials. The COMBI-D trial, reported by Long et al, randomized patients to dabrafenib and trametinib or dabrafenib and placebo. The combination of dabrafenib and trametinib resulted in a superior response rate (67% vs 51%) and superior 6-month overall survival rate (93% vs 85%), and the trial met its primary progression-free survival endpoint, with a progression-free survival time of 9.3 vs 8.8 months (HR = 0.75; P = .03). The COMBI-V trial (Robert et al, ESMO 2014) randomized patients to dabrafenib and trametinib or vemurafenib. The combination of dabrafenib and trametinib resulted in superior responses (64% vs 51%) and superior progression-free survival (11.4 vs 7.3 months), and the trial met its primary overall survival endpoint, with a hazard ratio of 0.69 (P = .002) in favor of the combination therapy. Finally, the coBRIM trial (Larkin et al, NEJM 2014) randomized patients to vemurafenib and the investigational agent cobimetinib or to vemurafenib and placebo. The combination of vemurafenib and cobimetinib resulted in a superior response rate (68% vs 45%) and a superior 9-month overall survival rate (81% vs 73%), and the trial met its primary progression-free survival endpoint, with a progression-free survival time of 9.9 vs 6.2 months (HR = 0.51; P < .001).

Interestingly, although the overall toxicity rates observed on these trials were similar between combination and single-agent arms, the spectrum of toxicities differed. With the combination of BRAF and MEK inhibition, the incidence of cutaneous toxicities and the development of secondary squamous cell malignancies was reduced when compared to the incidence observed with BRAF inhibition alone; however, toxicities such as drug-induced pyrexia were increased with combination therapy. Given the superior efficacy and manageable toxicities associated with combination therapy, it is now the standard of care to use the combination of dabrafeninib and trametinib for BRAF-mutant melanoma when targeted therapy is indicated.

Activating mutations in the KIT receptor were recently identified in patients with acral, mucosal, and lentigo maligna melanoma. The successful development of KIT-targeted therapies in gastrointestinal stromal tumors, in which KIT mutations also are found, has provided the opportunity for immediate investigation of these oral agents in patients with metastatic melanoma harboring KIT mutations. Several trials have now demonstrated that a subset of KIT-mutant melanomas respond to inhibitors of KIT, including imatinib (Carvajal et al, JAMA 2011; Guo et al, J Clin Oncol 2011; Hodi et al, J Clin Oncol 2013) and nilotinib (Carvajal et al, Clin Cancer Res 2014). Based on these data, the use of imatinib for KIT-mutant melanoma has now been included in the NCCN Melanoma Guidelines.

Uveal melanoma is a unique molecular subset of melanoma frequently harboring mutations in GNAQ and GNA11. In preclinical experiments using uveal melanoma models, anticancer activity was observed with selumetinib, an orally available inhibitor of MEK, in a mutation-dependent fashion (Ambrosini et al, Clin Cancer Res 2012; Ambrosini et al, Mol Cancer Ther 2013). In a phase II clinical trial, patients with patients with metastatic uveal melanoma, who were either temozolomide- or dacarbazine-treatment naive, were randomized to either selumetinib or chemotherapy with temozolomide or dacarbazine (Carvajal et al, JAMA 2014). Tumor regression was observed in 49% of patients treated with selumetinib, with an overall response rate by RECIST of 14% vs a response rate of 0% with chemotherapy. The trial met its primary endpoint of progression-free survival, with a progression-free survival time with selumetinib of 15.9 weeks vs 7 weeks with chemotherapy (HR = 0.46; P < .001). In April 2015, the FDA granted selumetinib Orphan Drug Designation for the treatment of uveal melanoma.

Immunotherapeutic agents

IL-2 was approved by the FDA as a treatment for metastatic melanoma on the basis of durable complete and partial remissions associated with the “high-dose” regimen. This regimen requires patients to be in excellent overall health to tolerate the physiologic stress of 5 days of inpatient therapy. The standard dose is 200,000 U/m2 repeated every 8 hours, for a maximum of 14 doses. This treatment is followed by a treatment break of 10 to 14 days and readmission for another course of therapy. Patients who demonstrate some degree of tumor regression are offered additional courses of therapy. Typical toxicities include fever, malaise, hypotension complicated by renal dysfunction, elevated levels of liver transaminases, and mood alterations. Clinical expertise among physicians and nurses is required to safely and effectively administer this therapy. As a consequence, the use of high-dose IL-2 has largely been restricted to high-volume referral centers.

The distinct mechanisms of action of biologic agents and evidence of single-agent activity have led investigators to combine biological agents such as IL-2 and interferon with chemotherapy for the treatment of metastatic melanoma. Given the toxicity associated with high-dose IL-2, it is not possible to safely administer chemotherapy concurrently. However, lower-dose IL-2 regimens can be safely coadministered with combination chemotherapy. Likewise, the high-dose interferon regimen that is the current standard therapy for adjuvant treatment of stages II and III melanoma cannot be easily combined with chemotherapy, whereas this is possible with modified schedules of interferon.

The first biochemotherapy regimens tested in phase II trials and then subsequently in large, randomized phase III trials combined interferon-α with dacarbazine. Despite early evidence suggesting a substantially higher response rate associated with the combination, definitive phase III trials failed to identify a survival advantage to this regimen over treatment with dacarbazine alone. More intensive regimens combining chemotherapy with biologic agents, requiring inpatient administration, have been evaluated. A regimen containing cisplatin, vinblastine, dacarbazine, given concurrently with interferon and IL-2, was evaluated in several phase II trials; in a small, single-institution phase III trial; and in a multicenter phase III trial in comparison to multiagent chemotherapy without the biologic agents. Although progression-free survival appeared modestly superior to outcomes seen with the chemotherapy backbone alone, no improvement in overall survival could be demonstrated. Likewise, a trial assessing the contribution of IL-2 to a regimen of cisplatin, dacarbazine, and interferon-α failed to demonstrate a significant improvement in outcome.

The management of advanced melanoma has been revolutionized by the development of antibodies targeting the immunological checkpoints CTLA-4 and PD1.

Ipilimumab is a monoclonal antibody that blocks CTLA-4 mediated downregulation of the T-cell response. In 2010, investigators reported results of the first phase III trial comparing ipilimumab combined with GP-100 peptide vaccine to vaccine alone or ipilimumab alone (Hodi et al, NEJM 2010). This trial demonstrated an overall survival benefit for both of the ipilimumab-containing arms, compared with peptide vaccine alone. The rates of overall survival at 12 months for ipilimumab plus GP-100 and ipilimumab alone were 44% and 46%, compared with 25% for peptide vaccine alone. The rates of overall survival at 24 months for the ipilimumab-containing arms were 22% and 24%, compared with 14% for peptide vaccine alone. These data confirm a durable benefit associated with this novel immunotherapy in patients with metastatic melanoma who had failed to respond to one prior therapy. A second, randomized, phase III trial compared ipilimumab combined with dacarbazine vs dacarbazine alone among 502 patients with metastatic melanoma. Survival rates at 1 year (47.3% vs 36.3%, respectively), 2 years (28.5% vs 17.9%), and 3 years (20.8% vs 12.2%) confirmed that ipilimumab can confer a long-term survival benefit to a subpopulation of patients treated (Robert et al, NEJM 2011).

In March 2011, the FDA approved ipilimumab for the treatment of patients with unresectable or metastatic melanoma. Ipilimumab is the first agent targeting an immunological checkpoint to receive regulatory approval.

Pembrolizumab and nivolumab are monoclonal antibodies targeting PD1, another key immunological checkpoint molecule. Hamid et al reported in 2013 that administration of pembrolizumab (formerly known as lambrolizumab) to patients with advanced, treatment-refractory melanoma resulted in an ORR of 38% and a CR rate of 10%, with no difference in outcome observed between patients who previously received therapy with ipilimumab and those who did not. Robert and colleagues reported a remarkable 1-year overall survival rate of up to 63% among ipilimumab-refractory patients treated with pembrolizumab in a randomized dose-comparison expansion cohort of a phase I trial (Robert et al, Lancet 2014).

In the CheckMate 066 study, nivolumab was compared with dacarbazine in patients with BRAF wild-type melanoma who were previously untreated (Robert et al, NEJM 2015). Nivolumab was compared with chemotherapy in patients with advanced melanoma who had previously been treated with anti-CTLA4 therapy in CheckMate 037 (Weber J et al, ESMO 2014). The overall response rates with nivolumab were 40% and 32% in CheckMate 066 and CheckMate 037, respectively, and compared favorably with response rates observed with chemotherapy. Checkmate 066 achieved its primary endpoint of overall survival, with a HR of 0.42 (P < .001), in favor of nivolumab. CheckMate 037 had co-primary endpoints of response rate and overall survival. The response rate observed in this study was 32% for nivolumab and 11% for chemotherapy. Survival data were premature at the time of ESMO 2014.

These results led the FDA to grant approval of pembrolizumab in September 2014 and nivolumab in December 2014 for patients with advanced melanoma who have received prior ipilimumab as well as a BRAF-targeted therapy among those with BRAF-mutant disease.

Ongoing studies are evaluating the combination of CTLA4 and PD1 inhibition, as well as the combination of these agents with other immunological and targeted agents, and with local treatment modalities such as radiotherapy, cryotherapy, and radiofrequency ablation.

Sidebar: Results of CheckMate 067, an international randomized double-blind phase III trial, were presented in a plenary session at ASCO 2015. A total of 945 patients with treatment-naive advanced melanoma were randomized to treatment with nivolumab plus placebo; ipilimumab plus placebo; or nivolumab plus ipilimumab in combination, followed by maintenance nivolumab. Combination therapy yielded better progression-free survival than ipilimumab alone, with a median PFS of 11.5 vs 2.9 months, respectively (hazard ratio [HR] = 0.42; 95% CI, 0.31–0.57; P < .00001). Patients randomized to nivolumab had a median progression-free survival of 6.9 months, but the study was not statistically powered for comparison with combination therapy. The combination of nivolumab plus ipilimumab yielded an overall response rate (ORR) of 57.6%, compared with an ORR of 43.7% for nivolumab and 19% for ipilimumab (P < .00001). Median duration of response was not reached in any of the treatment groups at the time of the study presentation (Wolchok JD et al: J Clin Oncol 33[suppl]: abstract LBA1, 2015).

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Non-melanoma Skin Cancer

The two most common skin cancers are basal and squamous cell carcinomas. Both of these skin cancers arise predominately on sun-exposed areas and may be considered in the differential diagnosis of melanoma. Classically, basal cell skin cancers are nodular and have a pearly, nonpigmented surface. Squamous cell carcinomas typically have a scaly, nonpigmented surface and can occasionally be ulcerated. Both diseases are generally slow to evolve. The diagnosis of these skin cancers should be made after pathologic analysis of the skin specimen. Excisional biopsy is recommended for any lesion that is suspected of being squamous cell cancer or basal cell carcinoma. The biopsy should extend to the subcutaneous tissue to provide an adequate estimate of the depth of invasion, particularly for melanoma. Biopsy specimens should be placed in formalin and submitted for expert pathologic preparation including embedding in paraffin. Careful attention to documenting the site of the biopsy is essential to subsequent care.

In most cases, squamous cell carcinomas are believed to arise from actinic keratoses. The differentiation between the two is based largely on size, with actinic keratoses being less than 1 cm in diameter. Actinic keratoses manifest as raised, nonpigmented lesions with a plaque-like surface. Typically, they have an erythematous base and arise on heavily sun-exposed skin. These lesions are typically treated with excision, cryotherapy, topical chemotherapy (5-fluorouracil [5-FU]), or immunotherapy (imiquimod). It is unclear what effect nonsurgical therapy has on the long-term risk of progression to squamous cell carcinoma, but the relatively indolent nature of most actinic keratoses suggests that nonsurgical therapy followed by close observation is reasonable, particularly for lesions arising on cosmetically sensitive areas such as the face.

Etiology

There is incontrovertible evidence linking immunosuppression and squamous cell skin cancer. This increased risk applies to patients with acquired immunodeficiency syndrome (AIDS) as well as transplant recipients on chronic treatment with immunosuppressive medications.

Burns (unrelated to sun exposure) and chronic wounds predispose to the formation of squamous cell carcinoma on permanently scarred areas (Margolin’s ulcers). Although relatively uncommon, a tumor or ulcer occurring in a chronic wound should raise concern for malignancy and the area should be biopsied.

Merkel cell papilloma virus appears to play an etiological role in these tumors, although the precise mechanism has not been defined.

Initial Management of Non-melanoma Skin Cancer

Surgery

Most non-melanoma skin cancers can be conservatively excised with much narrower margins than are required for cutaneous melanomas. Excision margins of 0.5 to 1 cm are adequate for most nonrecurrent basal cell and squamous cell cancers and yield local recurrence rates under 5%, provided that histologically negative margins are achieved. For tumors in most anatomic sites, these excision margins can be achieved using standard surgical techniques with local anesthesia and primary closure. Serial thin section techniques such as Mohs surgery can be appropriate for definitive management.

Radiation therapy

Radiotherapy is effective for the treatment of squamous cell and basal cell skin cancers, and is associated with a likelihood of cure similar to that of surgery. However, this practice is only considered standard in areas of the body where surgery would be disfiguring or debilitating. In instances in which negative margins cannot be obtained without an unacceptable cosmetic result, adjuvant radiotherapy to treat microscopic residual disease appears effective. This practice is also typically extended to Merkel cell skin cancers and sarcomas of the skin. The use of radiotherapy to the surgical bed when negative margins have been obtained is more controversial and is not well supported by data.

Topical and intralesional therapies

Topical therapy is a consideration for patients with large areas of skin affected by numerous or recurrent squamous cell or basal skin cancers. Immunocompromised patients and occasional patients with extremes of cumulative lifetime sun exposure are candidates for topical 5-FU or imiquimod. These therapies are generally not offered to patients who are otherwise good candidates for surgical resection.

5-FU is an antimetabolite chemotherapy that is effective in eradicating both actinic keratoses and squamous cell skin cancers. Following treatment, patients typically develop significant erythema in treated skin lasting for several weeks, until the treated skin has adequately regenerated its epithelium.

Imiquimod stimulates the activity of antigen-presenting cells in the skin when applied topically, which engenders an immune response in treated tumors. Complete regression of treated tumors is typically achieved. However, patients who are offered this therapy are typically at high risk for local recurrence and appearance of new lesions elsewhere, and thus require lifelong surveillance and, potentially, repeated treatment.

Intralesional therapy for unresectable or recurrent basal cell skin cancers has been investigated. The only readily available agent that has been employed for this purpose is interferon-α. Comparative trials have not been conducted with intralesional vs topical therapies.

Management of Locoregionally Recurrent Non-melanoma Skin Cancer

Local recurrence complicates approximately 5% of cases of non-melanoma skin cancer; if possible, surgical resection should be performed. In areas of skin where surgery would result in an unacceptable cosmetic result, radiotherapy can be offered. The vast majority of recurrent non-melanoma skin cancers can be cured with re-excision or radiotherapy.

Among the non-melanoma skin cancers, Merkel cell carcinoma is the most likely to be associated with regional lymph node involvement. The prognosis of patients with lymph node involvement appears to be significantly worse than that of patients with localized disease. Thus, SLNB is justified as a staging procedure in patients with primary Merkel cell carcinoma.

Basal cell carcinoma infrequently spreads to regional lymph nodes. Squamous cell skin cancer is also unlikely to involve regional lymph nodes (5% of all cases), and SLNB is generally reserved for patients with primary tumors that are large, deeply invasive, or poorly differentiated. Clinically evident lymph nodes should be evaluated with fine-needle aspiration to determine the need for lymph node dissection.

Management of Metastatic Non-melanoma Skin Cancer

Distant metastasis is uncommon in both squamous cell and basal cell carcinoma. Metastasis in squamous cell carcinoma occurs in approximately 2% of all cases and is generally limited to patients who are immunocompromised. Combination chemotherapy regimens used to treat squamous cell carcinoma from other sites are typically employed for patients with metastatic squamous cell carcinoma of the skin, although responses appear to be infrequent and are usually short-lived.

Fewer than 1 in 1,000 patients with basal cell carcinoma develop metastatic disease. Alterations in Hedgehog signaling are implicated in the pathogenesis of basal-cell carcinoma. In January 2012, the US Food and Drug Administration announced the approval of the oral drug vismodegib, an orally bioavailable small-molecule inhibitor of Hedgehog signaling, for the treatment of locally advanced and metastatic basal cell carcinoma. In the pivotal study, involving 96 patients, vismodegib (at 150 mg, once daily) shrank tumors or healed lesions in 43% of patients with locally advanced disease (27 of 63) and in 30% of patients with metastatic disease (10 of 33). The objective response rates for the two groups were 60% and 46%, respectively; progression-free survival for both groups was 9.5 months.

Suggested Reading

On Skin Cancers

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On Biology and Epidemiology of Melanoma

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On Prevention

Green AC, Williams GM, Logan V, et al: Reduced melanoma after regular sunscreen use: Randomized trial follow-up. J Clin Oncol 29:257–263, 2011.

On Surgical Treatment and Imaging

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On Adjuvant Therapy

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On Systemic Therapy

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On Metastatic Disease Treatment

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