Skin Cancer - Melanoma

Updated: Oct 13, 2020
  • Author: Michael R Holtel, MD; Chief Editor: Arlen D Meyers, MD, MBA  more...
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Overview

Overview

Epidemiology

Skin cancers are the most common cancers, and malignant melanoma is the most serious form of skin cancer. Melanoma is the fifth most common cancer in the United States. Despite declines in the overall incidence of cancer and the associated mortality rate, 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. According to the American Cancer Society, approximately 100,350 new melanomas were expected to be diagnosed in the United States in 2020, including about 60,190 in men and 40,160 in women. [1] 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. [2]  The American Cancer Society estimates that 6850 people will die from melanoma in 2020.{Ref 82} Approximately 10-20% of all melanomas of the skin arise in the head and neck region.

Although the rate of 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. From 2008-2014, the 5-year survival rate for patients with melanoma of the skin was 98.4% for localized disease, 63.6% for regional disease, and 22.5% for distant/metastatic disease; the overall 5-year survival rate was 91.8%. [2]

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 ultraviolet-B (UV-B) radiation. UV radiation causes multiple genetic changes that lead to malignant transformation of melanocytes. 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 in people with lower levels of ambient sunlight exposure but who also experience intense but intermittent levels of recreational exposure on the chest and back. Sunburns early in life, exposure to UV radiation from tanning beds, and UV-A therapy are other factors in the development of melanoma.

People who burn easily, such as those with fair or red hair, blue eyes, light-colored skin, and poor ability to tan, 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 has a heightened risk. Patients with a previously diagnosed melanoma are also at increased risk, and 5-10% eventually develop a second primary lesion.

Finally, genetics may play a role, as in the case of familial atypical multiple mole and melanoma (FAMMM) syndrome. Patients who have at least one affected first-degree relative have a higher likelihood of developing malignant melanoma. The CDKN2A (p16) chromosomal mutation is the most commonly isolated genetic culprit. [3]  Carriers of two or more of the melanocortin-1 receptor (MC1R) variants on chromosome 16q24 have a two-fold greater risk of melanoma. [4]

Individuals with high risk for melanoma should be given instructions on skin self-examination, as well as on proper sun safety. They should also receive regular dermatologic examinations in which risk stratification protocols are followed. For patient education resources, see the Cancer and Tumors Center, as well as Skin Cancer and Skin Biopsy.

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Diagnosis

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 for early melanoma warning signs. Melanoma should be suspected in any skin lesion that is Asymmetrical, has an irregular Border, is variegated or dark in Color, is larger than 6 mm in Diameter, or is Elevated. 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, and seborrheic keratosis.

Although fewer 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, with particular attention paid 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 overstated. 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 four main types of cutaneous malignant melanoma are superficial spreading, lentigo maligna, nodular, and acral lentiginous. [5] Other, rarer subtypes of melanoma include desmoplastic, amelanotic, spitzoid, and mucosal. [6]

Superficial spreading melanoma accounts for approximately 70% of all melanomas. The growth of superficial spreading melanoma is biphasic. An initial radial growth phase, in which growth is confined to the epidermis, is followed by a vertical phase, during which melanocytes invade deeply into the papillary and reticular dermis. More than 60% of superficial spreading melanomas present as a thin (< 1mm) lesion; these lesions have a high cure rate and may appear in multiple shades of red, blue, gray, black, and white. This type of lesion is most likely associated with a preexisting nevus, even though approximately two thirds of melanomas overall arise without an associated nevus. [7]

Approximately 13% of melanomas are of the lentigo maligna (LM) type. These typically are flat lesions with a long radial growth phase. Lentigo maligna is regarded as the least invasive form of melanoma. These lesions commonly arise in sun-exposed areas, particularly the face, neck, and extremities. [8]  Each lesion begins as a tan or brown macule that enlarges over years to become a darker, asymmetrical foci of pigmentation and color variegation with vertical growth. The incidence of lentigo maligna melanoma is increasing, especially in the older population. [9]

Nodular melanomas are aggressive lesions that have only a vertical growth phase. These lesions make up 15% of melanomas, and most of them are more than 2 mm thick at the time of diagnosis. They appear as darkly pigmented, pedunculated or polypoid papules or nodules.

Acral lentiginous melanoma (ALM) accounts for less than 5% of melanomas. It is the most common type of melanoma in dark-skinned people. The most common locations are palmar, plantar, and subungual areas. Acral lentiginous melanoma has the poorest prognosis compared with other types of melanoma. Hispanic Whites and Asian/Pacific Islanders have poorer survival rates than do members of other ethnic groups, likely because of factors such as increased tumor thickness and more advanced stage at presentation. [10] Acral lentiginous melanoma  is associated with a significantly lower frequency of BRAF mutations, which are often found in melanomas caused by intermittent sun exposure. [11]

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 can be applied to more typical cutaneous lesions. They are often found in conjunction with lentigo maligna lesions. Desmoplastic melanoma 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 prognosis. Although most patients present with clinically localized disease, more than 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%. [12]

Staging

In 2017, the American Joint Committee on Cancer (AJCC) Melanoma Expert Panel revised the staging system for cutaneous melanomas based on the results of their multi-institutional study of more than 46,000 patients. [13, 14, 15] The eighth edition of the AJCC Cancer Staging Manual was implemented in 2018. [16] Staging adheres to the traditional tumor-node-metastasis (TNM) classification system. This system classifies melanomas according to local, regional, and distant characteristics, as follows:

  • Stage I and II - Localized primary melanoma

  • Stage III - Metastasis to regional lymph node basin and/or any number of in-transit, satellite, and/or microsatellite metastases

  • Stage IV - Distant metastatic disease

Clark levels

Two popular microstaging systems for melanoma are the Clark levels and the Breslow thickness classification. 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. Clark levels are no longer considered in the AJCC staging system.

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 Breslow thickness classification was generally the most widely accepted method because its results were the most consistently reproducible. The system has now been replaced by the revised AJCC staging system, which, while also based on the measured vertical tumor thickness, has been updated to better reflect prognostic value according to evidence-based analysis. [13]

Definition of primary tumor(T) [13]

Less than or equal to 1.0 mm - Thin lesion (T1):

  • T1a - Less than 0.8 mm without ulceration
  • T1b - Less than 0.8 mm with ulceration
  • T1b - 0.8-1.0 mm with or without ulceration

Greater than 1.0 mm to 2.0 mm - Intermediate thickness (T2):

  • T2a - Without ulceration
  • T2b - With ulceration

Greater than 2.0 mm to 4.0 mm - Intermediate thickness (T3)

  • T3a - Without ulceration
  • T3b - With ulceration

Greater than 4 mm - Thick lesion (T4):

  • T4a - Without ulceration
  • T4b - With ulceration

Definition of regional lymph nodes (N) [13]

Nx- Regional nodes not assessed

N0- No regional metastases identified

N1 - One tumor-involved node or any number of in-transit, satellite, and/or microsatellite metastases with no tumor-involved nodes

  • N1a - One clinically occult node (ie, detected by sentinel lymph node [SLN] biopsy)
  • N1b - One clinically detected node
  • N1c - No regional lymph node disease with any number of in-transit, satellite, and/or microsatellite metastases

N2 - Two or three tumor-involved nodes or any number of in-transit, satellite, and/or microsatellite metastases with one tumor-involved node

  • N2a- Two or three clinically occult nodes (ie, detected by SLN biopsy)
  • N2b- Two or three nodes, at least one of which was clinically detected
  • N2c- One clinically occult or clinically detected node with any number of in-transit, satellite, and/or microsatellite metastases

N3 - Four or more tumor-involved nodes or any number of in-transit, satellite, and/or microsatellite metastases with two or more tumor-involved nodes, or any number of matted nodes without or with in-transit, satellite, and/or microsatellite metastases

  • N3a - Four or more clinically occult nodes (ie, detected by SLN biopsy)
  • N3b - Four or more nodes, at least one of which was clinically detected, or the presence of any number of matted nodes
  • N3c - Two or more clinically occult or clinically detected nodes and/or the presence of any number of matted nodes, with any number of in-transit, satellite, and/or microsatellite metastases

Definition of distant metastasis (M) [13]

M0 - No evidence of distant metastasis

M1 - Evidence of distant metastasis

M1a - Distant metastasis to skin; soft tissue, including muscle; and/or nonregional lymph node

  • M1a(0) - Lactose dehydrogenase (LDH) level not elevated
  • M1a(1) - LDH level elevated

M1b - Distant metastasis to lung with or without M1a sites of disease

  • M1b(0) - LDH level not elevated
  • M1b(1) - LDH level elevated

M1c - Distant metastasis to non–central nervous system (CNS) visceral sites with or without M1a or M1b sites of disease

  • M1c(0) - LDH level not elevated
  • M1c(1) - LDH level elevated

M1d - Distant metastasis to CNS with or without M1a, M1b, or M1c sites of disease

  • M1d(0) - LDH level not elevated
  • M1d(1) - LDH level elevated

AJCC Clinical Prognostic Stage Groups (cTNM) [13] (Open Table in a new window)

Primary Tumor (T) Regional Lymph Node (N) Distant Metastasis (M)

Clinical Stage Group

Tis* N0 M0 0
T1a N0 M0 Ia
T1b N0 M0 Ib

T2a

N0 M0 Ib
T2b N0 M0 IIa
T3a N0 M0 IIa
T3b N0 M0 IIb
T4a N0 M0 IIb
T4b N0 M0 IIc
Any T, Tis ≥N1 M0 III
Any T Any N M1 IV

*Melanoma in situ 

AJCC Pathologic (pTNM) Prognostic Stage Groups [13] (Open Table in a new window)

T N M  Pathologic Stage Group
Tis N0 M0 0
T1a N0 M0 Ia
T1b N0 M0 Ia
T2a N0 M0 Ib
T2b N0 M0 IIa
T3a N0 M0 IIa
T3b N0 M0 IIb
T4a N0 M0 IIb
T4b N0 M0 IIc
T0 N1b, N1c M0 IIIb
T0 N2b, N2c, N3b or N3c M0 IIIc
T1a/b–T2a N1a or N2a M0 IIIa
T1a/b–T2a N1b/c or N2b M0 IIIb
T2b/T3a N1a–N2b M0 IIIb
T1a–T3a N2c or N3a/b/c M0 IIIc
T3b/T4a Any N ≥N1 M0 IIIc
T4b N1a–N2c M0 IIIc
T4b N3a/b/c M0 IIId
Any T, Tis Any N M1 IV

Prognostic Factors

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

  • The thickness of the tumor [17]
  • The status of the regional lymph-node basin.

Prognostic indicators can be further subdivided based on TNM staging. When localized disease (T classification) is considered, 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%). [18] 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. [19, 20]

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Treatment & Management

Biopsy

The prognosis for and treatment of cutaneous melanoma depend greatly on the thickness of the lesion. Thus, the key to evaluation of suspected lesions is obtaining a full-thickness biopsy specimen. 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 for 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.

Excision

To date, four 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. [21, 22, 23, 24] 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 micrographic surgery

The indications for Mohs micrographic surgery (MMS) have been widely expanded in recent years. The American Academy of Dermatology has now recognized MMS as a useful technique for the treatment of melanoma, particularly of the face. The National Institutes of Health also recognizes MMS as a potentially useful technique for melanoma. However, in its 1997 Melanoma Surgical Practice Guidelines, the Society of Surgical Oncology maintains that MMS is inappropriate for the treatment of melanoma. [25]

In 1997, Zitelli et al showed that the 5-year survival and metastatic control rates for MMS were equivalent to or better than rates for matched historical controls treated with wide local excision. [26] 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. [27] MMS demonstrated lower overall recurrence rates (0.2% vs 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.

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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 gland 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 two 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 ELND. However, this benefit was limited to a subset of patients aged 60 years or younger, as well as those whose tumors were nonulcerated or measured 1-2 mm in thickness. [28]

Thus, a strong argument could previously 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. However, the results of the Eastern Cooperative Oncology Group trial of high-dose interferon (IFN) alfa-2b as adjuvant treatment for high-risk melanomas indicated that ELND should not be delayed until disease is clinically detectable. [29] In this randomized, prospective trial, the relapse-free survival and overall survival rates improved in patients treated with IFN alfa-2b versus control subjects. Striking differences were noted in a small subset of patients who had occult nodal metastases treated with IFN versus the control group. 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. [30] 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. [31] 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. [32] 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. [33] 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. [34, 35, 36, 37, 38]

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. [39, 40] 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. [41] 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%. [42]

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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. Consequently, chemotherapy has yielded poor results, and no regimen has been found that definitively impacts 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%. (DTIC is often used as the control agent in clinical trials to gauge the effectiveness of newer targeted therapies and immunotherapy.) Furthermore, even multiagent chemotherapy such as carboplatin and paclitaxel rarely yields a response rate greater than 40%. Generally speaking, standard chemotherapy has never been shown to induce durable remission or prolong survival in melanoma.

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. [43]

High-dose INF alfa-26 therapy

The Eastern Cooperative Oncology Group (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. [44, 45, 46] 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 demonstrated 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. With the advent of targeted therapies and immunotherapy, HDI treatment for melanoma is no longer considered a first-line treatment for advanced disease.

Inhibitors

An important part of normal cell signaling is the mitogen-activated protein kinase/extracellular signal-regulated kinase, or MAP kinase-ERK, signaling pathway, which is a signaling function that helps to turn cell growth “on” and “off.” Targeted therapies have been developed in an attempt to provide melanoma treatment based on mutations affecting this pathway, so-called “driver” mutations, which contribute to uncontrolled cell division.

BRAF inhibitors

BRAF is a protein kinase that activates the pathway, and BRAF is itself activated by Ras. A mutation affecting BRAF is frequently found in association with cancers. More than 50% of melanomas have a BRAF-activating mutation, and more than 90% are at codon 600 (BRAFV600E, followed by BRAFV600K, in order of frequency). [47] BRAF inhibitors, MEK inhibitors, NRAS inhibitors, and cKIT inhibitors all have the potential for targeting melanomas that have gene mutations affecting the MAPK-ERK pathway.

The first BRAF inhibitor, vemurafenib, was approved by the US Food and Drug Administration (FDA) in August 2011 for the treatment of unresectable or metastatic melanoma with the BRAFV600E mutation. [48, 49] Dabrafenib and encorafenib also directly target the BRAF molecule, and vemurafenib and dabrafenib as single-agent therapy have both been shown to increase survival in patients with metastatic melanoma. [48, 50, 51, 52] However, with single-agent BRAF inhibitor therapy, most survivors will eventually have disease progression. [48] As a result, a combination of BRAF inhibitor with other targeted treatments is preferred in practice. [53]

MEK, NRAS, and cKIT inhibitors

An MEK1 mutation may also occur, leading to tumor cell survival. MEK inhibitors approved by the FDA include trametinib, cobimetinib, and binimetinib. Trametinib has been shown to increase progression-free survival and overall survival as single-agent therapy in patients with metastatic melanoma with the BRAFV600E/K mutations. [54] However, MEK inhibitors are usually used in conjunction with BRAF inhibitors to target both steps in the MAPK/ERK signaling pathway with increased efficacy and the hope of decreased toxicity. The dabrafenib-trametinib and vemurafenib-cobimetinib combinations have both shown further improvements in progression-free survival and overall survival. [55, 52, 56, 57, 58] The binimetinib-encorafenib combination has not been prospectively compared with the other combination therapies, but initial results show the best progression-free survival and overall survival of the combination therapies in patients with BRAFV600 mutation–positive metastatic melanoma. [59]

NRAS and cKIT inhibitors are still undergoing clinical trials for melanoma treatment.

Adverse effects

More than 90% of patients receiving BRAF inhibitor monotherapy will develop cutaneous toxicity, including severe photosensitivity, hyperproliferative epidermal neoplasms, hypertrophic actinic keratosis, painful palmoplantar keratosis, verrucal keratosis, keratosis pilaris-type eruptions, and xerosis. [60, 61, 62] Adverse effects of MEK inhibitor therapy range from acneiform to severe papulopustular eruption, whereas using immune checkpoint inhibitors may be associated with nonspecific morbilliform dermatitis, vitiligo, and lichenoid skin eruption as well as worsening of eczema, psoriasis, sarcoidosis, or autoimmune bullous disease. [63, 64, 65, 66, 67] Collaboration of oncologists and dermatologists in controlling dermatologic toxicities from BRAF/MEK kinase or immune checkpoint inhibitor therapy can help to prevent unnecessary interruption of medication and improve patients’ quality of life.

Immunotherapy

As our understanding of the immune system has advanced, new methods of medical treatment that focus on improving the human immune system to help fight cancer have been developed. Advances in the understanding of melanoma tumor biology and antitumor immunology have resulted in breakthroughs in disease-free survival and even cures in some cases for patients with metastatic melanoma or those with localized melanoma but with a high risk for developing metastases.

The basis of the human cellular immunity response is the T lymphocyte, which recognizes specific antigens through the T-cell receptor (TCR), a surface protein that interacts with the major histocompatibility complex (MHC) molecule on the surface of the antigen-presenting cell (APC). [68] Through this TCR/MHC interaction, the T cell recognizes a specific antigen; however, the activation of the T cell requires another interaction with the APC, [69]  with the first such activation having been discovered through the interaction of CD28 on the T cell with B7 on the APC. [70, 71, 72] However, a second surface molecule on the T cell was discovered; called cytotoxic T-lymphocyte antigen 4 (CTLA-4), it can also bind to B7 on the APC, with the opposite effect of CD28/B7 binding. [73, 74]  That is, it effectively turns off the immune response when the antigen is recognized, rather than turning it on. [75, 76] Therefore, CTLA-4 serves as a “checkpoint” to prevent an immune response against normal, healthy cells recognized as “self."

Cancer cells can take advantage of CTLA-4 to inhibit the body’s own immune response to them. By blocking CTLA-4 molecules with anti–CTLA-4 antibodies, the checkpoint can be inhibited, allowing the T cell to recognize the tumor cell and also allowing the normal “activation” interaction to occur, turning on the body’s natural cellular immunity to attack the cancer cell. This checkpoint inhibition concept is crucial to the development of immunotherapy in the treatment of melanoma. Multiple other checkpoints in the interaction of T cells and APCs have been identified, and these checkpoints regulate the interaction of the T cell with the tumor cells. The second checkpoint that is important in melanoma is the programmed cell death protein 1 (PD-1) receptor on the T cell, which inhibits the T-cell response through its interaction with programmed death-ligand 1 (PD-L1) on the APC. [77, 78, 79] In essence, checkpoint inhibition is the use of monoclonal antibodies to block the “off” signal to the T lymphocyte, allowing the body to better combat the tumor cells through natural activation mechanisms once the tumor cells are recognized.

Ipilimumab, a CTLA-4 monoclonal antibody, was initially approved as immunotherapy after it was shown to prolong overall survival in large clinical trials. Ipilimumab was approved by the FDA in March 2011 for unresectable or metastatic melanoma. [80, 49]  It also improved survival rate and response rate in patients previously treated with chemotherapy or interleukin 2.{ref 52} A combined analysis of ipilimumab in the treatment of advanced melanoma showed a plateau of the survival curve of 21%, starting at around 3 years, indicating potential long-term cure for melanoma with immunotherapy. [81] However, ipilimumab can have serious adverse effects.

PD-1 inhibitors have become first-line agents for advanced melanoma because of their increased efficacy and tolerability compared with CTLA-4 inhibitors. Nivolumab and pembrolizumab are PD-1 inhibitors that have shown long-term, progression-free survival in a significant number of patients. [82, 83, 84, 85] Nivolumab showed increased overall survival, progression-free survival, and objective response rate compared with dacarbazine in new patients in the CheckMate 066 trial. [86, 87] However, in the CheckMate 037 trial, nivolumab did not lead to a significantly different survival rate compared with chemotherapy in patients previously treated with ipilimumab and a BRAF inhibitor. [88] In the KEYNOTE-02 trial, pembrolizumab had improved progression-free survival, but not overall survival, versus chemotherapy in the treatment of ipilimumab-refractory disease. [89] In the KEYNOTE-006 trial, which included patients with advanced melanoma with no prior treatment with immunotherapy, pembrolizumab was superior to ipilimumab in progression-free survival and overall survival.{ref116 [90, 91] Pembrolizumab showed a durable complete response after discontinuation of therapy in advanced melanoma, with 24-month disease-free survival from the time of complete response in 90.9% of all patients and 89.9% of patients who discontinued pembrolizumab after complete response.

Nivolumab has been approved for monotherapy, as well as for adjuvant therapy in combination with the CTLA-4 inhibitor ipilimumab in the treatment of advanced melanoma. The PD-1/CTLA-4 inhibitor combination of nivolumab/ipilimumab was studied in the CheckMate 067 trial and showed overall improved survival compared with ipilimumab alone; it also showed promise when compared with nivolumab alone. [92] However, the combination showed serious treatment-related adverse effects. The combination of pembrolizumab and ipilimumab has shown promise in phase 1 trials as well. [93]

Cemiplimab is also a PD-1 inhibitor. Atezolizumab, avelumab, and durvalumab are examples of PD-L1 inhibitors that function at the same checkpoint as PD-1.

Optimal sequencing of immunotherapy and targeted therapy is not well established, despite their success in treating advanced melanoma. The best long-term clinical response is most often seen with checkpoint therapy with an anti-PD1 antibody (pembrolizumab or nivolumab), alone or in combination with ipilimumab, especially in patients without a driver mutation. However, targeted therapy will often induce a more timely response and is often preferred for patients who have very symptomatic, advanced-stage disease with a driver mutation. A transient worsening of disease can also be noted before development of a response in treatment with checkpoint inhibitors. The role and timing of checkpoint inhibitors and targeted therapy are currently being investigated in clinical trials. Because of the rapidly evolving nature of these therapies, strong consideration should always be given to involving an oncologist who has familiarity with and access to clinical trials in the treatment of patients with advanced melanoma.

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 postoperative melanoma recurrence. It is administered by injection into lesions that are visible, palpable, or detectable by ultrasonographic guidance. [94, 95]

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 includes 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 the ganglioside GM2 administered in combination with bacille Calmette-Guérin (BCG) improved relapse-free survival and overall survival in patients with stage III melanoma.

The American Academy of Dermatology (AAD) recommends topical imiquimod 5% cream as a second-line treatment for melanoma in situ, lentigo maligna type, when surgery is not possible at the outset (primary setting) or when optimal surgery has been performed (adjuvant setting). [96]

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.

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Conclusion

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 SLN dissection or elective lymphadenectomy for intermediate-thickness lesions. Primary radiation therapy and chemotherapy are usually reserved for palliative treatment in far-advanced lesions. Targeted therapy and immunotherapy for advanced melanoma are recent treatment developments that show great promise and are the first such treatments that show a long-term plateau in the survival curve, indicating long-term cures. The greatest hope for controlling this disease lies in careful surveillance and early detection of atypical pigmented lesions.

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