Skin Cancer - Melanoma

Updated: Jun 21, 2018
  • Author: Michael R Holtel, MD; Chief Editor: Arlen D Meyers, MD, MBA  more...
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Despite declines in the incidence and mortality of cancer overall, the incidence of cutaneous melanoma continues to escalate, with the National Cancer Institute (NCI) reporting that the rate of new cases of melanoma of the skin has been increasing by an average of 1.5% annually. The NCI estimated that 91,270 new cases of skin melanoma would be diagnosed in the United States in 2018. Based on 2011-2015 statistics, 22.8 new cases of skin melanoma per 100,000 US men and women develop annually, while 2013-2015 data indicate that at some time in their lives, about 2.3% of US men and women will be diagnosed with skin melanoma. [1]  Approximately 10-20% of all melanomas of the skin arise in the head and neck region.

Although the rate for new cases of skin melanoma in the United States has grown, the mortality rate decreased by an average of 1.2% per year between 2006 and 2015. The 5-year survival rate for melanoma of the skin rose from 81.8% in 1975 to 93.7% in 2010, with the NCI estimating that 9320 people would die of the disease in 2018. [1]

Of the lesions that develop in the head and neck region, most melanomas arise in the face (47%). The remainder are found on the neck, which accounts for 29%, the scalp (14%), and the ear (10%). In addition, approximately 55% of mucosal melanomas are found in the head and neck.

Risk factors

Many risk factors for melanoma have been identified. The most important risk factor is exposure to sunlight, particularly UV-B radiation. Recent studies suggest that cutaneous melanomas of the head and neck are significantly more likely to occur in people with high levels of total sun exposure. Conversely, melanomas on the trunk tend to develop on people with lower levels of ambient sunlight exposure, but who also experience higher levels of recreational exposure on the chest and back. Sunburns early in life and exposure to UV radiation from tanning beds are other factors in the development of melanoma.

People who burn easily, such as those with fair or red hair, blue eyes, and light-colored skin, are most prone to develop melanoma. The presence of freckling and benign nevi also indicates an increased risk for melanoma development. The number of nevi appears to be more important than the size. The presence of more than 100 benign-appearing nevi in adults or greater than 50 clinically normal nevi in children increases risk.

Additionally, a patient with any atypical or dysplastic nevi is at a heightened risk. Patients with a previously diagnosed melanoma are also at increased risk, and 5-10% eventually develop a second primary.

Finally, genetics may play a role. Patients having at least one affected first-degree relative possess a higher likelihood of developing malignant melanoma. The CDKN2A (p16) chromosomal mutation is the most commonly isolated genetic culprit. [2, 3]

For patient education resources, see the Cancer and Tumors Center, as well as Skin Cancer and Skin Biopsy.



Despite great advances in the treatment of melanoma, the best hope for patients remains early diagnosis. Most melanomas are initially discovered by the patient or his/her partner. Classic warning signs and symptoms include any cutaneous lesion that changes color, size, or shape. Persistent pruritus is also a common early symptom. More advanced lesions frequently become friable, tender, painful, crusted, or ulcerated.

The American Cancer Society developed the ABCDEs to serve as a simple guideline of early melanoma warning signs. Melanoma should be suspected in any skin lesion that is A symmetric, that has an irregular B order, that is variegated or dark in C olor, that is larger than 6 mm in D iameter, or that is E levated. Experienced visual inspection is often the key to distinguishing a melanoma from other common benign pigmented skin lesions, such as: lentigo simplex, junctional nevus, compound nevus, intradermal nevus, blue nevus, solar lentigo, seborrheic keratosis.

Although less than 25% of melanomas are initially diagnosed during routine office examinations, those that are found by physicians tend to be thinner. Thus, a regular full-body cutaneous examination by the primary care provider is crucial to diagnosis at an early stage. The entire cutaneous surface of the head and neck should be examined, paying particular attention to sun-exposed areas. Certain areas are often overlooked: the scalp, the oral cavity, and the neck. The scalp can easily be examined by using a comb to separate the hair. The oral cavity is often forgotten in the search for melanoma; however, its importance cannot be understated. To achieve any hope of curing a mucosal melanoma, oral pigmented lesions must be found and a biopsy sample obtained early. The neck is important in the search for regional metastases.

Types of Cutaneous Malignant Melanoma

The 3 main types of cutaneous malignant melanoma on the head and neck are superficial spreading, lentigo maligna, and nodular lesions. [4] Other, more rare, subtypes include desmoplastic and mucosal lesions. [5]

Superficial spreading melanoma accounts for approximately 50% of all head and neck melanomas. The growth of superficial spreading melanoma is biphasic, with an initial radial growth phase, when growth is confined to the epidermis, followed by a vertical phase, when melanocytes invade deeply into the papillary and reticular dermis.

Approximately 20% of head and neck melanomas are of the lentigo maligna (LM) type. These typically are flat melanomas with a long radial growth phase. Lentigo maligna are regarded as the least invasive form of melanoma. These lesions commonly arise in sun-exposed areas, particularly the face, neck, and extremities. [6]

Nodular melanomas are aggressive lesions that have only a vertical growth phase. These lesions make up 15-30% of head and neck melanomas.

Desmoplastic melanomas (DM) are a rare subtype of melanoma. Although they account for only 1% of all cutaneous lesions, more than 75% of them are found within the head and neck region. The clinical presentation of desmoplastic melanomas is unique, and these tumors do not generally adhere to the ABCDE criteria that typify more traditional cutaneous lesions. They are often found in conjunction with LM lesions. DM tumors tend to be locally aggressive and highly infiltrative. Consequently, they are frequently associated with involvement of the cranial nerves and skull base. Approximately half of these lesions recur.

Mucosal melanoma is a rare form of melanoma that accounts for approximately 1-4% of cases of head and neck melanoma. Most of these tumors (55%) arise in the nasal cavity, followed by the oral cavity (40%). Although the growth patterns of mucosal melanoma tend to mirror the nodular pattern of their cutaneous counterparts, they differ in that tumoral thickness is not well correlated with the prognosis. Although most patients present with clinically localized disease, over 50% experience local recurrence after treatment. Prognosis is dismal, regardless of the thickness of the primary lesion. In the literature, mean 5-year survival rates range from 0-44%. [7]


In 2002, the American Joint Committee on Cancer (AJCC) Melanoma Task Force revised the staging system for cutaneous melanomas based upon the results of their multi-institutional study of 17,600 patients. Staging adheres to the traditional tumor-node-metastasis (TNM) classification system. This system classifies melanomas on the basis of their local, regional, and distant characteristics, as follows:

  • Stage I and II - Localized primary melanoma

  • Stage III - Metastasis to single regional lymph node basin (with or without in-transit metastases)

  • Stage IV – Distant metastatic disease

Clark levels

Two popular microstaging systems for melanoma are the Clark levels and the Breslow thickness classifications. The Clark method is used to stage the melanoma according to its depth of penetration into the deep levels of skin, as follows:

  • Level I - Confined to the epidermis

  • Level II - Spread into the papillary dermis

  • Level III - Spread into the papillary dermis–reticular dermis junction

  • Level IV - Spread into the reticular dermis

  • Level V - Spread into the subcutaneous fat

In the Clark system, level I or II lesions are typically tumors growing in the radial phase. Level III and higher tumors have reached the vertical growth phase. In their study, the AJCC Melanoma Task Force determined that the Clark level is an independent predictive feature for thin melanomas (T1) but not for thicker lesions. Therefore, the level of invasion is currently only considered for thin melanomas.

Breslow thickness

The Breslow thickness classification is used to stage melanoma according to the thickness of the lesion, as measured from the granular layer of the epidermis to the deepest point of tumor infiltration in the vertical dimension. The system is as follows:

  • Less than 0.76 mm - Thin lesion (T1)

  • 0.76-1.50 mm - Intermediate thickness (T2)

  • 1.51-4.00 mm - Intermediate thickness (T3)

  • More than 4 mm - Thick lesion (T4)

The Breslow thickness classification is generally the most widely accepted method because its results are most consistently reproducible. Based on the results of the Melanoma Task Force study, the revised AJCC staging system modified this classification system to use even-integer cut points of 1, 2, and 4 mm.

Prognostic Factors

Overall, the 2 most important prognostic factors for cutaneous melanoma of the head and neck are as follows:

  • The thickness of the tumor [8]

  • The status of the regional lymph-node basin.

Prognostic indicators can be further subdivided based on TNM staging. When considering localized disease (T classification), tumor thickness is the most significant prognostic indicator; however, the presence of ulceration has also been found to be an important predictor of outcome.

Three statistically significant prognostic factors have been identified in regional disease (N classification). The most important indicator for patients with nodal metastasis is the number of positive lymph nodes. Tumor burden within the lymph nodes (microscopic vs macroscopic disease) and ulceration of the primary tumor are also important factors.

Finally, in patients with distant metastases (M classification), the anatomic site of spread is the most important indicator of prognosis. Patients with involvement of the skin, subcutaneous tissues, or distant lymph nodes have a better prognosis than those with metastases to the lungs or visceral organs.

Although not included in formal staging systems, the anatomic location of primary lesions has also been found to correlate with prognosis. In their review of 5093 patients, Garbe et al discovered significantly lower 10-year survival rates for cutaneous melanoma on the head and neck (54%) than for those on the trunk (61%), the upper extremities (76%), or lower extremities (71%). [9] Furthermore, the prognosis for patients with lesions on the face appears to be more favorable than for those with cutaneous melanoma of the scalp or neck.

A retrospective study by Tellez et al suggested that cutaneous melanoma is more dangerous when found in women who are pregnant or have given birth within the past year. The study found that 12.5% of women diagnosed during or within a year after pregnancy had posttreatment cancer recurrence and that 25% had metastasis, versus 1.4% and 12.7%, respectively, of other women in the report. (Follow-up was typically at least 7 years.) However, the investigators cautioned that because the medical center where the study was conducted tended to see more complex cases, the study results might not be universally illustrative. [10, 11]


Treatment & Management


The prognosis and treatment of cutaneous melanoma depends greatly on the thickness of the lesion. Thus, the key to evaluation of suspected lesions focuses on obtaining a full-thickness biopsy. Excisional biopsy is the best choice for small lesions or for large lesions in cosmetically favorable locations. Excisional biopsy should extend down to the subcutaneous fat, with a small (2-3 mm) peripheral margin. Punch biopsy can be performed for large lesions or for lesions with a low suspicion of melanoma in a cosmetically unfavorable location. The biopsy should be performed at the highest or thickest point of the lesion.

Incisional biopsy is not recommended. Likewise, techniques that do not permit a full-thickness sample, such as shave or curette biopsy, are discouraged. Furthermore, pigmented lesions should not be definitively treated with laser therapy, electrocautery, or cryotherapy unless biopsy analysis proves them to be noncancerous.


To date, 4 prospective, randomized trials have been conducted to determine adequate margins of resection. Veronesi et al in 1988, Balch et al in 1993, Banzet et al in 1993, and Cohn-Cedermark et al in 2000 each examined the local recurrence rates for melanomas of varying thickness. [12, 13, 14, 15] On the basis of their results, margins of 0.5 cm are recommended for melanoma in situ, margins of 1 cm are proposed for lesions smaller than 1 mm, margins of 1-2 cm are proposed for lesions of 1.01-2.0 mm thickness, and margins of 2 cm are proposed for lesions larger than 2 mm. In general, the margin of excision should be approximately 10 times as wide as the deepest penetration of tumor; therefore, a 2-cm margin is recommended for a lesion that is 2 mm thick.

Surgeons operating in the head and neck face the difficult dilemma of removing enough tissue to obtain adequate tumor-free margins yet retaining normal tissue in a cosmetically sensitive area. The desire to retain tissue may contribute to the generally increased recurrence rate of head and neck melanoma.

Mohs surgery

The indications for Mohs micrographic surgery (MMS) have been widely expanded in recent years. The American Academy of Dermatology has now recognized Mohs micrographic surgery as a useful technique for the treatment of melanoma, particularly of the face. The National Institutes of Health also recognizes Mohs surgery as a potentially useful technique for melanoma. However, in its 1997 Melanoma Surgical Practice Guidelines, the Society of Surgical Oncology maintains that Mohs surgery is inappropriate for the treatment of melanoma.

In 1997, Zitelli et al showed that the 5-year survival and metastatic control rates for Mohs surgery were equivalent to or better than rates in matched historical controls treated with wide local excision. [16] Using the Mohs technique, the authors were able to spare normal tissue because 83% of the tumors were excised with a 6-mm margin. These results were confirmed by Bricca et al in their review of 625 patients who underwent MMS for primary cutaneous melanoma. [17] MMS demonstrated lower overall recurrence rates (0.2% versus 9%) and lower metastasis rates (across all Breslow thickness groups) when compared with treatment with conventional surgery.

Despite these promising results, MMS is not currently considered the standard of care for cutaneous melanoma of the head and neck. More study is required before any recommendations can be made regarding its use.


Management of the Lymphatic Basin

Elective dissection of the lymph nodes

For most solid tumors, including cutaneous malignant melanoma, the most powerful predictor of survival is the status of the regional lymph nodes. As the understanding of the tumor biology of malignant melanoma continues to evolve, the traditional role for lymphadenectomy in the evaluation of at-risk regional nodes has been challenged.

For a patient with clinical evidence of regional nodal metastases at presentation, lymph node dissection with treatment of the primary lesion is appropriate. The procedure can often be selective neck dissection to remove the specific lymphatic sites involved with disease because of the tendency of regional melanoma metastases to grow in a pushing rather than an invasive fashion. For clinically evident, extensive regional metastases in the neck, comprehensive neck dissection is appropriate.

The site of the primary lesion must be considered when neck dissection is planned in order to remove all intervening lymphatic drainage to the suspicious or positive node. The primary site must also be considered when one plans elective lymph node dissection (ELND) for clinically negative necks. For primary lesions involving the parietal or frontal scalp, temple, lateral forehead, lateral cheek, or ear, superficial parotidectomy in conjunction with neck dissection is appropriate because the parotid may harbor the primary echelon nodes. For a primary lesion on the scalp posterior to a line drawn from the tragus to the vertex of the scalp, posterior-lateral neck dissection, which includes the postauricular, suboccipital, external jugular, and posterior triangle nodal groups, is appropriate. For the patient with an unknown primary lesion with evidence of neck nodal disease, a level I-V comprehensive neck dissection is appropriate.

Notable controversy arises in the treatment of the clinically negative nodal basin. For thin (1.0 mm) melanomas, the risk of occult lymphatic metastases is sufficiently low that prophylactic neck dissection is unwarranted. Patients with thick (>4.0 mm) melanomas have a poor prognosis, and prophylactic neck dissection does nothing to alter that prognosis. The strongest support for elective treatment of the clinically negative nodal basin is for melanomas of intermediate thickness (1.01-4.00 mm).

Several retrospective studies have demonstrated a possible survival benefit for elective treatment of the clinically negative nodal basin; however, data from 2 large prospective multicenter trials failed to show such an advantage. The Intergroup Melanoma Surgical Trial (IMST) was the first prospective, randomized trial to show a survival benefit in patients with melanoma treated with elective node dissection. However, this benefit was limited to a subset of patients 60 years of age and younger, as well as those whose tumor was nonulcerated or measured 1-2 mm in thickness.

Thus, until recently, a strong argument could be made for the “wait-and-see approach” to the clinically negative nodal basin because of the morbidity of dissection without evidence of a clear survival benefit. That is, until results of the Eastern Cooperative Oncology Group trial of high-dose interferon (IFN) alfa-2b as adjuvant treatment for high-risk melanomas indicated that elective nodal dissection should not be delayed until disease is clinically detectable. [18] In this randomized prospective trial, the relapse-free survival and overall survival rates improved in patients treated with IFN alfa-2b versus controls subjects. Striking differences were noted in a small subset of patients who had occult nodal metastases treated with IFN versus control. Data from this trial strongly support an elective nodal staging procedure in all patients with intermediate-thickness malignant melanoma.

Biopsy of sentinel lymph nodes

The concept of the sentinel lymph node (SLN), as Morton first described it, has emerged as a potential solution to the debate over elective node dissection. [19] The SLN is the first node in the drainage pattern of a tumor. In theory, malignant cells must pass through the SLN before continuing on to second-echelon nodes. Therefore, by sampling the SLN, the surgeon can detect the earliest evidence of regional disease in the clinically negative nodal basin.

The techniques of biopsy and examination of the SLN have evolved rapidly over the past few years. In the current technique, radioactive material and/or blue dye is injected at the periphery of the tumor. Preoperative lymphoscintigraphy, in addition to an intraoperative, handheld gamma probe, is then used to locate the first lymph node(s) draining the tumor. These nodes are excised and sent for pathologic evaluation. Patients with pathologically positive SLNs receive therapeutic nodal dissection.

Over a decade of experience has consistently demonstrated that intraoperative lymphatic mapping and SLN biopsy function is a highly sensitive surrogate to elective lymph node dissection, accurately reflecting the histologic status of the entire nodal basin. With the combination of blue dye and gamma probe lymphoscintigraphy, SLN biopsy has a success rate of over 90%, with a false-negative rate of 2% or less.

The technique of SLN biopsy has many potential advantages over ELND. First, preoperative lymphoscintigraphy has the ability to identify all nodal basins involved in the drainage of the primary tumor. Conversely, ELND has traditionally been directed at the most likely site of nodal drainage. Several lymphoscintigraphy studies have revealed that a significant number of tumors drain to either multiple or unpredictable nodal basins. This is particularly true for lesions developing in areas with rich lymphatics, such as the head and neck.

This was confirmed by O’Brien et al, who reported a 34% rate of discordance between clinically predicted lymphatic drainage pathways and the pathways found during lymphoscintigraphy of 97 patients with cutaneous head and neck melanoma. [20] Thus, elective nodal dissection can be misdirected in up to one third of cases. By contrast, SLN biopsy targets the most likely node basins to present with metastatic disease, thereby providing surgeons with more accurate information for prognosis and staging.

A second advantage of SLN biopsy over ELND stems from the fact that an average of 1-3 nodes are excised, rather than an entire nodal basin. This feature allows more thorough examination of the sampled nodes for evidence of metastatic disease. Typical examination of a lymph node involves the staining of 1 or 2 sections through the middle of the node with routine hematoxylin and eosin. Using this technique, less than 1% of the submitted material is scrutinized. This technique is accurate for detecting 1 tumor cell in the background of 1,000 healthy cells.

Newer techniques have been developed to increase the sensitivity of tumor cell detection. These include immunohistochemical techniques, cell culture, and polymerase chain reaction (PCR)–based techniques, which can augment sensitivity up to 1 tumor cell in 100,000 healthy cells, an increase of 2 magnitudes. Nevertheless, these sophisticated methods are too costly and labor intensive to be routinely applied to the entire contents of a lymphatic basin.

The SLN biopsy technique also produces less morbidity than ELND. When lymphoscintigraphy and intraoperative gamma-probe localization is combined with a blue dye technique, the precise location of sentinel lymph nodes can usually be identified in 3 dimensions to within 1 cm. The SLN can then be removed through a skin incision that is often shorter than 1 cm, typically on an outpatient basis.

Sentinel lymph node biopsy in the head and neck

The widespread use of sentinel lymph node (SLN) biopsy in the management of head and neck melanoma has been limited by several concerns. As previously stated, lymphatic drainage in the head and neck region is complex, with multiple primary channels and the potential for multiple SLN sites. [21] Excision of these nodes can also be technically challenging secondary to the small distances between sentinel nodes, making detection and isolation difficult. Furthermore, approximately 25-30% of the sentinel nodes are found within the parotid gland, and concerns of facial nerve injury have led many surgeons to advocate superficial parotidectomy over SLN biopsy. [22] Furthermore, the cooperation of experienced pathologists and nuclear medicine staff are essential to the success of the procedure.

Although several articles have examined the utility of SLN biopsy for malignant melanoma of the head and neck, no clear consensus has been established. A number of papers (including those by Alex et al in 1998, Bostick et al in 1997, Schmalbach et al in 2003, Wagner et al in 2000, and Wells et al in 1997) present convincing evidence that SLN biopsy is a reliable and safe technique for detecting melanoma metastases in the head and neck. [23, 24, 25, 26, 27]

SLNs were successfully localized in greater than 90% of cases. In fact, with the combined use of blue dye mapping and gamma probe lymphoscintigraphy, 5 studies demonstrated success rates of 95% or better. The rate of tumor-containing SLNs ranged from 11-17%, with a 0-4.5% false-negative rate. Additionally, reviews by Schmalbach et al and Loree et al describe accurately localizing intraparotid SLNs in at least 93% of cases. [28, 29] These nodes were subsequently excised without any permanent facial nerve injury. Superficial parotidectomy served as a safe alternative for nodal harvest when the SLN could not be isolated.

Other studies, such as the prospective review by Jansen et al, demonstrate the difficulties of SLN biopsy in the head and neck region. [30] In their series of 30 patients, SLNs were found in 90% of the cases, but 15% of these nodes could not be identified surgically. Furthermore, intraparotid SLNs in 4 of 10 patients were left untouched secondary to concerns of injuring facial nerve branches during dissection. Finally, 2 false-negative SLN specimens were found in the series of 10 patients with lymph node metastases. The sensitivity rate of 80% in this study compares unfavorable with those of previously mentioned articles.

Thus, more long-term studies are clearly required to evaluate whether SLN biopsy will provide any prognostic importance or significant survival benefit in patients with cutaneous melanoma of the head and neck. However, most data suggest that SLN theory applies to the head and neck region and that the technique may be a promising adjunct to management of this devastating disease.

A retrospective study by Evrard et al suggested that in patients with cutaneous head and neck melanoma, SLN biopsy results are a good prognostic indicator. The investigators found that patients with a positive SLN status had a recurrence risk of 69.2%, compared with 30.8% for those with negative SLNs. Additionally, rates for overall and disease-free survival were 49% versus 82% and 41.8% versus 69.3%, respectively. The false omission rate in SLN biopsy was 7.1%. [31]


Medical Treatment

In the treatment of cutaneous melanoma, adjuvant systemic therapy is primarily reserved for 2 subpopulations of patients. The first group of patients is those with Stage IIB or Stage III disease, who are at high risk of recurrence after definitive surgery. This includes individuals with ulcerated lesions, with thick tumors (greater than 4 mm deep), or with nodal metastases. The second subgroup of patients includes those with distant metastases.

Malignant melanoma is known to be a relatively chemoresistant tumor. As such, chemotherapy has yielded poor results and no regimen has been found to definitively impact survival. Dacarbazine (DTIC) has been the only chemotherapeutic agent to demonstrate significant activity against melanoma. Nevertheless, response rates to single-agent therapy with DTIC have been disappointing, averaging 10-20%. Furthermore, even multiagent chemotherapy rarely yields a response rate greater than 40%.

Interferons function as biologic response modifiers, enhancing phagocytosis and free radical production in macrophages, as well as increasing the activity of natural killer cells. Since 1984, a series of 4 Eastern Cooperative Oncology Group (ECOG) and Intergroup trials have evaluated the efficacy of high-dose interferon alfa-2b (IFN alfa-2b) in approximately 2,000 patients with Stage IIB and Stage III melanoma.

Peginterferon alfa-2b is an immunomodulatory cytokine that enhances phagocyte and lymphocyte activity. It was approved by the US Food and Drug Administration (FDA) in March 2011 as adjuvant therapy following definitive surgical resection, including complete lymphadenectomy.

The drug’s approval was based on a 5-year, open-label, multicenter trial in which cancer recurrence was delayed about 9 months longer in patients who took peginterferon alfa-2b than it was in patients who did not take the drug. [32]

The ECOG Trial E1684, the Intergroup Trial E1690, the Intergroup Trial E1694, and the ECOG Trial E2696 collectively confirmed a statistically significant benefit in relapse-free survival (RFS) with high-dose IFN alfa-2b (HDI) therapy versus observation alone. [33, 34, 35] Although the impact on overall survival (OS) varied among the studies, the E1684 trial demonstrated a significant survival benefit associated with HDI versus observation alone, and the E1694 trial illustrated a similar benefit over the ganglioside GM2/keyhole limpet hemocyanin (GMK) vaccine. Based on the results of these trials, the FDA has approved a 52-week adjuvant therapy regimen consisting of HDI administered intravenously 5 days a week for 4 weeks, followed by a maintenance dose of subcutaneous INF alfa-2b given 3 times a week for 48 weeks.

Despite the promise of HDI therapy, the associated side effects and toxicities are not insignificant. Most patients experience flu-like symptoms, and many (20-30%) suffer from severe, intolerable fatigue. Neurologic and psychiatric side effects are also common.

Ipilimumab, a CTLA-4 blocker, has demonstrated remarkable promise in patients with metastatic melanoma. Ipilimumab was approved by the FDA in March 2011 for unresectable or metastatic melanoma. [36, 37]

The first BRAF inhihibor, vemurafenib (Zelboraf), was approved by the FDA in August 2011 for treatment of unresectable or metastatic melanoma with BRAF-V600E mutation as detected by the cobas 4800 BRAF V600 Mutation Test. [38, 37]

Other recent FDA approvals include trametinib (Mekinist), dabrafenib (Tafinlar), and pembrolizumab (Keytruda). Trametinib is a MEK inhibitor indicated for melanoma with BRAF V600E or V600K mutations. Dabrafenib is a BRAF protein kinase inhibitor indicated for melanoma with BRAF V600E mutation. Pembrolizumab is a monoclonal antibody to programed cell death-1 (PD-1) protein. It blocks the interaction between PD-1 and its ligands (ie, PD-L1 and PD-L2). [39]

In October 2015, the FDA approved melanoma treatment with talimogene laherparepvec (Imlygic), a genetically modified, live attenuated herpes simplex virus programmed to replicate within tumors and manufacture an immunostimulatory protein, granulocyte-macrophage colony-stimulating factor (GM-CSF). The first oncolytic viral therapy approved by the FDA, talimogene laherparepvec is indicated for the local treatment of unresectable cutaneous, subcutaneous, and nodal lesions in cases of postsurgery melanoma recurrence. It is administered by injection into lesions that are visible, palpable, or detectable by ultrasonographic guidance. [40, 41]

Vaccines are another alternative for addressing melanoma, and the various vaccination strategies may be divided into 2 categories. Polyvalent tumor-cell vaccines present melanoma-specific antigenic targets to the immune system, thus stimulating antibody and T-cell responses. One such vaccine is currently undergoing Phase III trials at the John Wayne Cancer Center. A second category of vaccines include gangliosides and peptides, which elicit antibody and/or T-cell responses in a more focused and reproducible manner than their polyvalent counterparts. A study conducted at Memorial Sloan-Kettering Cancer Center demonstrated that ganglioside GM2 administered in combination with bacille Calmette-Guérin (BCG) improved RFS and OS in Stage III melanoma patients.

Finally, although melanoma has traditionally been considered a radiation-resistant tumor, data from recent trials show that external-beam radiation may be valuable as an adjuvant therapy for melanoma. For patients with evidence of multiple positive lymph nodes or those with extracapsular spread, postoperative radiation therapy after neck dissection is appropriate. Radiation can also be used to palliate metastatic disease. However, surgery remains the primary treatment modality for most localized melanomas.



The incidence of melanoma of the head and neck has been increasing dramatically in the last several decades. Much of this change is related to increased sun exposure in the general population. For melanoma, like other cancers, the best opportunity for cure is with early and aggressive treatment. The primary treatment of melanoma is wide surgical excision, with most surgeons performing SLND or elective lymphadenectomy for intermediate-thickness lesions. Primary radiation therapy and chemotherapy are usually reserved for palliative treatment in far-advanced lesions. IFN alfa-2b has shown promise as adjuvant therapy of melanoma. Many other adjuvant therapies are under investigation. The greatest hope for controlling this disease lies in careful surveillance and early detection of atypical pigmented lesions.