Risk Factors for Melanoma

Assessment of risk identifies people who may benefit from more aggressive education and surveillance strategies to prevent or detect early-stage melanoma. This section will review risk factors for melanoma, including demographic, environmental, phenotypic, and genetic risks.

Genetic and Molecular Alterations

Several genetic and molecular alterations contribute to the development of melanoma, and the identification of molecular subgroups of melanoma has resulted in targeted therapies to improve patient outcomes. This section will describe the key pathways involved in melanoma pathogenesis.

CDNK2A

Cell-cycle regulatory proteins are required for the precise regulation of cell growth and division and therefore are critical targets in the malignant transformation of all cells. The observation of frequent deletions in the 9p21 locus in familial primary melanomas led to the identification of the CDNK2A tumor-suppressor gene in familial melanoma.9,10 The CDNK2A gene encodes an inhibitor of the cyclin-dependent kinases, CDK4 and CDK6, which leads to cell-cycle arrest at the G1 phase. If p16 is not expressed, CDK4/CDK6 may phosphorylate the retinoblastoma protein Rb and inactivate its tumor suppressor function. Expression of CDNK2A is silenced in sporadic melanomas via multiple mechanisms, including epigenetic inactivation through promoter methylation CDK4 amplification and cyclin D gene amplification. Loss of p16 expression is associated with disease progression and a poor prognosis.¹¹

Primary Prevention

UVR exposure is the only modifiable risk factor for melanoma. Protection from UVR is the primary strategy to decrease melanoma risk; optimal use of sunscreen and sun protection results in a decreased risk of melanoma.²² Protection from UVR can mitigate one’s risk for skin cancer, regardless of the age at which it is implemented. Standard recommendations to decrease UVR exposure include avoidance of the sun between the peak hours of 10 am to 4 pm, seeking shade whenever possible, covering the skin surface with sun-protective clothing including wide-brimmed hats, long-sleeved shirts, long pants, and sunglasses, and using broad-spectrum sunscreen with a sun protection factor (SPF) of 15 or greater to cover exposed skin surfaces. Regular application of SPF 15+ sunscreen in adults has been demonstrated to decrease melanoma risk in a randomized trial.²³ Appropriate type, timing, frequency, and amount of sunscreen applied are important factors in effective primary prevention. The United States Food and Drug Administration (FDA) has legislated regulations for over-the-counter sunscreens (http://www.fda.gov/forconsumers/consumerupdates/ucm258416.htm). Highlights of these new regulations are that sunscreen products that protect against both UVA and UVB radiation will be labeled “broad spectrum” and “SPF 15” (or higher) on the front label; sunscreen products that are not broad spectrum or that are broad spectrum with SPF values from 2 to14 will be labeled with a warning; and the front label must limit water resistance claims to either 40 minutes or 80 minutes, based on standard testing to determine how much time a user can expect to get the declared SPF level of protection while swimming or sweating. Sun-protective clothing guards the skin from UVR more effectively than sunscreen. As opposed to sunscreen, which is frequently applied unevenly and insufficiently, sun-protective clothing provides uniform and constant protection for the areas it covers. The UVR-protective properties of clothing vary according to the thickness, color, and type of fabric. Most regulatory agencies have adopted the UV protection factor as the standard of measurement of UV protection for clothing. Clothing can achieve a UV protection factor >500, which is vastly superior to sunscreen. Barriers to the implementation of sun protection behaviors include discomfort from sun-protective clothing, inconvenience of applying sunscreen, and denial of personal risk for skin cancer. Furthermore, studies indicate that tanning may be an addictive behavior. Recent legislation may help to decrease access of minors to indoor tanning salons; however, modifying exposure to natural UVR remains a challenge.

Secondary Prevention

Patients with early-stage disease have an excellent prognosis after complete excision of the melanoma. Strategies to improve detection of early-stage melanoma include regular self-skin examinations and skin examinations by a trained medical practitioner. Self-skin examination, defined as a careful and deliberate self-conducted examination of all areas of the skin for changes in spots or moles, may reduce mortality from melanoma but are performed by only a small percentage of patients²⁴ and are not recommended for prevention in the general public. The majority of melanomas are detected by patients or their partners. Physician recommendation is one of the strongest determinants of self-skin examination and cancer screening. Health care practitioners may increase compliance by strongly recommending regular self-skin examination and by educating patients to examine their skin with confidence. Offering patients full-body photography can improve their ability to diagnose new and changing nevi during self-skin examination. Full-body photography can aid both patients and physicians by providing a fixed reference point to compare new or changing lesions. Although no strong evidence exists that skin cancer screening in the general population by primary care providers or self-examination reduces skin cancer morbidity and mortality, some evidence indicates that screening for melanoma with skin examinations by experienced physicians reduces melanoma mortality because experienced physicians are more likely to detect melanomas at an earlier stage than are patients. Regular screening skin examinations provide an opportunity for physicians to educate patients and their families about melanoma and to increase efforts aimed at primary prevention.

Melanoma Histopathology

The histopathologic diagnosis of melanoma relies heavily on the presence of specific alterations in growth patterns relative to those of benign nevi. Melanocytes are easily identified and differentiated from keratinocytes by the presence of halos that surround melanocytes on well-prepared routine hematoxylin and eosin–stained sections. In normal skin, the melanocytes are usually located in the basal layer of the epidermis, where the ratio of melanocytes to keratinocytes varies from approximately 1 : 4 in areas exposed to the sun to 1 : 30 in nonexposed areas. Benign nevi are characterized by the presence of nevus cells that are arranged in clusters or nests. Their nuclei are small, without prominent nucleoli or mitoses. Nevic melanocytes are arranged uniformly and predominantly as nests and occasional single units at the rete tips of the dermoepidermal junction and within the dermis. Nevus cells “mature” or diminish in size as they descend into the dermis. Significant alterations in these basic growth patterns are cause for concern, and when they occur, a diagnosis of melanoma must be considered. In contrast to nevi, and with few exceptions, melanomas are asymmetric and poorly circumscribed. Melanocytes, as nests and single units, may be present at all levels of the epidermis, a pattern known as Pagetoid spread. Dermal melanocytes do not “mature” evenly and are characterized by enlarged nuclei with prominent nucleoli. Melanoma in situ is defined as an irregular proliferation of uniformly atypical melanocytes confined to the epidermis. Invasive melanoma is defined as the presence of melanoma cells, at a minimum, within the papillary dermis.

Melanoma has been conceptualized as growing first in a radial growth phase with little risk of metastatic behavior. This phase is followed by the vertical growth phase with the capacity for metastasis.²⁵ Different clinical and histologic features are associated with these two phases. Histologically, the radial growth phase refers to a progressive intraepidermal proliferation of melanocytes in which they are largely confined to the epidermis and the superficial dermis, without forming a tumor in the dermis, and without having competence for metastasis. This radial growth phase precedes the vertical growth phase of melanoma in all subtypes except nodular melanoma, which lacks prominent radial growth. Approximately one third of melanomas arise in association with a preexisting nevus. Distinguishing between melanoma and a benign nevus can be challenging, particularly when attempting to distinguish special types of nevi such as a Spitz nevus, cellular blue nevus, combined nevus, or deep penetrating nevus from a melanoma, or when attempting to distinguish a nevus from a nevoid melanoma.²⁶ In these instances, the histologic differences may be subtle, and interpretation by an experienced dermatopathologist is necessary.

Superficial Spreading Melanoma

SSM is the most common histologic subtype among most groups of patients; in black patients, ALM is most common. SSM may occur on any area of the body, but it most commonly occurs on the trunk and proximal extremities of young to middle-aged adults. SSM is more commonly associated with intense, intermittent sun exposure. Clinically, the lesions are often asymmetric; have irregular or indistinct borders; display various shades of brown, black, pink or other colors; and are larger compared with other nevi on the patient’s skin. Patients frequently note a change in size or color. In its early stages, SSM is flat. As dermal invasion progresses, the lesion may first become raised and then ulcerate or bleed. SSM can be associated with BRAF mutation.

A biopsy should be performed on any skin lesion suspicious for melanoma. Obtaining adequate biopsy specimens is essential because staging of the primary melanoma depends on three microscopic features: Breslow depth or thickness, mitotic rate, and presence or absence of ulceration. Excision of the entire lesion is preferred; partial biopsies increase the risks of both misdiagnosis (false negative or false positive) and microstaging inaccuracy (either the biopsy transects the base of the melanoma or fails to sample the deepest portion of the melanoma). Performing a partial biopsy may be necessary and reasonable in cosmetically or functionally sensitive anatomic locations or if the lesion is large. Shave biopsies can compromise histologic interpretation and proper measurement of thickness and should be avoided.

Staging Classification

The 7th edition of the AJCC staging system was adopted in 2009 and is based on a study of patient outcomes from the AJCC Melanoma Database, which consisted of a total of 38,918 patients with melanoma, including 7972 patients with stage IV melanoma.²⁹ The data were merged from prospective databases of patients from 17 major medical centers, stand-alone cancer centers, and cancer cooperative groups. Box 69-1 and Tables 69-1 and 69-2 list the current melanoma TNM categories and the stage groupings, respectively. The 15-year survival curves for patients with stage I to IV melanoma are shown in Figure 69-2.The distinction between clinical and pathologic staging is worth noting.

Box 69-1

American Joint Committee on Cancer TNM Definitions

Primary Tumor (T)

Tx: Unable to assess (e.g., curettage or severely regressed melanoma)

T0: No evidence of primary tumor

Tis: Melanoma in situ

T1: 0.1- to 1.0-mm thick

T1a: Without ulceration and mitosis <1/mm²

T1b: With ulceration or mitoses ≥1/mm²

T2: 1.01- to 2.0-mm thick

T2a: Without ulceration

T2b: With ulceration

T3: 2.01- to 4.0-mm thick

T3a: Without ulceration

T3b: With ulceration

T4: >4.0 mm thick

T4a: Without ulceration

T4b: With ulceration

Regional Lymph Nodes (N)

NX: Patients in whom the regional nodes cannot be assessed (e.g., previously removed for another reason)

N0: No regional lymph node metastasis

N1: metastasis in one node

N1a: Micrometastasis (clinically occult)

N1b: Macrometastasis (clinically apparent)

N2: Metastasis in two to three nodes or in-transit metastases without nodal metastases

N2a: Micrometastases (clinically occult)

N2b: Macrometastases (clinically apparent)

N2c: In-transit met(s)/satellite(s) without metastasis in nodes

N3: Metastasis in four or more regional nodes, matted notes, or in transit metastasis or satellite(s) with metastasis in node(s)

Distant Metastases (M)

M0: No detectable evidence of distant metastasis

M1a: Skin, subcutaneous, distant lymph node metastases

M1b: Lung metastases

M1c: All other visceral metastases, or distant metastases at any site with elevated serum lactate dehydrogenase

From American Joint Committee on Cancer. Cancer staging manual. 7th ed. New York: Springer-Verlag; 2010.

Table 69-1

American Joint Committee on Cancer Pathologic Stage Grouping*

Stage	Grouping
Stage 0	TisN0M0
Stage IA	T1aN0M0
Stage IB	T1bN0M0
	T2aN0M0
Stage IIA	T2bN0M0
	T3aN0M0
Stage IIB	T3bN0M0
	T4aN0M0
Stage IIC	T4bN0M0
Stage IIIA	T1–4aN1aM0
	T1–4aN2aM0
Stage IIIB	T1–4bN1aM0
	T1–4bN2aM0
	T1–4aN1bM0
	T1–4aN2bM0
	T1–4a/bN2cM0
Stage IIIC	T1–4bN1bM0
	T1–4bN2bM0
	Any T N3M0
	Any T, any N, M1

^*Note that the stage groupings involve upstaging to account for melanoma ulceration, where thinner melanomas with ulceration are grouped with the next greatest T substage for nonulcerated melanomas.

From American Joint Committee on Cancer. Cancer staging manual. 7th ed. New York: Springer-Verlag; 2010.

Table 69-2

American Joint Committee on Cancer 5-year Survival Rates of Pathologically Staged Patients

	IA	IB	IIA	IIB	IIC	IIIA	IIIB	IIIC
Ta: nonulcerated	T1a 97%	T2a 91%	T3a 79%	T4a 71%		N1a N2a 78%	N1b N2b 48%	N3 47%
Tb: ulcerated*		T1b 94%	T2b 82%	T3b 68%	T4b 53%		N1a N2a 55%	N1b N2b N3 38%

^*The presence of tumor ulceration of a primary melanoma (designated Tb) causes upstaging by one substage compared with a nonulcerated melanoma (designated Ta).

From American Joint Committee on Cancer. Cancer staging manual. 7th ed. New York: Springer-Verlag; 2010.

Clinical Staging

Patients with clinical stage I and II disease have invasive melanoma with no evidence of metastases at either regional or distant sites, based on clinical, radiologic, or laboratory evaluation. Patients with clinical stage III melanoma have clinical or radiologic evidence of regional metastases in the regional lymph nodes or evidence of intralymphatic satellite or in-transit metastases. Because the clinical or radiologic assessment of the regional lymph nodes is inherently difficult, especially with respect to assessing the presence and number of metastatic nodes, no subgroup definitions of clinically staged patients with nodal or intralymphatic regional metastases exist. Patients with clinical stage IV melanoma have metastases at a site distant from the primary melanoma and are also not further subgrouped.

Pathologic Staging

In contrast to clinical staging, greater accuracy is possible in defining distinctive prognostic subgroups for appropriate patients for whom pathologic information is available about the regional lymph nodes (after sentinel or complete lymphadenectomy). Pathologic stage I and II melanoma has no evidence of regional or distant metastases, based on the absence of nodal metastases after pathologic examination of the regional lymph nodes and absence of distant metastases based on routine clinical and radiologic examination. Pathologic stage III melanoma has pathologic evidence of regional metastases by virtue of satellite lesions, in-transit metastases, or metastatic regional lymph nodes. Quantitative classification of pathologic nodal status requires that pathologists perform a careful examination of the surgically resected nodal basin and report on the number of lymph nodes examined and the number of nodes involved with metastases, and it requires that they determine whether the nodes are microscopically or macroscopically involved. Pathologic stage IV melanoma has histologic documentation of metastases at one or more distant sites.

TNM Criteria

The primary criteria for the T classification are tumor thickness (measured in millimeters), the presence of histologic ulceration, and additionally, for thin melanomas (≤1.00 mm), the mitotic rate. A threshold of 1.0 mm or less is used for T1 melanomas. T2 melanomas are 1.01 to 2.0 mm thick, T3 melanomas are 2.01 to 4.0 mm thick, and T4 melanomas are greater than 4.0 mm thick. Ulceration of the primary tumor is associated with poorer survival outcomes; survival rates for patients with an ulcerated melanoma are remarkably similar to those for patients with nonulcerated melanomas of the next highest T category. Mitotic rate in the most recent AJCC staging system for melanoma is identified as an independent prognostic feature in “thin” (T1) melanomas^. and is incorporated into the stage grouping definitions for T1 lesions only. In the cohort of T1 melanomas, the assignment of T1a is restricted to patients whose lesions meet three criteria: (1) lesion thickness of 1.0 mm or less; (2) absence of ulceration; and (3) mitoses <1/mm². T1b melanomas are defined as those with a thickness of 1.0 mm or less and with the more aggressive features of either ulceration or mitotic rate ≥1/mm². The Clark level of invasion is no longer used in risk stratifying T1 melanomas (as in prior staging classifications) except in the rare situations when mitotic rate cannot be determined. Ulceration status of the primary tumor, presence of in-transit metastases or satellitosis, number of nodal metastases, and presence of microscopic versus macroscopic metastases in the node(s) are the determinants of the stage III subgroup classification. Tremendous heterogeneity exists in 5-year survival rates among patients with stage III disease (Fig. 69-3). In patients with distant metastases, the site (or sites) of metastasis and presence of an elevated serum level of lactate dehydrogenase (LDH) have prognostic value and are therefore used to classify the M categories into three groups: M1a, M1b, and M1c. The 1-year survival rates range from 33% for M1c disease to 62% for M1a disease. When the serum LDH level is elevated above the upper limits of normal at the time of staging, patients are classified as M1c, regardless of the site of distant metastasis, because they have a similar prognosis to patients with nonpulmonary visceral sites of metastasis.

Patient Evaluation

Melanoma has the potential to metastasize to any organ; common sites include the skin, subcutaneous tissues, lymph nodes, lung, liver, brain and bone. The initial evaluation of a patient with melanoma includes personal and family histories and an appropriate physical examination, including a total skin examination and palpation of regional (draining) lymph nodes. The focus of this evaluation is to identify risk factors, signs or symptoms of metastases, dysplastic nevi, and additional primary melanomas. The extent of the workup for patients with the initial diagnosis of melanoma is based on the risk of recurrence associated with the primary melanoma. In general, for low-risk melanomas (i.e., ≤1.0 mm and no ulceration), no further search for occult metastatic disease is indicated. In patients with higher risk primary melanomas, a chest radiograph, liver function tests, and measurement of LDH often are performed; however, no data exist to support this common practice. A more extensive staging evaluation with computed tomography (CT) alone or in combination with positron emission tomography (PET) scans of the chest, abdomen, or pelvis can be considered for patients with thick primary melanomas (>4 mm, high-risk stage II melanoma) or node-positive disease (stage III melanoma), for whom the risk of distant metastatic disease is higher. Again, no data exist to support this approach, and considerable variation is found in clinical practice. Nonetheless, CT scans or PET/CT scans along with complete blood cell count, serum LDH, and blood chemistry tests are frequently performed in patients with stage III or high-risk stage II melanoma. Other imaging, such as bone scans or screening magnetic resonance imaging (MRI) scans of the brain, are not recommended for asymptomatic patients. CT or PET imaging is not indicated for patients with stage I melanoma and most patients with stage II melanoma unless screening history and physical examination findings raise concern. Currently, no tumor markers are sensitive and specific for melanoma. Assays to detect molecular markers of melanoma cells in the blood and sentinel lymph nodes are being investigated.

Management of the Primary Lesion

Every primary melanoma requires wide local excision of the surrounding skin to decrease the risk of local and satellite recurrences. In most cases, wide local excision involves excision of the lesion with 1- to 2-cm radial margins (depending on the depth of the melanoma). Larger surgical excisions are not necessary. Five randomized clinical trials have addressed the issue of surgical margins around a primary melanoma, none of which has demonstrated a difference in overall survival (OS) using wider (3-5 cm) versus more narrow (1-2 cm) excision margins for melanomas up to 4 mm in thickness.37–42 Based on these studies, the recommended excision margin should be 0.5 cm around the visible lesion for melanoma in situ, 1 cm for melanomas 1 mm or less, 1 to 2 cm for melanomas measuring 1.01 to 2 mm, and 2 cm for melanomas greater than 2 mm in thickness. In cosmetically sensitive areas, such as the face, or areas that are anatomically difficult to work with, such as the ears, hands, and feet, achieving the desired margins may be difficult. In those situations, at least a 1-cm margin should be obtained. Digital melanoma often requires amputation at the mid-phalanx proximal to the melanoma and follows the same margin recommendations as other sites.

Management of Regional Lymph Nodes

The surgical management of clinically normal lymph nodes is determined by the characteristics of the primary melanoma. A direct relationship exists between the thickness of the melanoma and the risk of regional lymph node involvement. SLNB is the primary method for regional nodal assessment for pathological staging. Sentinel lymph node mapping is recommended for melanomas that are greater than 1 mm thick (T2 melanomas). For melanomas that are 1 mm thick or less, the likelihood of regional lymph node involvement is low (less than 10%), and thus SLN mapping is not recommended but should be considered if adverse prognostic features are present, including ulceration of the primary melanoma or a high mitotic count ≥1/mm² (T1b melanomas), lymphovascular invasion, positive deep margins, thickness greater than 0.75 mm, or Clark level IV or V. The morbidity of SLNB is relatively low, and the staging information can be valuable. Patients with positive findings in the node have pathological stage III melanoma and typically undergo a completion lymphadenectomy of the involved nodal region followed by consideration of systemic adjuvant therapy with interferon or enrollment in a clinical trial.

Accurate detection of the sentinel node depends on mapping the lymphatic drainage from the skin directly next to the melanoma in a coordinated effort by the surgeon and the nuclear medicine specialist, who performs a preoperative lymphoscintigraphy. With truncal or head and neck primary lesions, drainage to more than one nodal basin can occur, and it is important to retrieve the sentinel node(s) from each node basin in which a sentinel node is identified during lymphoscintigraphy. A vital blue dye (1% isosulfan blue) injected into the skin directly next to the melanoma is also used intraoperatively to further assist with the localization of the sentinel nodes.

Analysis of the sentinel nodes is performed after the tissue has been fixed in formalin because frozen section analysis has a decreased accuracy. Multiple sections are taken of the node and evaluated with immunohistochemical stains (e.g., HMB-45, S-100, and Melan-A) to look for microscopic evidence of disease. Risk of histologic node positivity correlates with thickness of the primary melanoma; in patients with T1 melanomas, SLN positivity rates are 5% or less, whereas for melanomas 4 mm or thicker, the SLN positivity rates are in the range of 30% to 49%. The Multicenter Selective Lymphadenectomy Trial (MSLT-1) of 1269 patients with intermediate-thickness melanomas (1.2-3.5 mm) confirmed the prognostic significance of the pathological status of the sentinel node, with improved disease-free survival (DFS) with sentinel node–negative disease compared with sentinel node–positive disease among patients who were randomly assigned to undergo sentinel node biopsy. SLN status was the most significant predictor of survival in a multifactorial analysis for patients randomized to the SLNB arm. Nodal metastases were detected 16 months earlier (median) in patients randomized to SLNB than in the patients randomized to nodal observation, although an equal number of patients (approximately 16%) on both arms of the study had nodal metastases.43,44

Most patients randomized to the nodal observation group who experienced a regional recurrence underwent a radical lymphadenectomy, because the regional nodes remained the solitary site of metastatic disease. In these patients with a clinically detected regional recurrence, a greater number of metastatic involved lymph nodes were identified on lymphadenectomy (3.3 metastatic lymph nodes vs. 1.4 in the SLN group). The two randomized groups in the multicenter international trial (MSLT-1) had equivalent OS rates. However, in the 16% of patients in each group who had nodal metastases, survival rates were higher in the 16% of microscopic SLN–positive patients who underwent early surgical intervention as directed by the SLNB, compared with the 16% of clinically node-positive patients who underwent lymphadenectomies at the time that clinical stage III disease developed on the observation arm.

The use of SLNB is the standard of care in persons with melanoma that is greater than 1 mm in thickness. More accurate staging via SNLB allows for earlier referral of patients with nodal micrometastases to be considered for adjuvant therapy or clinical trials. Complete lymphadenectomy currently is standard treatment for patients with histologically identified regional nodal metastases on SLNB. The goals of surgery include staging and regional disease control. The OS benefit of a completion lymph node dissection (CLND) after a positive SLNB is unclear. Only 15% to 20% of patients with a positive SLNB will have additional nodal metastases in nonsentinel nodes on CLND. Moreover, disease in the nonsentinel lymph nodes (the very patient population that could stand to benefit from a CLND) has been associated with poor prognosis. A multicenter international trial (MSLT-II) is currently accruing patients to address the question of whether a CLND offers benefit to patients with a positive SLN versus close observation with ultrasonographic evaluation of their nodal basin.

Patients presenting with clinically suspicious nodal disease at the time of diagnosis (clinical stage III) should be evaluated with a fine-needle aspiration, if possible, with an excisional biopsy performed only if the results of the fine-needle aspiration are indeterminate. Patients with confirmed nodal metastases should undergo a staging evaluation for distant metastatic disease prior to undergoing a lymph node dissection. Therapeutic axillary dissections for melanoma should include complete dissection of levels I, II, and III and carries approximately a 10% risk of lymphedema in the upper extremity. Therapeutic inguinal dissections most commonly consist of a superficial groin dissection. A deep groin dissection (with removal of external iliac and obturator nodes) is rarely indicated in the era of SLNB when most disease is identified microscopically in the superficial nodal basin, but it should be considered in patients with a positive Cloquet node, bulky nodal disease in the superficial groin, or with radiographic evidence of pelvic nodal disease. Inguinal dissection wounds have an infection rate of at least 10% to 15%. The risk of symptomatic lymphedema of the lower extremity is greater than 20%. Early recognition and aggressive measures to treat lymphedema can reduce the morbidity of this complication. The extent of cervical lymphadenectomy depends on the location of the positive node and the presence of direct invasion into the structures of the neck.

Radiation Therapy

The risk of regional recurrence sometimes can be lowered by judicious use of radiation therapy after lymphadenectomy in selected patients at particularly high risk, such as those with four or more positive nodes or bulky nodal disease with extracapsular extension. Although no prospective randomized studies show a superior survival outcome with the addition of postoperative radiation, retrospective studies suggest that radiation may improve regional control in patients with a particularly high risk for local recurrence.

Local Recurrence

Local recurrence rates after appropriate wide local excision are low. With long-term follow-up of intermediate-thickness lesions in the Intergroup Melanoma Trial, 2.1% to 2.6% of patients overall had a local recurrence.⁴¹ Patients at particularly high risk for local recurrence include those with thick primary lesions (≥4 mm) and those with histologic ulceration, desmoplastic features, or a high mitotic rate. Local recurrence can be a sign that the patient either has or soon will have systemic disease. When local recurrence is detected, the minimal systemic workup that should be done includes careful physical examination, chest radiograph, and measurement of liver enzyme levels, including LDH. If any abnormalities are found by this examination, CT scans, a PET scan, or other investigations may be indicated. Local recurrences are treated with wide local excision with 1-cm margins whenever possible.

In-Transit Disease

In-transit metastases of melanoma appear as identifiable tumor nodules in the subcutaneous or cutaneous tissues between a primary site and its nearest draining node basin. Approximately 2% to 4% of patients with melanoma eventually have in-transit disease after excision of the primary melanoma. As with local recurrence, in-transit disease can be a harbinger of impending systemic disease; therefore patients with in-transit disease should undergo a staging evaluation. If limited in-transit lesions are present and they are amenable to excision, wide local excision with negative margins is the standard treatment of choice.

Nodal Recurrence

Patients with recurrence in a previously undissected node basin should undergo evaluation and complete node dissection, as described previously. Recurrence in a previously dissected basin should be evaluated with a staging workup, including CT scans and measurement of liver enzymes, including LDH, and patients should undergo surgical excision of the area of recurrence if no additional evidence of distant metastatic disease is found. Adjuvant radiation therapy can be considered as well.

Isolated Limb Perfusion or Infusion

The indications for isolated limb perfusion or infusion are confined to extensive in-transit lesions or unresectable local recurrences involving an extremity. Limb perfusion with hyperthermia and melphalan has not been shown to improve survival, but it has a role in improving local and regional control for patients with unresectable local recurrence or a large volume of in-transit disease of an extremity. The risk of regional toxicity is significant; isolated limb perfusion should only be performed in centers with experience with the technique, preferably in the setting of a clinical trial. A technique of isolated limb infusion using a low-flow infusion of melphalan and actinomycin without oxygenation via percutaneous catheters is technically simpler and has reported responses similar to those of melphalan limb perfusion with hyperthermia. Overall response rates have been reported at 85% (41% complete response) with a median response duration of 16 months.45,46

Systemic Adjuvant Therapy

Postoperative adjuvant therapy can be considered for patients at high risk for recurrent melanoma. High risk is generally defined as melanomas that are more than 4 mm thick or node-positive (stage III) disease. Adjuvant therapy options include high-dose interferon alfa-2b, a clinical trial, or observation. In 1996, based on a randomized trial showing a survival benefit of 1 year, high-dose interferon alfa-2b was approved by the FDA as adjuvant therapy for patients with resected stage IIB (≥4 mm primary) or stage III (regional lymph node involvement) disease.⁴⁷ A variety of therapies, including vaccines, biochemotherapy, and biologic agents, continue to be evaluated in clinical trials for high-risk patients in the adjuvant setting.

Early Adjuvant Therapy Trials

During the past 40 years, well over 100 randomized adjuvant clinical trials have investigated numerous therapies including cytotoxic chemotherapy, nonspecific immunostimulants such as bacilli Calmette-Guérin, corynebacterium parvum, or levamisole and vaccine approaches, but none has shown any survival benefit in the adjuvant setting. A variety of chemotherapeutic agents, including dacarbazine and combination therapy regimens, showed no benefit in the adjuvant setting, nor did high-dose chemotherapy with autologous bone marrow support or hormonal therapy with megestrol.⁴⁸

High-Dose Interferon Alfa-2b

On the basis of potent immunologic effects of interferon and its modest activity in patients with metastatic melanoma, a series of studies with interferon have been conducted in the postoperative adjuvant setting. Three large published randomized trials conducted by the Eastern Cooperative Oncology Group (ECOG) evaluated 1 year of treatment with high-dose interferon alfa-2b in high-risk patients. All studies defined high-risk patients as those with primary melanomas at least 4 mm thick or with regional lymph node involvement. The high-dose interferon alfa-2b dose schedule was the same in all three studies: 20 million units/m² intravenously (IV) Monday through Friday for 4 weeks, followed by 10 million units/m² subcutaneously (SC) three times a week for the remaining 48 weeks of the year-long treatment course. In ECOG protocol 1684, the first trial, 287 patients were randomly assigned to receive high-dose interferon alfa-2b or no treatment postoperatively. In 1996, a statistically significant DFS benefit (1.72 vs. 0.98 years) and an OS benefit (3.82 vs. 2.78 years) were seen in the interferon alfa-2b arm, at a median follow-up of 6.9 years.⁴⁶ The FDA then approved high-dose interferon alfa-2b for high-risk patients, as defined in this study. However, with longer follow-up and a more mature data set (median follow-up of 12.6 years), the DFS benefit persisted but the OS benefit did not persist (hazard ratio [HR] 1.22; P = .18).⁴⁹

The follow-up study, ECOG protocol 1690, involved a three-way randomization with patients receiving high-dose interferon alfa-2b, low-dose interferon alfa-2b (3 million units/day SC three times a week for 2 years), or no therapy. The study enrolled 642 patients; statistical analysis in this study focused on HRs. At a median follow-up of 4.3 years, high-dose interferon alfa-2b led to a reduction in the risk of recurrence compared with no treatment (HR = 1.28; P = .025). However, no difference in OS was found.⁵⁰ The relapse-free survival (RFS) benefit and lack of OS benefit were confirmed as well with a median follow-up of 6.6 years, although the RFS benefit was no longer significant (HR 1.24; P = .09). Two differences between the studies were that lymphadenectomies were not required for clinical stage II disease in the second study and some of the patients randomly assigned to observation in the second study eventually received high-dose interferon alfa-2b therapy, which was not available to patients during the first study. In ECOG protocol 1694, high-dose interferon alfa-2b was compared with a GM2-ganglioside vaccine in 880 high-risk patients (high risk as defined previously). The Data Safety Monitoring Committee stopped this study early, at a median follow-up of 16 months, because a statistically significant DFS benefit (HR = 1.47; P = .0015) and an OS benefit (HR = 1.52; P = .009) were noted for the high-dose interferon alfa-2b arm. The estimated DFS rate at 2 years for the patients receiving high-dose interferon alfa-2b was superior (62% vs. 49%), as was OS (78% vs. 73%).⁵¹ This study did not include an observation arm; it is impossible to assess whether the vaccine was inferior to or equivalent to no therapy. A pooled analysis of ECOG trials upheld the finding of prolonged RFS, but not OS, in patients treated with high-dose interferon alfa-2b versus observation on two-sided univariate log-rank analysis of E1684 and E1690 pooled data. Multivariate models adjusted for negative prognostic factors also confirmed a significant RFS benefit in pooled populations. A metaanalysis of adjuvant interferon randomized trials also attempted to clarify the varied results. RFS and OS were evaluated; a subgroup analysis was performed according to interferon alfa-2b dose. Again, a significant RFS improvement was seen in those treated with high-dose interferon alfa-2b (three studies) compared with control (HR = 0.83, confidence interval [CI]: 0.77-0.90). However, the benefit in OS was less clear because the CI crossed 1.0 (HR = 0.93, CI 0.85-1.02).^52,53 The same authors have more recently published an abstract of an individual patient data metaanalysis in which they did demonstrate an improvement in both RFS and OS (odds ratio [OR] = 0.9, 0.84-0.97, P = .008). Their data also suggested that patients with ulcerated primary tumors may have derived more benefit from interferon than did patients with no ulceration.⁵⁴ Consistent with these results, another recent metaanalysis including data from 8122 patients and 14 randomized controlled trials has also demonstrated a small but statistically significant improvement in OS (HR = 0.89, 95% CI 0.83-0.96; P = .002).⁵⁵ Subgroup analyses did not demonstrate an optimal interferon-alfa dose and/or treatment duration or a subset of patients more responsive to adjuvant therapy. However, another recent metaanalysis of two randomized trials also demonstrated a greater impact of treatment in patients with ulcerated tumors compared with nonulcerated tumors for both RFS and OS. Most recently, an ongoing large phase III randomized adjuvant study is testing CTLA-4 blockade with ipilimumab compared with high-dose interferon in patients with completely resected high-risk stage III or IV melanoma (ECOG 1609).

High-dose interferon alfa-2b is associated with a number of potential toxicities that necessitate dose reduction in approximately 75% of patients. Adverse effects include fatigue, anorexia, flu-like symptoms, depression, liver abnormalities, and cytopenias. Patients require frequent blood draws—weekly for 4 weeks, and then monthly. Many patients are not candidates for high-dose interferon alfa-2b because of age or co-morbid conditions.

Other Interferon Alfa-2b Schedules

A number of other interferon alfa-2b schedules have been evaluated in the adjuvant setting. Trials of very low-dose, low-dose, or intermediate-dose interferon alfa-2b given for periods ranging from 6 months to 2 years were all ineffective in improving OS. Of note, a trial comparing the 4-week induction high-dose interferon alfa-2b alone versus the standard 52-week regimen did not improve OS.⁵⁶ Another European Organization for Research and Treatment of Cancer protocol (18991) that involved an extended course of pegylated interferon alfa-2b for 5 years versus observation in 1256 patients with stage III melanoma demonstrated improved RFS but not improved OS.⁵⁷

Vaccines

Despite the scientific promise of melanoma vaccines, none has proven beneficial in the adjuvant setting when tested in a randomized clinical trial. A large randomized phase 3 trial (DERMA Phase 3 trial, NCT00796445) of the MAGE-A3 Antigen-Specific Cancer Immunotherapeutic (ASCI) is currently ongoing; the trial was initiated on the basis of results of a prior phase 2 study in patients with metastatic melanoma (NCT00086866) in which objective responses were observed. The MAGE-A3 antigen is expressed in the majority of metastatic melanomas and is a target of antitumor CD4+ and CD8+ T-cells.⁵⁸ The ongoing phase 3 adjuvant study is a double-blind, placebo-controlled, 2 : 1 randomized trial of MAGE-A3 ASCI versus placebo. The MAGE-A3 ASCI combines the tumor-specific antigen MAGE-A3 delivered as a recombinant protein with the immunostimulant AS15.

Granulocyte-Macrophage Colony-Stimulating Factor

Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a colony-stimulating factor approved by the FDA for treatment of bone marrow transplant graft delay or failure and for speeding neutrophil recovery after induction chemotherapy in elderly patients with acute myelogenous leukemia. Based on promising early-phase trial results, a randomized placebo-controlled phase III study of GM-CSF was conducted in patients with resected high-risk stage III and IV melanoma. Adjuvant GM-CSF improved DFS in patients with completely resected high-risk melanoma; no improvement in OS occurred.⁵⁹

Adjuvant Biochemotherapy

Intergroup trial S0008 compared three cycles of biochemotherapy (BCT) with 1 year of high-dose interferon alfa-2b administration in very high-risk patients with stage III disease (i.e., ulcerated primary lesion with regional lymph node involvement, grossly involved or clinically palpable nodes, matted nodes, two or more involved nodes, or satellite lesions). BCT as used in the study consisted of dacarbazine, 800 mg/m² on day 1; cisplatin, 20 mg/m² on days 1 to 4; vinblastine, 1.2 mg/m² on days 1 to 4; interleukin (IL)-2, 9 MIU/m²/day by continuous IV on days 1 to 4; interferon, 5 MU/m²/day SC on days 1 to 4, 8, 10, and 12; and G-CSF, 5 µg/kg/day SC on days 7 to 16. BCT cycles were given every 21 days for three cycles (9 weeks total). Subsequent to this inception of the adjuvant study, data on the use of biochemotherapy in patients with stage IV disease were reported, with no survival benefit compared with combination chemotherapy alone. At a median follow-up of 6 years, BCT improved RFS compared with 1 year of high-dose interferon (HR 0.77, P = .02); no improvement in OS occurred, with a 5-year survival of 56% for both arms.⁶⁰

Neoadjuvant Therapy

Neoadjuvant therapy is not routinely recommended for treatment of regionally advanced melanoma. This approach has been the subject of investigation. A study included patients with stage IIIB-C melanoma who were treated with standard high-dose interferon alfa-2b, IV infusion daily for 4 weeks prior to curative surgical resection, followed by SC injections three times a week for 11 months after resection. Of the 20 enrolled patients, 11 patients demonstrated an objective clinical response and 3 demonstrated a complete pathologic response. Fifty percent of patients were free of recurrent disease at a median follow-up of 18.5 months.⁶¹ However, this approach has not been confirmed in larger or randomized clinical trials.

Surveillance after Primary Therapy

Patients with a history of melanoma should be followed up regularly for evidence of local-regional recurrence, distant metastatic disease, and second primary melanomas, for which they have a cumulative lifetime risk of 2% to 5%. The most important components of surveillance are the history and physical examination. The physical examination should include a thorough skin examination, because the risk of a second primary melanoma is increased for patients who have a history of melanoma. An annual skin examination is recommended for life; more frequent skin examinations are indicated in some patients based on individual risk factors. Regional lymph nodes should be thoroughly examined, especially in patients who have not had surgical resection of nodes. The remainder of the examination should be comprehensive, with awareness of frequent metastases to the skin, lungs, liver, and brain. Patient education is an integral part of the treatment of patients with melanoma; patients should receive instruction on how to perform monthly self-examinations of the skin for detection of new primary melanomas and recurrent disease. Patients should be taught about the clinical characteristics of melanoma and the importance of safe-sun strategies. Educating family members about melanoma risk factors and changes in behavior related to sun exposure is also important.

The optimal follow-up and surveillance program for patients with melanoma has not been defined. To date, no data exist to show that regular screening with radiologic studies affects OS for patients with melanoma. Most series that have examined the value of imaging studies for routine follow-up were retrospective and showed that the majority of recurrences (80%-90%) were discovered by history and physical examination and not by imaging or laboratory studies; many recurrences are detected by the patient. The follow-up schedule and the extent of the evaluation (i.e., blood test or radiographic evaluation) are influenced by the risk of recurrence. For patients with thin melanomas, no specific radiologic or laboratory investigations to detect occult disease are recommended. For patients with melanomas greater than 1 mm in thickness, follow-up studies generally include a complete blood cell count, serum chemistry analyses with liver function tests, and a serum LDH level. An elevated level of LDH may be suggestive of metastatic melanoma but is neither sensitive nor specific. Because the lungs are the most frequent sites of distant disease, periodic chest radiographs may be considered. The routine use of screening CT, MRI, PET (with or without CT), or bone scans is not viewed as necessary but certainly may be performed as clinically indicated. The National Comprehensive Cancer Network has proposed surveillance guidelines. In general, for patients with stage I or II melanoma, regular physical examination and annual skin examination are recommended. Chest radiographs and blood tests for LDH levels are optional. In addition to these tests, CT or PET/CT scanning can be considered for patients with stage III melanoma. Significant variability in clinical practice exists, and thus these guidelines allow for flexibility in follow-up. The clinician should choose a follow-up schedule and selection of tests based on the patient’s risk of recurrence and symptoms and the physician’s experience. Additional studies are needed to define the role of imaging in following patients with a history of melanoma. Earlier detection of metastatic melanoma may be warranted as more effective therapies are developed.

Diagnosis and Evaluation

When metastatic disease is suspected, the diagnosis should be pathologically confirmed whenever possible, which often can be accomplished with a minimally invasive procedure, such as excisional biopsy, fine-needle aspiration, or a core biopsy. Routine staining of the pathology slides plus immunohistochemical staining with S100, HMB-45, and anti–MART-1/Melan-A should confirm the diagnosis of melanoma and differentiate it from other malignancies. The disease should be fully staged with appropriate imaging studies before therapy is initiated. All patients should undergo routine blood work, including a complete blood cell count, a metabolic panel including liver chemistries, and an LDH. Patients should undergo whole-body imaging with either spiral CT scans of the chest, abdomen, and pelvis or a combined PET/CT. A brain MRI scan should be strongly considered in all patients and should always be performed in patients with any neurologic symptoms (including headaches) suggestive of possible CNS metastasis. Patients with bony symptoms should have a bone scan, plain radiographs, or MRI, depending on the clinical assessment.

Role of Surgery in Advanced Melanoma

Because of the limitations of systemic therapy for melanoma, surgery can be an appropriate treatment strategy for isolated metastases. Surgical excision of isolated metastatic melanoma can provide quick and effective palliation and, in some cases, can be associated with long-term survival outcomes.⁶² The decision for metastasectomy should include consideration of any potential therapeutic value of the procedure, as well as the morbidity of the surgery. Patient selection should include consideration of both tumor biology factors (e.g., sites and number of metastatic lesions and disease-free interval) and patient factors (performance status and medical suitability for proposed surgery). Depending on the number of lesions and disease-free interval, systemic therapy or a period of observation can sometimes be considered first in patients who are surgical candidates, followed by repeat imaging and resection if disease progression to additional sites has not occurred.

Cytotoxic Chemotherapy

Numerous cytotoxic chemotherapy agents have demonstrated modest activity in the treatment of metastatic melanoma. However, neither single agent nor combination chemotherapy has been shown to consistently improve OS.

Single Agent Chemotherapy

Dacarbazine (DTIC) remains the only cytotoxic chemotherapy agent approved by the FDA for the treatment of metastatic melanoma. DTIC is an alkylating agent that is converted to its active metabolite, 5-(3-methyl-1-triazeno) imidazole-4-carboxamide (MTIC), in the liver. As a single agent, it has been studied extensively in metastatic melanoma. In early studies, DTIC had an overall response rate of 20%, with 5% of patients achieving complete responses. Most of the patients responding to this treatment had nodal or cutaneous metastases. Subsequent randomized studies showed objective response rates of 5% to 20%.63,64 Responses are not durable, lasting a median of 3 to 4 months, and long-term complete responses are seen in only 1% to 2% of patients. With modern antiemetic agents, DTIC is very well tolerated. Although multiple dosage schedules have been studied, 800 to 1000 mg/m² IV over 1 hour every 3 to 4 weeks is more convenient and at least as effective as any other schedule. The most frequent adverse effects are nausea and vomiting, which can be severe but are well controlled with standard supportive care with antiemetic agents. Mild to moderate myelosuppression is a common dose-related adverse effect. Unfortunately, DTIC has not been proven to provide a survival benefit compared with best supportive care.

Temozolomide, also an alkylating agent, is a pro-drug of MTIC. In contrast to DTIC, temozolomide is orally available and penetrates the blood-brain barrier. It currently is approved by the FDA for the treatment of primary brain tumors but not for melanoma. A phase 2 trial of temozolomide at a dose of 150 to 200 mg/m² orally on days 1 to 5 in a 28-day cycle demonstrated a complete response rate of 5% and an overall response rate of 21%, with some responses in the CNS.⁶⁵ The major adverse effect is mild to moderate myelosuppression. Mild nausea and vomiting also are common but can be readily controlled with standard antiemetic therapy. This schedule of temozolomide was compared with dacarbazine in a phase 3 clinical trial of 305 patients with stage IV melanoma.⁶⁶ Temozolomide was associated with a nonsignificant improvement in median survival (7.7 months compared with 6.4 months with dacarbazine). Response rates were 13.5% and 12.1%, respectively. An extended dosing schedule of temozolomide has been investigated, which comprises a lower daily dose for prolonged periods (75 mg/m² daily for 6 weeks on and 2 weeks off). This dosing regimen of temozolomide is associated with more lymphopenia (selective CD4+ lymphopenia) and opportunistic infections. Pneumocystis pneumonia has been reported. Consideration should be given to prophylaxis against Pneumocystis jiroveci (formerly P. carinii) pneumonia in these patients, especially those who are receiving concomitant radiation. Newer approaches combine temozolomide and other agents, including antiangiogenesis and immunotherapeutic agents. Several chemotherapeutic agents have shown low levels of activity in metastatic melanoma, including the platinum compounds cisplatin and carboplatin, BCNU, vindesine, paclitaxel, docetaxel, fotemustine, and vinorelbine. None has been shown to be superior to DTIC as a single agent, in either efficacy or toxicity profile. The nanoparticle albumin-bound formulation of paclitaxel (nab-paclitaxel) is currently being compared with dacarbazine in a randomized phase 3 clinical trial in patients with metastatic melanoma.

Combination Chemotherapy

Several combination cytotoxic chemotherapy regimens have been evaluated in patients with metastatic melanoma. Examples include the “Dartmouth regimen,” which includes cisplatin, dacarbazine, carmustine, and tamoxifen, or combination cisplatin, vinblastine, and dacarbazine (CVD). Initial phase 2 studies of these regimens were associated with response rates in the range of 30% to 50%. However, as data from larger, multicenter clinical studies have accumulated during the past several years, the high response rates reported in these initial studies have not been reproduced; no evidence exists that combination chemotherapy is more effective than single-agent chemotherapy.⁶⁴ More recently, paclitaxel and carboplatin combination therapies have been evaluated with modest activity in patients with metastatic melanoma.⁶⁷ In summary, at present no evidence indicates that combination chemotherapy is more effective than single-agent chemotherapy with dacarbazine for patients with metastatic melanoma.

Biochemotherapy

BCT is the combination of immunotherapy and cytotoxic chemotherapy (described in the earlier section on adjuvant therapy). BCT has been studied in patients with metastatic melanoma and is associated with considerable toxicity, including myelosuppression, nausea, vomiting, rash, hypotension, and fluid retention. Given the lack of survival benefit and the associated toxicity, BCT is not a standard of care for patients with stage IV melanoma. Two large single-institution randomized phase 3 studies have been reported comparing combination chemotherapy with biochemotherapy. The National Cancer Institute Surgery Branch compared a regimen of cisplatin, DTIC, and tamoxifen with the same regimen followed immediately by high-dose IL-2 and interferon alfa-2b. The overall response rate was higher in the BCT arm, but median survival was superior in the chemotherapy arm (15.8 vs. 10.7 months).⁶⁸ A large randomized Intergroup study led by ECOG (protocol 3695) compared CVD with the combined CVD, IL-2, and interferon alfa-2b regimen, with several modifications, including reducing the dose of vinblastine by 25%, using prophylactic G-CSF, and limiting the number of chemotherapy cycles to four. The overall response rate was 17.1% in the biochemotherapy arm versus 11.4% in the chemotherapy arm, and complete response rates were 3% versus 1.4%, respectively. OS was equally poor in both arms of the study—8.7 months for biochemotherapy versus 8.4 months for chemotherapy.⁶⁹ It is possible that the reduced vinblastine dose and the lack of familiarity by physicians and nurses with the complex biochemotherapy regimen contributed to the low response rates in the cooperative group setting. However, the results indicated that BCT, as given in this trial, leads to very few durable responses and should not be considered a standard therapy.

Immunotherapy

Immunotherapy has emerged as an important treatment strategy for patients with advanced melanoma. A variety of approaches with distinct proposed mechanisms of action have been explored, with an increasing number of agents showing promising results in early- and late-phase studies. These approaches now extend far beyond earlier efforts to develop “therapeutic” cancer vaccines, none of which has yet to be shown to provide any clinical benefit in randomized studies of patients with metastatic melanoma.

An increased mechanistic understanding of T-cell activation and anergy has led to new therapeutic approaches, including the development of ipilimumab, a monoclonal antibody that blocks the CTLA-4 receptor on T cells. Ipilimumab gained regulatory approval in the United States in 2011 and became the first therapy ever to improve overall survival in patients with advanced melanoma. Evidence from numerous studies indicates that the molecule CTLA-4 has a negative regulatory activity on T-cell activation by displacing the T-cell co-stimulatory molecule CD28 from interacting with CD80 and CD86 (also known as B7-1 and B7-2, respectively). As such, CTLA-4 serves a critical role in controlling the immune responses. Blockade of CTLA-4 via administration of ipilimumab results in enhanced antitumor immunity, most likely through direct activation of T cells by releasing the negative regulatory action of CTLA-4. Based on promising results in phase 1 and 2 studies, two large phase 3 trials have been conducted with ipilimumab. In the first study, 676 patients with metastatic melanoma who were previously treated were randomly assigned to one of three arms in a 3 : 1 : 1 ratio: ipilimumab plus peptide vaccine (gp100), ipilimumab alone, or peptide vaccine alone. Ipilimumab (3 mg/kg) and/or peptide vaccine were given every 3 weeks for four doses.⁷⁰ Patients with confirmed partial response (PR) or complete response (CR) were allowed to receive reinduction with their original therapy provided they had not experienced significant toxicity. The median OS was 10.0 and 10.1 months in the arms containing ipilimumab compared with 6.4 months in the peptide-alone arm (HR, 0.68; P < .003). The objective response rate was significantly improved in the groups of patients who received ipilimumab compared with the peptide vaccine–alone arm (5.7% and 10.9% vs. 1.5%, respectively). In a second phase 3 clinical trial, 502 patients with previously untreated metastatic melanoma were randomized to ipilimumab (10 mg/kg) plus dacarbazine (850 mg/m², IV) or dacarbazine plus placebo with maintenance ipilimumab for patients with responding disease and no dose-limiting toxicity. The overall survival in this study was longer in the group receiving ipilimumab plus dacarbazine compared with dacarbazine alone (11.2 months vs. 9.1 months), with higher survival rates in the ipilimumab-dacarbazine group at 1 year (47.3% vs. 36.3%) and at 3 years ( 20.8% vs. 12.2%) (HR for death, 0.72; P < .001).⁷¹ The overall incidence of grade 3 and 4 toxicity was significantly higher in the ipilimumab and chemotherapy arm, especially hepatic toxicity. Objective responses were low (15.2% vs. 10.3%), but the response duration was long: 19.3 months for ipilimumab plus dacarbazine versus 8.1 months for dacarbazine alone. Based on these results, ipilimumab was approved by the FDA for the treatment of unresectable stage III or stage IV melanoma. The FDA-approved dose and schedule is 3 mg/kg IV every 3 weeks for four treatments without maintenance.

Two important features of ipilimumab are unique compared with other standard cancer therapies. First, some patients receiving therapy with ipilimumab have radiographic evidence of disease progression during treatment before disease stabilizes or regresses. Therefore caution should be taken in stopping therapy early. Second, treatment with ipilimumab results in immune-mediated adverse reactions as a result of T-cell activation and proliferation. These immune-mediated reactions may involve any organ system; however, the most common immune adverse reactions are enterocolitis, hepatitis, dermatitis, neuropathy, and endocrinopathy. Endocrinopathies include hypopituitarism and hypothyroidism. The majority of these immune-mediated reactions occur during treatment; however, reactions can occur weeks to months after discontinuation of ipilimumab. Treatment of immune-mediated toxicity requires interruption of ipilimumab and use of corticosteroids depending on the severity of symptoms. Patients receiving ipilimumab require close monitoring with blood tests, including liver and thyroid function, before starting treatment and during treatment. The FDA has created a Risk Evaluation and Mitigation Strategy to provide additional information regarding adverse effects and management of ipilimumab-associated adverse events. Ongoing studies will further define the activity of ipilimumab in the adjuvant setting.

A second investigational approach to inhibit negative regulation of T-cell activation and thereby activate the immune response against melanoma involves use of monoclonal antibodies or other agents to block the programmed death-1 (PD-1)/PD-L1 pathway. PD-1 protein, a T-cell co-inhibitory receptor, and one of its ligands, PD-L1, help mediate the ability of tumor cells to evade the host immune system. In a recent phase 1 study, blocking anti–PD-1 antibody (at escalating doses from 0.1 to 10 mg/kg every 2 weeks) was given IV to patients with advanced melanoma, non–small-cell lung cancer, prostate cancer, renal carcinoma, or colorectal cancer.⁷² Patients received up to 12 cycles until disease progression or a complete response occurred. Among 236 patients in whom response could be evaluated, objective responses (CRs or PRs) were observed in those with melanoma (28%), non–small cell lung cancer (18%), and renal cell carcinoma (27%). The responses were durable, with many lasting more than 1 year. Of 17 patients with PD-L1–negative tumors by immunohistochemistry, none had an objective response, but 9 of 25 patients (36%) with PD-L1–positive tumors had an objective response (P = .006). Grade 3 or 4 drug-related adverse events occurred in 14% of patients, including three deaths from pulmonary toxicity. Like ipilimumab, adverse events consistent with immune-related causes were observed.

In another recently reported phase 1 trial, anti–PD-L1 antibody (at escalating doses ranging from 0.3 to 10 mg/kg) was given to 207 patients with selected advanced cancers, including melanoma (every 14 days IV in 6-week cycles for up to 16 cycles or until the patient had a complete response or confirmed disease progression).⁷³ An objective response (a CR or PR) was observed in 9 of 52 patients with melanoma, as well as a similar or smaller fraction of patients with renal cell cancer, non–small cell lung cancer, and ovarian cancer. Some responses lasted for 1 year or more. Grade 3 or 4 toxic effects related to treatment occurred in 9% of patients.

In immunological contrast to CTLA-4 and PD-1 blockade are efforts to directly activate the immune system. IL-2 (aldesleukin) is a potent T-cell activator and is a well-established and approved therapy that can result in durable complete responses in patients with advanced melanoma. Two large series have been published using the high-dose schedule. The National Cancer Institute reported an overall response rate of 18% and a complete response rate of 5%, with some durable responses.⁷⁴ Similar results were reported in another series.^75,76 Both series noted a few long-term durable responses, some longer than 120 months. The current FDA-approved regimen consists of two 5-day courses of IL-2 separated by a rest period of 7 to 10 days. Two high-dose regimens have been used: 600,000 IU/kg or 720,000 IU/kg, administered every 8 hours. Repeat courses can be given at 8 to 12 weeks if the disease responds to treatment. Typically, two or three courses are given when a good response occurs, with a maximum of five courses. The toxicity of IL-2 is clearly dose related. The most common adverse effects include hypotension, diarrhea, renal dysfunction with oliguria, respiratory failure, fever, chills, and vomiting. Many of the adverse effects of this treatment result from a capillary-leak syndrome caused by the drug. Most of the adverse effects are self-limiting and resolve after discontinuation. Because of low response rates and the substantial toxicity of high-dose IL-2, its use should be restricted to carefully selected patients and should be administered by experienced clinicians at established cancer treatment centers. Careful assessment of cardiac and pulmonary function is mandatory prior to initiation of high-dose IL-2 therapy.

Other dosing regimens include continuous intravenous infusion or subcutaneous administration with lower doses of IL-2. Less serious adverse effects with these alternative doses and methods of delivery have been reported in some studies, but it remains unclear whether efficacy is comparable.

Other immune “activators” continue to be investigated, many showing promise. For example, an agonist antibody against CD40 has produced clinical responses in patients with metastatic melanoma. CD40 is a cell-surface molecule expressed by antigen-presenting cells and regulates immune responses. In a recent trial of 29 patients with advanced solid tumors, 4 patients with melanoma (14% of all patients and 27% of patients with melanoma) had objective partial responses.⁷⁷ Toxicity included mild to moderate cytokine release syndrome but no colitis, endocrinopathies, or other adverse events seen with ipilimumab. Agonist antibodies to other tumor necrosis factor receptor superfamily molecules such as OX40 and CD137 are also being developed.

Cancer vaccines are a form of active immunotherapy, the effects of which depend on target-specific activation of the patient’s immune system. Vaccines directed against melanoma-associated or melanoma-specific proteins (antigens) have proved capable of enhancing antitumor immune responses in patients that can be detected in vitro, and yet have had limited clinical success in advanced metastatic disease. Most melanoma vaccine trials for advanced melanoma have been nonrandomized phase 1/2 studies. These vaccines have included inoculation with whole melanoma cells or gene-modified cells, heat shock proteins, naked DNA, recombinant viral vectors, recombinant proteins, synthetic peptides, and dendritic cells pulsed with peptides or cell lysates.⁷⁸ However, the results of melanoma vaccine trials to date, and cancer vaccine trials overall, have been generally disappointing in the setting of advanced disease, with objective response rates of less than 5%.⁷⁹

Adoptive immunotherapy, a form of passive immunotherapy involving the transfer of ex vivo–expanded tumor-specific T lymphocytes into immune-replete or depleted patients, has been under study for the past two decades as a treatment for advanced metastatic melanoma.⁸⁰ Preclinical models have indicated the potential advantages of removing tumor-specific lymphocytes from the immunosuppressive in vivo milieu and manipulating them in vitro to express a “favorable” phenotype of rapid proliferation and antitumor reactivity (cytokine secretion, cytolysis, and highly avid T-cell receptors) prior to transfer back into the autologous cancer-bearing host. For patients with at least one surgically resectable metastatic lesion, TIL therapy seems to offer the highest probability of objective clinical response. Adoptive TIL transfer in the context of lymphodepleting chemotherapy and high-dose IL-2 has yielded an objective response rate of 51%, including heavily pretreated patients who have not responded previously to high-dose IL-2 therapy.⁸¹ Serious toxicities related to chemotherapy-induced cytopenias and IL-2 administration, as well as some significant autoimmune events, have been encountered. Currently, clinical development of adoptive T-cell transfer still is restricted to a limited number of medical centers because of the complex and intensive nature of this treatment.

BRAF, a member of the MAPK pathway, is somatically mutated in approximately 50% of cutaneous melanomas and leads to constitutive activation of the pathway. Activated BRAF phosphorylates and activates MEK, which then phosphorylates and activates ERK, activating a variety of cytosolic and nuclear targets. The first therapeutic agents targeted against the MAPK pathway, prior to the discovery of activating BRAF mutations, were MEK 1/2 inhibitors.

Sorafenib, a multikinase inhibitor, was initially developed as a CRAF inhibitor and also has activity against mutant and wild-type BRAF, c-KIT, VEGFR-2, VEGFR-3, and flt-3. It did not show objective responses in melanoma as a single agent. Two randomized phase 3 studies of carboplatin and paclitaxel with or without sorafenib for first- or second-line therapy in unselected patients with metastatic melanoma have been completed. In the second-line setting, there was no difference in progression-free survival (PFS) or response rate (RR) with the addition of sorafenib to carboplatin and paclitaxel.⁸² The first-line trial, sponsored by ECOG, accrued and treated 823 patients but was stopped at the third interim analysis for futility.⁶⁷ No difference in OS, PFS, or RR was found between the two arms.

Selective BRAF inhibitors (BRAFIs) have been developed, including vemurafenib and dabrafenib. Vemurafenib is an orally available tyrosine kinase inhibitor that selectively inhibits V600E mutant melanoma and gained FDA approval in 2011. A phase 1 dose escalation study enrolled 55 subjects with V600E BRAF mutant melanoma, the majority with previously treated, poor-risk (M1c) melanoma, and identified 960 mg twice a day as the recommended phase 2 dose (RP2D).⁸³ The most common toxicities seen were primarily low grade and included arthralgias, rash, photosensitivity, cutaneous squamous cell carcinoma (SCC), pruritus, palmar–plantar dysesthesia, nausea, and fatigue. Pharmacodynamic assessments demonstrated reduction in p-ERK, cyclin D1, and Ki-67 staining, as well as a significant decrease in fluorodeoxyglucose uptake on PET scans. Of 16 evaluable patients with V600E BRAF melanoma, a 69% response rate was reported with 10 PRs and 1 CR. Responses were seen at all metastatic sites, including viscera and bone. Vemurafenib had no benefit in the five patients with melanoma who did not have BRAF mutations. The extension cohort enrolled 32 additional patients with V600E BRAF mutant melanoma and yielded an 81% response rate (2 CRs and 24 PRs). A single arm, multicenter phase 2 study in previously treated V600E BRAF mutant metastatic melanoma was completed, with RR as the primary end point.⁸⁴ A confirmed RR of 53% was seen in 132 subjects at a median follow-up of 12.9 months, with a 6% CR rate and a 47% PR rate. The median PFS for the phase 2 study was 6.8 months, with a median duration of response of just 6.7 months. The median OS was 15.9 months. Toxicities were similar in incidence and grade to the phase 1 study with cutaneous SCC and keratoacanthomas (KAs) seen in 26% of patients. Photosensitivity from vemurafenib can be significant, and daily sunscreen use, including lip balm with sunscreen, is recommended in addition to aggressive sun avoidance. BRIM3, the phase 3 study, randomized 675 subjects with previously untreated V600E BRAF mutant metastatic melanoma to vemurafenib or DTIC, 1000 mg/m² IV, every 3 weeks. OS and PFS were the co-primary end points. After interim analysis by an independent Data Safety and Monitoring Board, crossover was permitted. The median OS was 13.6 versus 9.7 months for vemurafenib versus DTIC; the 12-month OS was 56% versus 44%, favoring vemurafenib.⁸⁵ RRs were 57% for vemurafenib with a 5.6% CR rate and 8.6% for DTIC with a 1.2% CR rate. The HR for OS was 0.70, representing a 30% reduction in risk of death with vemurafenib. Twenty-five percent of patients in the DTIC arm crossed over to vemurafenib therapy; 44% received additional therapy, including 22% who went on to receive ipilimumab. The FDA approved vemurafenib for the treatment of metastatic or unresectable melanoma associated with a V600E BRAF mutation in 2011 based on the results of the BRIM3 study.

Dabrafenib, another selective, reversible, adenosine triphosphate–competitive, orally bioavailable inhibitor of V600 BRAF kinase, showed similar preclinical activity in V600E BRAF mutant melanoma. A phase 1 study with an accelerated dose escalation in persons with V600 BRAF mutant solid tumors was conducted with subsequent dose expansions in three cohorts: metastatic melanoma, metastatic melanoma with untreated brain metastases, and nonmelanoma solid tumors.⁸⁶ A total of 184 subjects were enrolled, and 156 had metastatic melanoma; the RP2D was 150 mg twice daily. Common treatment-related adverse events were typically grade 1/2 and included cutaneous SCC/KA (11%), fatigue, and pyrexia in the absence of neutropenia or infection; photosensitivity was not reported. The majority of the BRAF mutations were V600E, but approximately 20% were V600K. Thirty-six patients with BRAF V600 mutant melanoma received the RP2D with a confirmed RR of 50%; in BRAF V600E melanoma only, the confirmed RR was 56% (15/27). A total of 18 patients with V600K BRAF melanoma were treated at any dose with a confirmed RR of 22%. However, many were treated at doses other than 150 mg twice daily. The median PFS for both groups was approximately 5.5 months. No objective responses were seen in K601 BRAF mutants.

BREAK 2, a single-arm phase 2 study of dabrafenib in V600E/K BRAF mutant stage IV melanoma, enrolled 92 patients with a confirmed RR of 59%⁸⁷ and a similar toxicity profile. A multicenter, randomized phase 3 study (BREAK3) was designed to evaluate PFS in patients with metastatic melanoma who had a V600E BRAF mutation. Two hundred fifty patients were randomized (3 : 1) to dabrafenib, 150 mg twice daily, or DTIC, 1000 mg/m² IV every 3 weeks. The majority of patients were previously treated; crossover to the dabrafenib arm was permitted for patients who received DTIC upon progression. Persons with active brain metastases were not permitted to enroll in this study or in the BREAK2 study. Median PFS was 5.1 months versus 2.7 months, favoring dabrafenib. Response rates for dabrafenib and DTIC were similar to those seen in BRIM3: 50% for dabrafenib and 6% for DTIC.⁸⁸

The antitumor activity of dabrafenib in patients with melanoma who have asymptomatic, untreated brain metastases (ranging in size from 3-15 mm) was notable.⁸⁹ Of the 10 treated patients, 9 had a reduction in size of the brain metastases, which correlated with clinical response in extracranial metastases. Four subjects achieved complete resolution of the brain metastases. Melanoma often involves CNS metastasis, which can be difficult to control with local therapies and limited systemic agents that penetrate the blood-brain barrier. The BREAK-MB phase 2 trial evaluated dabrafenib in patients with V600E/K BRAF mutation-positive metastatic melanoma with brain metastases. This trial enrolled 172 patients with asymptomatic brain metastases measuring 0.5 to 4 cm into two cohorts, those with and without prior local therapy to the brain. Of the patients without prior brain treatment, an intracranial (IC) disease control rate (CR + PR + stable disease) of 81% was observed in V600E (n = 74) patients with a median duration of IC response of 20.1 weeks and a median OS of 33.1 weeks; in the V600K patients, the IC disease control rate was 33% (5/15). In the patients who had received prior brain therapy, the IC disease control rate was 89% for V600E patients with a median duration of response of 28.1 weeks (median OS 31.4 weeks) and 50% in V600K patients. Some data exist for CNS activity of vemurafenib. Data regarding vemurafenib activity in V600K BRAF mutant melanoma are limited⁹⁰; however, these patients were excluded from the initial BRIM studies.

The skin toxicities of molecularly targeted agents are frequent and varied.⁹¹ To date, patients treated with selective BRAFI have experienced cutaneous SCCs (predominantly keratoacanthomas), photosensitivity, warty dyskeratomas, verrucous keratoses, darkening of nevi, new nevi, palmar-plantar hyperkeratosis, Grover disease, changes in hair texture and/or color, acnelike rash or milia, and new primary melanomas. Hyperkeratotic skin lesions occur in a majority of patients, with cutaneous SCC or KAs in approximately 10% to 25% on both sun-exposed and non–sun-exposed sites, and they typically present within the first several weeks of therapy. To date, the majority of cases of cutaneous SCC and KAs have been well differentiated, confined to the skin, and easily treated with local procedures. In BRAF wild-type cells exposed to a selective mutant BRAFI, paradoxic activation of the MAPK pathway appears to occur via RAF dimerization and/or signaling via CRAF.^94–94 Upstream mutations, such as RAS, can then lead to further MAPK pathway activation and cellular proliferation, such as proliferation of keratinocytes. Molecular analysis of a series of cutaneous SCC and KAs that developed in patients who were treated with vemurafenib showed higher rates of RAS mutations compared with cutaneous SCC from patients not treated with a BRAFI. ⁹⁵ Other series demonstrated that 60% to 71% of cutaneous SCC/KAs from patients treated with vemurafenib harbored RAS mutations, predominantly HRAS. ^96,97 Rather than supporting the action of BRAFI as a tumor initiator or promoter, in vitro studies support the role of selective BRAFI as a growth accelerant in preexisting RAS-mutant keratinocytes, leading to formation of cutaneous SCCs/KAs.⁹⁸ Similar findings were demonstrated for patients treated with dabrafenib; in these cases, cutaneous SCC, KAs, and benign verrucous keratoses were analyzed and evidenced RAS, PIK3A, and EGFR mutations in many malignant and benign lesions, suggesting that benign verrucous lesions may be a precursor to cutaneous SCC/KAs in this setting.⁹⁹

Clinical investigation of the MEK inhibitor (MEKI) trametinib has demonstrated toxicities typical of other MEKIs, including ocular adverse effects, skin rash, diarrhea, edema, and asymptomatic left ventricular ejection fraction decrease. Treatment with single-agent trametinib demonstrated antitumor activity in BRAF mutant metastatic melanoma with a confirmed RR of 33%, as well as prolonged minor responses in non-BRAF V600 mutated melanoma.⁸⁶ A phase 2 study in patients with BRAF mutant melanoma who had and had not previously received BRAFI therapy demonstrated a similar preliminary response rate of 33% with an 81% disease control rate (CR + PR + SD).¹⁰⁰ However, minimal activity was seen in patients previously treated with a BRAFI with a low PFS of 1.8 months, and thus sequential BRAFI and MEKI therapy is not an effective strategy. A randomized phase 3 study demonstrated improved OS with trametinib compared with DTIC in persons with BRAFI-naïve metastatic melanoma.¹⁰⁰ Crossover to trametinib was permitted when progression occurred upon taking DTIC. PFS was the primary end point. Trametinib demonstrated an improvement in PFS of 4.8 months versus 1.5 months for chemotherapy (HR = 0.45; P < .001). Trametinib also demonstrated an improvement in OS at 6 months of 81% versus 67% (HR = 0.54; P = .01). Fifty-one (out of 108) patients on the chemotherapy arm crossed over to trametinib therapy, and other patients on the chemotherapy arm went on to receive vemurafenib or ipilimumab, two agents established to improve OS.

A phase 1/2 trial of dabrafenib in combination with trametinib demonstrated a confirmed RR of 56% (4 CR +39 PR) and a PFS of 7.4 months. A lower incidence of skin toxicities was seen for the combination than was seen with both agents as monotherapy, including a lower incidence of cutaneous SCC/KAs.101,102 Phase 3 studies evaluating the combination in advanced disease are ongoing.

A small percentage of patients with V600 BRAF mutant melanoma do not respond to selective BRAFI. The mechanism(s) of innate resistance is uncertain but is likely related to the preexisting genetic/molecular profiles of the tumors. Secondary BRAFI resistance is also related to preexisting as well as acquired additional genetic and molecular changes. The average duration of benefit from treatment with selective BRAFI is 6 to 7 months. Although some patients progress rapidly, others experience slow progression that is isolated to one or few metastases, suggesting multiple varied mechanisms of resistance. The mechanisms of resistance can be divided into MEK-dependent and MEK-independent mechanisms. The MEK-dependent mechanisms center around reactivation of the MAPK pathway through a variety of alterations, including NRAS mutation or receptor tyrosine kinase (RTK) activation, increased CRAF activity, BRAF amplification or truncation/splice variants, or MEK1 mutations. MEK-independent mechanisms that have been described include overexpression of RTKs or RTK ligands and PI3K-AKT activation through PTEN loss/depletion.105–105

In summary, BRAF mutational analysis is now a standard of care in the treatment of advanced, unresectable melanoma. Although the greatest activity is in V600E mutant melanoma, BRAFIs do have some activity in V600K mutant melanoma and possibly in other V600 variants. BRAFI therapy is not indicated for patients without BRAF mutations. Multiple resistance mechanisms appear to play a role in both innate and acquired resistance to targeted therapy. Tailored combination strategies may result in prolonged clinical benefit.

Treatment of Approach to Advanced Melanoma

For patients with metastatic melanoma with V600 activating BRAF mutation, treatment with vemurafenib is suggested, particularly in patients for whom a prompt response to treatment is desirable because of symptoms or bulky disease. In addition, a number of clinical trials are available for patients with V600E mutations that are designed to evaluate other BRAF-targeted agents, either as single agent or combined with other targeted therapies or immunotherapies. Ipilimumab rather than vemurafenib as first-line therapy could also be considered in patients with limited metastatic disease and/or symptoms.

For patients whose tumors do not contain BRAF mutation, treatment with ipilimumab rather than cytotoxic chemotherapy is suggested. High-dose IL-2 can be considered for patients who have access to treatment centers where high-dose IL-2 is available if the patient is able to tolerate the toxicity associated with IL-2.

Ending Treatment/Palliative Care

Patients with a poor performance status, co-morbid conditions, multiple brain metastases, or advanced age are unlikely to benefit from intensive systemic therapy. These patients also may experience more adverse effects than healthier patients from the currently available therapies. Providing comfort measures only may be a reasonable option in some patients with metastatic melanoma. Likewise, if first-line therapy for metastatic melanoma has been unsuccessful, the patient should undergo a thoughtful assessment of his or her overall status before additional antitumor therapy is given. In any case, supportive care and comfort measures are essential aspects of oncologic practice.

Brain Metastasis

Patients with brain metastases generally do poorly. Standard therapy is whole-brain irradiation, which offers some palliation. Patients with a solitary brain lesion and no disease elsewhere, or with responding or slowly growing systemic disease, should undergo strong consideration for neurosurgical resection, stereotactic radiosurgery, or gamma-knife therapy. For patients with multiple brain metastases and a good performance status, consideration should be given to stereotactic radiosurgery or gamma-knife surgery after whole-brain radiation. Patients with brain metastases should also be considered for systemic therapy, in addition to local measures. In the appropriate setting, these approaches can provide significant local control and palliation.

Ocular Melanoma

Ocular melanoma is rare. Uveal melanomas can arise from the choroid, ciliary body, or iris, which comprise the uveal tract of the eye and represent the most common intraocular malignancy in the United States. Although ocular melanoma can be morphologically similar to cutaneous melanoma, clinically it behaves differently. Risk factors include light eye color, fair skin, propensity to sunburn, cutaneous and iris nevi, and exposure to UV light. Primary ocular melanoma most often is treated with iodine-125 plaque brachytherapy or enucleation with a very high cure rate. Ocular melanoma metastasizes via a hematogenous route, often spreading primarily to the liver. The metastatic process can occur relatively slowly, with several years passing before recurrence with metastatic disease. Several clinical trials have demonstrated that uveal melanoma responds less often to chemotherapy and biologic therapy. Palliative liver-directed therapy with chemoembolization or hepatic artery infusion can provide local control, but no evidence exists of any overall survival benefit for any therapy in persons with advanced uveal melanoma. The prognosis is poor; patients can be encouraged to participate in clinical trials.

Loss of DNA on chromosome 3 confers a poor prognosis in persons with uveal melanoma in addition to correlating with a molecular classification that also confers poor prognosis (class 2) based on a 15-gene expression profile assay.110,111 The assay identifies two distinct groups: class 1 (low risk of metastases/death) and class 2 (high risk) and has been prospectively validated. On multivariate analysis, the gene expression profile has independent association with risk of metastasis.

Several novel molecular findings have further elucidated the basis of the distinct clinical behavior of uveal melanoma. Oncogenes GNAQ and GNA11 carry activating somatic mutations in 83% of uveal melanomas.112,113 Although targeting downstream effectors of GNAQ signaling may represent one therapeutic strategy, preliminary efficacy results with MEKI have been modest, suggesting that the pathway may not be the primary driving pathway in the setting of metastatic disease. More recently, a high frequency of BRCA1-associated protein 1 (BAP1) mutation has been reported in metastasizing uveal melanoma. The group initially sequenced two tumors with chromosome 3 monosomy and found BAP1 to be the only chromosome 3 gene mutated in both tumors, both of which also exhibited the class 2 poor prognosis signature. Both tumors contained somatic inactivating mutations in BAP1; corresponding normal DNA samples did not contain the mutations. Further sequencing of 29 class 2 and 26 class 1 uveal melanomas identified BAP1 mutations as being present in 84% of class 2 tumors and in only one of 26 class 1 tumors. Chromosome 3 monosomy was present in all BAP1-mutant class 2 tumors for which cytogenetic data were available, suggesting BAP1 loss of heterozygosity as a possible mechanism of pathogenesis in uveal melanoma. Of note, even class 2 tumors in which BAP1 mutations were not identified expressed very low levels of BAP1 messenger RNA, the mechanism of which is not known at this time, strengthening the concept of impaired BAP1 function as a mechanism of pathogenesis in metastatic uveal melanoma. No correlation was found between GNAQ and BAP1 mutation status.¹¹⁴ Uveal melanoma is highly aggressive and presents a clinically significant unmet need in cancer therapeutics, because no approved effective treatments are available once it has metastasized. The development of novel targeted agents with a specific focus on uveal melanoma will significantly affect both treatment rates and clinical outcomes in this patient population. Although some patients with primarily liver metastases appear to benefit from chemoembolization or liver perfusion, the identification of new molecular signatures in uveal melanoma, including alterations in GNAQ, GNA11, and BAP1, has led to novel trials of targeted therapy and epigenetically directed approaches.

In addition to uveal melanomas, conjunctival melanomas constitute approximately 5% of ocular melanomas. Regional lymph nodes can be involved, and a disease-specific TNM staging system is used. These lesions are managed with surgical resection with cryotherapy and topical alcohol. There is a high rate of local recurrence, which can be reduced with adjuvant radiation or topical mitomycin C, although topical treatment-related adverse effects are common.¹¹⁵

Mucosal Melanoma

Mucosal melanoma represents a rare subtype of melanoma with distinct biological, clinical, and management considerations.¹¹⁶ Mucosal melanomas arise from melanocytes in epithelial lining of the respiratory, gastrointestinal, and genitourinary tracts. The anatomic sites at which mucosal melanomas most often originate are the head and neck, vulvo-vaginal, and anorectal regions. Patients often present with advanced disease at the time of initial diagnosis because primary sites in locations such as the gastrointestinal tract or sinuses make early detection difficult. The median age at diagnosis is higher than for cutaneous melanoma, and mucosal melanoma tends to be more common in women. Mucosal melanomas make up a greater proportion of all melanomas diagnosed in Black, Asian, and Hispanic patients, reflecting the much lower prevalence of cutaneous melanomas in these populations. The understanding of the pathogenesis of mucosal melanoma is limited, and clear risk factors have not been described. Exposure to sunlight, which is important in the development of cutaneous melanoma, plays no role in the development of mucosal melanomas. More recently, the molecular pathogenesis of mucosal melanoma has provided new insights into this disease, with the potential for new therapeutic strategies. Mucosal melanomas are associated with activating mutations and/or amplifications in KIT, which may confer sensitivity to c-KIT inhibition.¹⁸ BRAF and NRAS mutations are rare in mucosal melanomas.

The current AJCC staging system for cutaneous melanoma has limited applicability to mucosal melanoma because tumor thickness as a prognostic factor has not been established. Regional node disease develops in the majority of patients with mucosal melanoma. A simplified staging system, as originally developed for melanoma, is often used. Stage I disease is localized to the primary site, stage II is regional nodal involvement, and stage III is distant, metastatic disease.