Cutaneous Melanoma 

Updated: Apr 29, 2019
Author: Susan M Swetter, MD; Chief Editor: Dirk M Elston, MD 

Overview

Background

Melanoma is a malignancy of pigment-producing cells (melanocytes) located predominantly in the skin, but also found in the eyes, ears, GI tract, leptomeninges, and oral and genital mucous membranes. Melanoma accounts for less than 5% of all skin cancers; however, it causes the greatest number of skin cancer–related deaths worldwide.[1] Early detection of thin cutaneous melanoma is the best means of reducing mortality. Characteristic images are shown below.

Cutaneous melanoma with characteristic asymmetry, Cutaneous melanoma with characteristic asymmetry, irregular borders, and color variation. Courtesy of Wendy Brick, MD.
Malignant melanoma. Courtesy of Hon Pak, MD. Malignant melanoma. Courtesy of Hon Pak, MD.

See Can You Recognize Benign Skin Lesions From Cancerous Ones?, a Critical Images slideshow, to help identify various skin lesions.

Also see the Critical Images slideshow, Cutaneous Clues to Diagnosing Metastatic Cancer, to help identify skin lesions that are cause for concern.

Pathophysiology

The sequence of events in which normal melanocytes transform into melanoma cells, referred to as melanomagenesis, is poorly understood. It likely involves a multistep process of progressive genetic mutations that (1) alter cell proliferation, differentiation, and death and (2) impact susceptibility to the carcinogenic effects of ultraviolet radiation.[2] Recent data suggest multiple pathways of melanoma pathogenesis, with melanomas in sun-protected skin (trunk) developing in association with a high nevus count and intermittent ultraviolet radiation as opposed to those developing on sun-exposed skin in patients with low nevus counts and chronic sun exposure.[3, 4]

Differences in frequency of BRAF or NRAS mutations are also related to patterns of sun exposure, with BRAF mutations more common in intermittently UV-exposed skin compared with chronically sun exposed skin or relatively unexposed skin (eg, acral sites, mucosal sites), which more frequently demonstrate KIT mutations.[4, 5]

A meta-analysis by Lee et al demonstrated that the prevalence of these mutations may also depend on melanoma histologic subtype.[6]

Primary cutaneous melanoma may develop in precursor melanocytic nevi (ie, common, congenital, and atypical/dysplastic types), although more than 70% of cases are believed to arise de novo (ie, not from a preexisting pigmented lesion).

The development of melanoma is multifactorial and appears to be related to multiple risk factors, including fair complexion/sun sensitivity, excessive childhood sun exposure and blistering childhood sunburns, an increased number of common or atypical/dysplastic nevi (moles), a family history of melanoma, the presence of a changing mole or evolving lesion on the skin, and, importantly, older age.[7, 8, 9]

Etiology

Melanoma shows an increased worldwide incidence in fair-complexioned individuals living in sunny climates and nearer the equator, suggesting a causative role for ultraviolet radiation. Most data support the hypothesis that melanoma development is related to intermittent, intense sun exposure, particularly in childhood or adolescence.[10, 11] In contrast, chronic sun exposure does not appear to confer increased risk, except for the more UV-related melanoma subtypes (lentigo maligna and lentigo maligna melanoma). The use of tanning beds has also increased the risk of melanoma in young patients.[12]

Primary risk factors and clinical warning signs for melanoma include the following:

  • Changing mole (most important clinical warning sign)

  • Presence of xeroderma pigmentosum or familial atypical mole melanoma syndrome: These genodermatoses confer a 500- to 1000-fold greater relative risk of developing melanoma.

  • Clinical atypical/dysplastic nevi in familial melanoma

  • Sporadic (nonfamilial) clinical atypical/dysplastic nevi (particularly >5-10)

  • Melanoma in first-degree relative(s) (especially multiple)

  • Large numbers of common nevi (>100)

  • Previous melanoma

  • Male sex

  • Age older than 50 years

  • Sun sensitivity/history of excessive sun exposure or sunburns

  • Large (giant) congenital nevi (>20 cm diameter in an adult)

  • Prior nonmelanoma skin cancer (basal cell and squamous cell carcinoma)[12]

  • Immunosuppression

A fair-skin phenotype (blue/green eyes, blond or red hair, light complexion, sun sensitivity) and the occurrence of blistering sunburn(s) in childhood and adolescence are universal risk factors for melanoma. Individuals with these traits have been the focus of preventive efforts worldwide.

Pregnancy or hormonal therapy with oral contraceptives or hormone replacement does not appear to be a risk factor for melanoma development.[13, 14, 15, 16, 17]

Epidemiology

Frequency

United States

The incidence of melanoma has more than doubled in the white population over the last 30 years, and melanoma currently is the sixth most common cancer in the United States. Approximately 87,110 Americans (52,1709 men and 34,940 women) will develop invasive cutaneous melanoma in 2017, with an estimated additional 74,680 or more cases of melanoma in situ.[18] The incidence may be higher due to melanoma underreporting to cancer registries, particularly for tumors that are diagnosed and managed in the outpatient setting.[19] The current lifetime risk for developing invasive melanoma is 1 case per 54 Americans, a 2000% increase since 1930. This risk rises to 1 case per 33 Americans if noninvasive melanoma in situ is included.

Encouragingly, a stable-to-reduced melanoma incidence rate has been noted in younger age groups in the United States, which may be a result of primary prevention campaigns aimed at reducing excessive sun exposure over the past 30 or more years; however, the full impact of primary prevention strategies on melanoma incidence and mortality will not be apparent for several decades.

Of recent concern, however, is the rising melanoma incidence in white women younger than 40 years; annual incidence of melanoma more than doubled in this group from 1980-2004. Increased UV radiation exposure through tanning bed use, a World Health Organization (WHO)–classified carcinogen, has been proposed as a potential explanation for this alarming trend.[20] In addition, a study assessing melanoma incidence among young white girls and women (15-39 y) in California showed significantly higher incidence in those living in higher socioeconomic areas, with the highest UV radiation exposure compared with those from lower socioeconomic neighborhoods, suggesting that affluence (and associated lifestyle behaviors) may have a bigger impact on melanoma risk than UV exposure alone.[21] Pilots and flight crews demonstrate melanoma risk double that of the general population.[22]

International

Melanoma incidence has continued to increase worldwide, with the highest incidence in Australia and New Zealand. The most recent analysis of global cancer statistics for melanoma, from 2012, demonstrated an age-standardized incidence of 34.9 cases per 100,000 men and women in Australia and 35.84 cases per 100,000 men and women in New Zealand, compared with 14.3 cases per 100,000 men and women in the United States.[23]

Race

Melanoma is primarily a malignancy of white individuals, with an annual incidence of 26 cases per 100,000 population in 2017.[18] African American persons develop melanoma approximately one twentieth as frequently as white persons (annual incidence rate of 1 case per 100,000 population in 2017), and the prevalence in Hispanic persons is approximately one fifth of that in white persons (annual incidence 5 cases per 100,000 population in 2017). However, mortality rates are higher in African Americans and Hispanics, who are more likely to have acral melanoma and advanced disease at presentation.

Sex

In the United States, invasive melanoma has a higher female predilection from birth to age 49 years (1 in 155 women compared with 1 in 220 men in 2017). However, from age 50 years and older, melanoma in men predominates, occurring in 1 in 28 men compared with 1 in 44 women over a lifetime.[18]

Worldwide, of the 232,000 new cases estimated to have occurred in 2012, women were affected slightly more than men. Conversely, of the estimated 55,000 worldwide deaths in 2012, more occurred in men than in women.

Age

The median age at melanoma diagnosis is 63 years; however, it is the most common cancer in women aged 25-29 years and is second only to breast cancer in women aged 30-34 years. The most striking differences in melanoma incidence and mortality occur in individuals older than 65 years, although modest differences in age-specific incidence and mortality are notable in persons older than 50 years.[24]

Older individuals are both more likely to acquire and to die from melanoma; thus, elderly persons should be a primary target for secondary melanoma prevention, including early detection and screening.[25] Treatment options in elderly persons may also be limited because of comorbid medical conditions, an inability to tolerate adverse medication effects or toxicity, the increased likelihood of drug interactions, and potential exclusion from clinical trials based on age criteria.[25]

Prognosis

Prognosis is multifactorial and primarily depends on (1) tumor thickness, (2) the presence or absence of histologic ulceration, and (3) lymph node involvement (most important). Despite remarkable advances in the treatment of metastatic disease, detection and treatment of cutaneous melanoma in its thin, early phase remains the best chance for cure.

Cutaneous melanoma (stages I and II) prognosis

Thin primaries (≤1 mm) are associated with a 5-year survival rate of 94-97%, depending on the presence or absence of histologic ulceration and mitotic rate of greater than or equal to 1/mm2 versus less than 1/mm2.

Intermediate-thickness melanoma (1.01-4 mm) is associated with a 5-year survival rate of 68-91%, depending on ulceration, thickness (1.01-2 mm, 2.01-4 mm) of the primary tumor, and sentinel lymph node biopsy status.

Patients with high-risk tumors (>4 mm) have a 5-year survival rate of 71% without ulceration, compared with 53% with an ulcerated primary, although higher rates have been reported in the absence of sentinel lymph node involvement.

Ulceration significantly reduces survival at each tumor stage, even when regional lymph nodes are involved.

Stage III disease prognosis

Regional lymph node metastasis is associated with a 5-year survival rate of 38-78%, depending on the number of nodes involved, microscopic or macroscopic (matted nodes/gross extracapsular extension) disease, and ulceration of the primary melanoma. In-transit metastasis/satellite lesions are associated with a 69% 5-year survival rate, with a significantly worse prognosis in the setting of concomitant regional nodal metastasis (40%).

Stage IV disease prognosis

Prior to the advent of checkpoint inhibitors and targeted therapy for melanoma, prognosis for distant metastatic disease was extremely poor, with median survival of only 6-9 months and 5-year survival rates of less than 20%, depending on the site(s) of metastasis. In general, patients with soft tissue, nodal, and isolated lung metastases have had slightly better prognoses than those with other visceral metastases and/or elevated LDH levels. With immune checkpoint blockade or targeted therapy, high overall response rates and disease control has become the norm in patients with unresectable stage III and IV melanoma. Durable complete responses have been observed, particularly with novel immunotherapies.

Systemic chemotherapy is no longer the mainstay of treatment for metastatic melanoma; it is associated with low response rates (< 20%), which also tend to be of short duration.

Biochemotherapy, using standard chemotherapeutic agents with biologic response modifiers such as IL-2, IFN alfa, or granulocyte macrophage colony-stimulating factor, has shown limited success in the management of unresectable stage IV melanoma and no OS benefit or durable responses in patients with metastatic disease.[26] High-dose IL-2 alone, or combined with histamine dihydrochloride, has resulted in durable remission in a very small subset of patients with advanced disease, but is characterized by significant toxicity and need for hospitalization and careful monitoring during drug administration.[27]

Mortality/morbidity

While melanoma accounts for roughly 4% of all skin cancers, it is responsible for nearly 75% of skin cancer deaths. In the United States, one person each hour dies from metastatic disease. Treatment of melanoma in its early stages provides the best opportunity for cure.

US mortality/morbidity

An estimated 9,730 deaths will occur in 2017 (6,380 men and 3,350 women).[18] Analysis of US Surveillance, Epidemiology, and End Results (SEER) data from 1969-1999 has demonstrated a disproportionate burden of melanoma deaths among middle-aged and older white men. While melanoma mortality rates have fallen 39% in women and 29% in men aged 20-44 years over this period, they have increased 66% in men aged 45-64 years and 157% in older men (>65 y).[24] Incidence data generally parallel mortality data and have shown a 3-fold increase in middle-aged men and a 5-fold increase in older men over a similar period. Subsequent analyses continue to demonstrate the highest incidence and mortality rates in older white men in the United States.

Worldwide mortality/morbidity

Individuals with cutaneous melanoma have higher survival rates in developed countries (92% in US SEER registries and 81% in Europe) than in developing countries (approximately 40%). Increased educational efforts in developed areas result in earlier diagnosis, treatment, and potential cure of thinner lesions. Worldwide, 232,000 new cases of melanoma were estimated to occur in 2012, with over 55,000 deaths reported. Australia and New Zealand have the highest reported mortality.[23]

Patient Education

Educate patients with a history of melanoma regarding the following:

  • Sun-protective measures (including sun-protective clothing and sunscreens)

  • Skin self-examinations for new primary melanoma, particularly important in individuals with numerous moles (common or atypical) or a strong family history of melanoma

  • Possible recurrence within the melanoma scar

  • Screening of first-degree relatives, particularly if they have a history of atypical moles

  • Potential referral to a cancer genetics clinic for individuals with 3 or more invasive melanomas (personal or in the same side of the family) or families with 3 or more “cancer events,” including 2 invasive melanomas and 1 pancreatic cancer (or vice versa) for discussion of genetic testing for the CDKN2A (P16) mutation.[28] (However, a negative result would not affect the need for ongoing dermatologic surveillance in patients at increased risk or history of multiple primary melanomas.)

For patient education resources, visit the Cancer Center, Skin Cancer, Skin Biopsy, and Mole Removal.

 

Presentation

History

A new or changing mole or blemish is the most common warning sign for melanoma. Variation in color and/or an increase in diameter, height, or asymmetry of borders of a pigmented lesion are noted by the majority of patients with melanoma at the time of diagnosis. Symptoms such as bleeding, itching, ulceration, and pain in a pigmented lesion are less common but warrant an evaluation. Again, because the majority of cutaneous melanoma arises de novo (ie, on normal-appearing skin and not in association with a precursor nevus), routine sampling or mass removal of stable-appearing melanocytic nevi is not warranted for melanoma prevention. However, individuals with numerous moles (common or atypical/dysplastic) or a family history of melanoma are at increased risk of developing melanoma and should be educated regarding the importance of skin self-examination for early detection.

A total-body skin examination is critical when evaluating a patient at risk for melanoma, particularly those with increased mole count, presence of clinical atypical nevi, prior nonmelanoma skin cancer, and/or strong family history of melanoma. Multiple studies have demonstrated that thinner melanomas are associated with physician detection during routine skin or physical examinations, compared with patient detection of melanoma when a lesion changes or becomes symptomatic.[29]

Clinician and patient education regarding the warning signs of early melanoma (particularly the superficial spreading subtype) has been achieved successfully through the use of the ABCDE criteria for a changing mole,[30, 31] which are as follows:

  • Asymmetry: Half the lesion does not match the other half.

  • Border irregularity: The edges are ragged, notched, or blurred.

  • Color variegation: Pigmentation is not uniform and may display shades of tan, brown, or black; white, reddish, or blue discoloration is of particular concern.

  • Diameter: A diameter greater than 6 mm is characteristic, although some melanomas may be smaller in size; any growth in a nevus warrants an evaluation.

  • Evolving: Changes in the lesion over time are characteristic; this factor is critical for nodular or amelanotic (nonpigmented) melanoma, which may not exhibit the ABCD criteria above.

The ABCDEs have the greatest diagnostic accuracy when used in combination. Lesions exhibiting these features should be considered potential melanoma, although severely atypical/dysplastic nevi may be difficult to distinguish clinically. More recent use of the "ugly duckling" warning sign, in which skin examination is focused on recognition of a pigmented or clinically amelanotic lesion that simply looks different from the rest, may assist with detection of lesions that lack the classic ABCDE criteria (eg, nodular, amelanotic, or desmoplastic melanomas).[32, 33]

Physical Examination

Melanoma occurs most commonly on the trunk in white males and the lower legs and back in white females. In African American, Hispanic, and Asian persons, the most common site is the plantar foot, followed by subungual, palmar, and mucosal sites. Melanoma can occur on any skin or mucosal surface, although a history of cutaneous melanoma does not appear to increase the risk of developing primary intraocular, oral, or other mucosal melanoma.

Four major clinicopathologic subtypes of primary cutaneous melanoma have been identified, although newer classifications of melanoma include location on chronically sun-exposed versus intermittently or non‒sun-exposed skin and incorporate the presence of driver mutations in BRAF, NRAS, NF-1, and other oncogenes. Classic histopathologic melanoma subtypes include superficial spreading, nodular, lentigo maligna, and acral lentiginous. Distinction among these subtypes is based on histologic growth pattern (predominantly junctional in lentiginous types vs pagetoid in superficial spreading and predominantly dermal in nodular), anatomic site, and degree of sun damage. The pattern of sun exposure varies between the types (chronic in lentigo maligna vs intermittent in superficial spreading and nodular subtypes vs noncontributory in acral lentiginous and mucosal subtypes).

Whether the melanoma subtype affects the overall prognosis remains controversial. However, molecular analysis has demonstrated different patterns of cell death; oncogene expression; gene amplification; and BRAF, NRAS, and KIT mutation frequency among the four main histogenetic types.[34, 35, 36] Differing microRNA signatures between superficial spreading melanoma and nodular melanoma have also been described, which supports the concept of molecular classification of superficial spreading melanoma and nodular melanoma as two distinct phenotypes.[37]

A pooled analysis of more than 30 studies from 1989-2010 concludes that the incidence of BRAF and NRAS mutations differ based on histologic subtype and anatomic site.[6] BRAF mutations are more commonly detected in superficial spreading melanomas and melanomas that arise on nonchronically sun-damaged skin. NRAS mutations are more common in patients with nodular melanomas and melanomas arising on chronically sun-damaged skin. Recent data have shown that NRAS mutations may be associated with thicker tumors (>1 mm) and higher mitotic rate (>1/mm2) compared with mutations in BRAF, and that NRAS mutation status may be associated with worse clinical outcomes, including shorter melanoma specific survival.[38, 39] These studies suggest that further molecular classification of melanoma may assist in the development of more effective targeted therapies.

With the exception of nodular melanoma, the growth patterns of the other subtypes are characterized by a preceding in situ (radial growth) phase that lacks the biologic potential to metastasize and may last from months to years before dermal invasion occurs. While all in situ melanoma may not necessarily progress to invasive melanoma, complete removal is recommended to prevent invasion and result in cure.

Superficial spreading melanoma

It accounts for nearly 70% of cutaneous melanoma and is the most common subtype in individuals aged 30-50 years, as well as those with clinical atypical/dysplastic nevi. It is most common on the trunk in men and women and on the legs in women. See the image below.

Superficial spreading melanoma, left breast, 1.3-m Superficial spreading melanoma, left breast, 1.3-mm Breslow depth.

Superficial spreading melanoma commonly displays the ABCD warning signs. It manifests as a flat or slightly elevated brown lesion with variegate pigmentation (ie, black, blue, pink, or white discoloration). It is generally greater than 6 mm in diameter. Irregular asymmetric borders are characteristic.

Histologically, it is characterized by buckshot (pagetoid) scatter of atypical melanocytes within the epidermis.

Nodular melanoma

This subtype occurs in 15-30% of patients. It is seen most commonly on the legs and trunk in men and women. Rapid growth occurs over weeks to months; this subtype is responsible for most thick melanomas.[40, 41]

It may be clinically amelanotic (ie, not pigmented); thus, any rapidly growing flesh-colored lesion that persists after 1 month or ulcerates or bleeds should prompt medical evaluation. It manifests as a dark brown-to-black papule or dome-shaped nodule, which may ulcerate and bleed with minor trauma; it may be clinically amelanotic (ie, not pigmented).

It tends to lack the typical ABCDE melanoma warning signs and, thus, may elude early detection. More commonly, it exhibits elevation, ulceration with bleeding, or both at presentation.

Histologically, it is believed to lack a preceding radial or in situ growth phase.

Lentigo maligna melanoma

The incidence of lentigo maligna subtypes (in situ and invasive) appears to be rising in the United States.[42]  It is typically located on the head, neck, and arms (chronically sun-damaged skin) of fair-skinned older individuals (average age 65 y). See the image below.

Lentigo maligna melanoma, right lower cheek. Centr Lentigo maligna melanoma, right lower cheek. Centrally located erythematous papule represents invasive melanoma with surrounding macular lentigo maligna (melanoma in situ).

It grows slowly over 5-20 years. The in situ precursor lesion (termed lentigo maligna) is usually large (>1-3 cm in diameter), present for a minimum of 10-15 years, and demonstrates macular (flat) pigmentation ranging from dark brown to black, although hypopigmented (white) areas are common within lentigo maligna. Dermal invasion (progression to lentigo maligna melanoma) is characterized by the development of raised blue-black nodules within the in situ lesion.

Histologically, it is characterized by a predominantly junctional confluent proliferation of melanocytes and extension along adnexal structures, although dysplastic nevuslike features may be observed.[43] Solar elastosis is typically prominent.

Acral lentiginous melanoma

This is the least common subtype of melanoma in white persons (2-8% of melanoma cases). It is the most common subtype of melanoma in dark-skinned individuals (ie, African American, Asian, and Hispanic persons), representing 29-72% of melanoma cases and, because of delays in diagnosis, may be associated with a worse prognosis.[44, 45]

Acral lentiginous melanoma occurs on the palms, on the soles, or beneath the nail plate (subungual variant). See the image below.

Acral lentiginous melanoma (1-mm Breslow depth), l Acral lentiginous melanoma (1-mm Breslow depth), left sole. Diagnostic punch biopsy site is located superiorly.

Subungual melanoma may manifest as diffuse nail discoloration or a longitudinal pigmented band (melanonychia striata) within the nail plate. It must be differentiated from a benign junctional melanocytic nevus of the nail bed, which has a similar appearance. Pigment spread to the proximal or lateral nail folds is termed the Hutchinson sign, which is a hallmark for subungual melanoma. Subungual melanoma may be mistaken for a subungual hematoma, which is usually due to trauma and resolves with time.

Fungal infection of the nail (onychomycosis) can also be confused with subungual melanoma, particularly in the setting of nail dystrophy without suspicious pigmentation. Nonresponsiveness to antifungal agents should prompt more thorough evaluation, including potential biopsy.

Rare variants

Rare melanoma variants (< 5% of melanomas) include (1) desmoplastic/neurotropic melanoma, (2) mucosal (lentiginous) melanoma,[46] (3) blue nevuslike melanoma, (4) melanoma arising in a giant/large congenital nevus, and (5) melanoma of soft parts (clear cell sarcoma).

Desmoplastic melanoma

Desmoplastic melanoma is a less common but important melanoma subtype, given its predilection for older-age individuals, clinical features similar to nonmelanoma (keratinocytic) skin cancer, and potential indication for adjuvant radiation therapy for improved local control following wide excision.

It may occur in association with macular, lentigo maligna-type pigmentation, or it may present de novo as a firm, amelanotic nodule or scar. It occurs most often on sun-exposed areas of the head and neck, with a mean age of 60-65 years.[47]  Lack of pigmentation and clinical features more suggestive of keratinocytic (“nonmelanoma”) skin cancer may result in delay in detection and thicker tumors at diagnosis.

Desmoplastic melanoma frequently exhibits perineural extension and has a predilection for local recurrence. Wide excisional margins (≥2 cm) and adjuvant radiation therapy are frequently recommended for improved local control of this uncommon melanoma subtype.

Amelanotic melanoma

Amelanotic melanoma (< 5% of melanomas) can occur with any subtype. This type is nonpigmented and, clinically, appears pink or flesh-colored, often mimicking basal cell or squamous cell carcinoma, dermatofibroma, or a ruptured hair follicle. It occurs most commonly in the setting of the nodular or desmoplastic melanoma subtype or melanoma metastasis to the skin, presumably because of the inability of these poorly differentiated cancer cells to synthesize melanin pigment.

Complications

Metastasis may occur locally (within or around the primary site), in the regional lymph node basins, or distally in the following sites:

  • Remote skin (away from the melanoma scar)

  • Remote lymph node(s)

  • Viscera

  • Skeletal

  • CNS sites

Disease relapse is seen most commonly in the skin, subcutaneous tissue, and lymph nodes.

 

DDx

Diagnostic Considerations

For subungual melanoma, also consider chronic paronychia, subungual hematoma, and melanonychia striata. For superficial spreading or nodular subtypes, also consider traumatized nevus.

Differential Diagnoses

 

Workup

Laboratory Studies

The most important aspects of the initial workup for patients with cutaneous melanoma are a careful history, review of systems, and physical examination.

Sentinel lymph node biopsy (SLNB) is generally indicated for pathologic staging of the regional nodal basin(s) for primary tumors greater than 1 mm depth and when certain adverse histologic features (eg, ulceration, high mitotic rate, lymphovascular invasion) are present in thinner melanomas.

Published data have shown that baseline laboratory studies (eg, lactate dehydrogenase [LDH] level, liver function tests, chemistry panel, CBC count), chest radiography (CXR), and other imaging studies (eg, CT scanning, positron emission tomography [PET] scanning, bone scanning, MRI) are not useful for stage I/II (cutaneous) melanoma patients without signs or symptoms of metastasis, and obtaining these studies is discouraged.[48, 49, 50, 51]

A metastatic workup should be initiated if physical findings or symptoms suggest the presence of metastasis at the time of diagnosis or of metastatic disease recurrence following initial treatment of cutaneous melanoma. Screening CT or PET-CT may be considered if the patient has documented regional nodal micrometastasis based on results from the SLNB, although the yield is low (0.5-3.7%) and correlates with increasing tumor thickness, ulceration of the primary tumor, and/or large tumor burden in the sentinel lymph node(s).[52]

Practice guidelines developed by the National Comprehensive Cancer Network (NCCN) support the concept that most melanoma recurrences are diagnosed clinically. The current guidelines recommend against further workup (ie, baseline laboratory tests and imaging studies) in patients with stage 0 (melanoma in situ) and in asymptomatic patients with any thickness of invasive cutaneous melanoma (stages I and II). Further imaging (CT, PET-CT, MRI) should be obtained only as clinically indicated to evaluate specific signs or symptoms.

Guidelines established by the American Academy of Dermatology in 2011 also do not recommend baseline imaging or laboratory tests in asymptomatic patients with any stage of cutaneous melanoma (IA-IIC).[53]

The key components to melanoma follow-up are careful physical examination (with attention to lymph nodes and skin) and review of systems. Patients should be educated in the performance of monthly skin self-examination for early detection of new primary melanoma as well as self-lymph node examinations (in those with invasive melanoma).

Current NCCN guidelines do not recommend surveillance (follow-up) laboratory or imaging studies for asymptomatic patients with stage IA, IB, and IIA melanoma (ie, tumors ≤4 mm depth). Imaging studies (chest radiograph, CT and/or PET-CT) should be obtained as clinically indicated for confirmation of suspected metastasis or to delineate the extent of disease and may be considered to screen for recurrent/metastatic disease in patients with stage IIB-IV disease, although this latter recommendation remains controversial. Routine laboratory or radiologic imaging in asymptomatic melanoma patients of any stage is not recommended after 3-5 years of follow-up.[54]

While abnormal laboratory test results are rarely the sole indicator of metastatic disease, serum LDH levels were incorporated into the American Joint Committee on Cancer (AJCC) 2002 melanoma staging guidelines for the classification of stage IV (distant) disease. Elevated LDH levels are associated with worse survival in this subgroup and remain a powerful predictor of survival in the 2009 AJCC Cancer Staging Manual (7th ed) for melanoma of the skin. Serum S-100 protein levels may also be useful as a tumor marker in patients with metastatic disease, but this practice is not widely used in the United States.[55]

Imaging Studies

As discussed previously, studies have confirmed that extensive radiologic studies such as CT, MRI, PET, PET-CT, and bone scans have an extremely low yield in asymptomatic patients with primary cutaneous melanoma (AJCC stages I and II) and are generally not indicated. However, maintaining a low threshold for obtaining symptom-directed tests is important in melanoma surveillance.

Surveillance CXR, CT, or PET-CT may be obtained for asymptomatic melanoma patients with primary tumors greater than 4 mm in depth, although this practice remains optional in the absence of signs or symptoms of metastatic disease.[54]

Current NCCN guidelines recommend the use of regional nodal ultrasound in certain clinical settings, including physical examination with equivocal lymph node findings. Regional nodal ultrasound has shown to be superior to palpation alone for assessment of regional lymph node metastasis and surveillance of the regional nodes. A meta-analysis of 74 studies conducted between 1990 and 2009 encompassing 10,528 patients demonstrated the superiority of ultrasonography over CT, PET, and PET-CT for detecting lymph node metastasis.[56] As such, NCCN guidelines now recommend consideration of regional nodal ultrasound in patients (1) with an equivocal lymph node examination, (2) who were offered but did not undergo SLNB staging, (3) in whom SLNB was not possible or technically successful, and (4) with a positive SLNB who did not undergo complete lymph node dissection.[54]

Procedures

The criterion standard for melanoma diagnosis is histopathologic examination of clinically suggestive skin or mucosal lesions. An excisional biopsy with narrow margins is preferred and may consist of a fusiform/elliptical excision, an excisional punch biopsy, or a saucerization/deep shave biopsy (into the deeper reticular dermis), the latter of which is the most common technique used. In the case of melanoma in situ, lentigo maligna type, a broad shave biopsy (into the deeper papillary or superficial reticular dermis) may be the best technique to provide optimal tissue for histopathologic assessment. The biopsy report should generally include the following[53] :

  • Tumor thickness in millimeters (mm), ie, Breslow depth

  • Ulceration (present or absent)

  • Dermal mitotic rate (measured as number of mitoses/mm2)

  • Microsatellitosis

  • Anatomic level of invasion (Clark level) – Only for tumors 1 mm or smaller when mitotic rate cannot be determined)

Optional histologic features for primary melanoma include the following:

  • Angiolymphatic/lymphovascular invasion

  • Histologic subtype

  • Neurotropism/perineural invasion (particularly in desmoplastic melanoma)

  • Regression (which is associated with lower rates of sentinel node positivity and improved disease-free survival)[57]

  • Host response (tumor-infiltrating lymphocytes)

  • Vertical growth phase

Immunohistochemical staining for lineage (S-100, homatropine methylbromide 45 [HMB-45], melan-A/Mart-1) or proliferation markers (proliferating cell nuclear antigen, Ki67) may be helpful in some cases for histologic differentiation from melanoma simulators. Additionally, evidence of lack of maturation with HMB-45 staining and patchy, rather than diffuse, staining with S-100A6 may be helpful for distinguishing spitzoid melanoma from Spitz nevus.

Generally, when an excisional biopsy is performed, 1-3 mm of normal skin surrounding the pigmented lesion should be removed to provide accurate diagnosis and histologic microstaging. Wider margins (>1 cm) could theoretically disrupt afferent cutaneous lymphatic flow and affect the ability to identify the sentinel node(s) accurately in patients eligible for this staging procedure. Most data, however, suggest that accurate mapping is possible after wider excision, although an increased number of regional lymph nodes may be removed as a result.

Superficial shave biopsies of suggestive pigmented lesions are discouraged because partial removal of the primary melanoma may not provide an accurate measurement of tumor thickness, which is the most important histologic prognostic factor for cutaneous melanoma. As noted above, an important exception to this rule is the lentigo maligna subtype of melanoma in situ. In the case of lentigo maligna, the risk of misdiagnosis is high if small (partial) biopsy specimens are taken. The best diagnostic biopsy technique in this case is often a broad shave biopsy that extends into at least the papillary dermis, which provides the opportunity to exclude microinvasive melanoma and allows for optimal histopathologic interpretation of the tumor.

Histologic Findings

Superficial spreading melanoma has an in situ (radial growth) phase characterized by increased numbers of intraepithelial melanocytes, which (1) are large and atypical, (2) are arranged haphazardly at the dermoepidermal junction, (3) show upward (pagetoid) migration, and (4) lack the biologic potential to metastasize. Lentigo maligna melanoma and acral lentiginous melanoma demonstrate predominant in situ growth at the dermoepidermal junction and with little tendency for the pagetoid scatter of cells.

Dermal invasion confers metastatic potential, although the greatest risk occurs in the setting of a vertical growth (tumorigenic) phase.[58, 59] Tumorigenicity is characterized by a distinct population of melanoma cells with evidence of proliferation (mitoses, MIB-1 staining) and nuclear pleomorphism within the dermis and, possibly, the subcutaneous fat. Lateral intraepidermal extension of melanoma cells occurs in all subtypes except nodular melanoma. Failure of melanocyte maturation and dispersion as the tumor extends downward into the dermis is characteristic of melanoma. Some investigators have defined a vertical growth phase as (1) any dermal nest larger than the largest junctional nest or (2) invasion into either the reticular dermis or band of solar elastosis.

Tumor thickness, as defined by the Breslow depth, is the most important histologic determinant of prognosis and is measured vertically in millimeters from the top of the granular layer (or base of superficial ulceration) to the deepest point of tumor involvement. Increased tumor thickness confers a higher metastatic potential and a poorer prognosis.[60, 61] Analysis of worldwide data has shown that the presence of ulceration microscopically, defined as a full-thickness epidermal defect overlying the melanoma, is the next most important histologic determinant of patient prognosis and, when present, should be used to up-stage patients with both primary and nodal melanoma.[62] Data have suggested that both the presence and extent of histologic ulceration predict survival, with extent of ulceration (measured either as diameter or percentage of tumor width) providing more accurate prognostic information than the presence of ulceration alone. Specifically, in an analysis of 4661 patients,those with minimally/moderately ulcerated tumors (defined as less than or equal to 70% or less than or equal to 5mm) had a significantly higher risk of death (HR=1.53 and HR=1.39, respectively), compared with nonulcerated melanoma, and the risk of death was even higher for patients with extensively ulcerated tumors (>70%: HR=2.20 and >5 mm: HR=2.03).[63]

The Clark level has been used for more than 40 years and provides a measurement of tumor invasion anatomically. However, analysis of the worldwide AJCC 2008 melanoma staging database has demonstrated lower statistical correlation with melanoma survival when level of invasion was compared with thickness, mitotic rate, ulceration, age, sex, and site. As such, the seventh edition of the AJCC Cancer Staging Manual (effective January 2010) no longer includes the Clark level in T1a melanomas (≤1 mm depth). Dermal mitotic rate of greater than or equal to 1/mm2 has been incorporated in thin melanomas in place of Clark level and upstages a T1a melanoma to a T1b melanoma.[64]

Data from the AJCC Melanoma Staging Database and other studies have demonstrated a highly significant correlation between increasing mitotic rate and declining survival rates, particularly in thin melanomas. Higher mitotic rate (as a continuous variable) across all tumor thicknesses confers a greater risk for metastasis and is an independent predictor of worse survival.

Staging

The melanoma staging system initially developed in 1983 by the AJCC and the International Union Against Cancer (UICC) divided melanoma into 4 stages and incorporated tumor thickness and anatomic level of invasion for stages I and II (localized cutaneous disease), with the later recommendation to follow Breslow depth over Clark level when any discordance arose. Stage III disease involved the regional lymph nodes; stage IV disease included distant skin, subcutaneous, nodal, visceral, skeletal, or CNS metastasis.

Major revisions in the 2002 AJCC/UICC melanoma staging system were made based on a critical analysis of prior versions of the staging protocol.[62] The AJCC formed an international multidisciplinary Melanoma Staging Committee and established a new clinicopathologic database of more than 17,000 patients worldwide to test the validity of the proposed staging changes.[65, 66, 67]

Several important modifications in the 2002 AJCC staging system included the incorporation of histologic ulceration of the primary tumor and number of lymph nodes involved (instead of size) to better stratify metastatic risk and patient prognosis.[27] In the 2002 staging system, Clark level was included only in thin primary tumors (≤1 mm depth, stages IA and IB) because its prognostic value was minimal in thicker primary melanomas. Furthermore, microscopic regional lymph node metastasis detected largely by SLNB was differentiated from macroscopic (palpable) nodal metastasis.

The seventh edition of the AJCC Cancer Staging manual (effective January 2010) recommended no major changes for TNM categories and stage groupings, with the exception of removing Clark level and instead incorporating mitotic rate of greater than or equal to 1/mm2 to upstage T1a to T1b melanomas, given the adverse effect of higher mitotic rate on melanoma survival.[64] Updated analysis of the worldwide AJCC collaborative melanoma database is underway, in preparation for revised AJCC melanoma staging based on the best available prognostic information.

The estimated 5-year overall survival (OS) in the Table below is based on analysis of worldwide data encompassing nearly 60,000 patients in the 2008 AJCC Melanoma Staging Database.[64] Publication of current survival data used for the AJCC eighth edition is pending.

The eighth edition of the AJCC Cancer Staging manual (published in 2016 and effective January 2018) recommended several important changes for cutaneous melanoma, including reporting of Breslow thickness to the nearest 0.1 mm, rather than the nearest 0.01 mm, owing to the lack of precision in measurement beyond the 1/10th decimal point.[68] Tumor mitotic rate was removed as a staging criterion in T1 melanoma, although histopathologic measurement of mitotic rate (in #/mm2) is recommended across all tumor thicknesses given its impact on prognosis. Finally, the eighth edition excludes Clark level from staging, noting its lack of predictive value for survival, compared with other prognostic variables.

Table. AJCC 2002 Revised Melanoma Staging (Open Table in a new window)

Stage

TNM Classification

Histologic/Clinical Features

5-Year Survival Rate, %

0

Tis N0 M0

Intraepithelial/in situ melanoma

100

IA

T1a N0 M0

≤1 mm without ulceration and mitotic rate < 1/mm2

97

IB

T1b N0 M0

T2a N0 M0

≤1 mm with ulceration or mitotic rate ≥1/mm2

1.01-2 mm without ulceration

91-94

IIA

T2b N0 M0

T3a N0 M0

1.01-2 mm with ulceration

2.01-4 mm without ulceration

79-82

IIB

T3b N0 M0

T4a N0 M0

2.01-4 mm with ulceration

4 mm without ulceration

68-71

IIC

T4b N0 M0

>4 mm with ulceration

53

IIIA

T1-4a N1a M0

T1-4a N2a M0

Single regional nodal micrometastasis, nonulcerated primary

2-3 microscopic positive regional nodes, nonulcerated primary

78

IIIB

T1-4b N1a M0

T1-4b N2a M0

T1-4a N1b M0

T1-4a N2b M0

T1-4a/b N2c M0

Single regional nodal micrometastasis, ulcerated primary

2-3 microscopic regional nodes, nonulcerated primary

Single regional nodal macrometastasis, nonulcerated primary

2-3 macroscopic regional nodes, no ulceration of primary

In-transit met(s)* and/or satellite lesion(s) without metastatic lymph nodes

54-59

IIIC

T1-4b N2a M0

T1-4b N2b M0

Any T N3 M0

Single macroscopic regional node, ulcerated primary

2-3 macroscopic metastatic regional nodes, ulcerated primary

4 or more metastatic nodes, matted nodes/gross extracapsular extension, or in-transit met(s)/satellite lesion(s) and metastatic nodes

40

IV

Any T any N M1a

Any T any N M1b

Any T any N M1c

Distant skin, subcutaneous, or nodal mets with normal LDH levels

Lung mets with normal LDH

All other visceral mets with normal LDH or any distant mets with elevated LDH

< 20

*Met is metastasis.

 

Treatment

Medical Care

Numerous adjuvant therapies have been investigated for the treatment of localized cutaneous melanoma following complete surgical removal. No overall survival (OS) benefit has been demonstrated for adjuvant chemotherapy, nonspecific (passive) immunotherapy (including interferon [IFN] and now ipilimumab), radiation therapy, retinoid therapy, vitamin therapy, or biologic therapy.[69] IFN alfa-2b was the first US Food and Drug Administration (FDA)‒approved adjuvant therapy for high-risk melanoma (currently defined as stages IIB, IIC, and III), which is associated with a 40-80% chance of relapse and death.

Adjuvant IFN-alfa trials

In the United States, three prospective, multicenter, randomized, controlled trials have been conducted to assess the effect of adjuvant high-dose IFN alfa-2b on relapse-free survival (RFS) and OS rates in patients with high-risk melanoma (primary tumors ≥4 mm depth and regional nodal disease). The Eastern Cooperative Oncology Group (ECOG) trial 1684 showed an 11% increase (26% to 37%) in RFS rates at 5 years in the IFN-alfa treatment group compared with the observation arm. Similarly, this trial showed an increase in 5-year OS rates from 37% to 46% (median OS, 2.78 to 3.82 y) in the treatment arm compared with observation.[70]

The confirmatory Intergroup trial (ECOG 1690) again showed an increase in the estimated 5-year RFS rates from 35% in the observation arm to 44% in the high-dose IFN-alfa arm. No significant benefit in the RFS rate was associated with low-dose IFN. Important to note, no difference in the OS rate was seen in the IFN-treated groups (high- or low-dose) compared with the observation arm.[71] Despite further data analysis that suggested postrelapse salvage therapy with an IFN-alfa–containing regimen may have confounded the OS results (ie, "crossover effect"), the ECOG 1690 trial is largely viewed as a negative study for high-dose IFN effects on OS.

The last Intergroup trial (ECOG 1694) compared the use of standard high-dose IFN alfa with GM2 ganglioside vaccine (GMK). The study was closed prematurely because a significant benefit was observed for IFN alfa over GMK for both RFS and OS rates. Hazard ratio analysis revealed that the likelihood of disease relapse and death in patients treated with high-dose IFN was reduced by one third compared with GMK.[72]

A pooled analysis of the three ECOG/Intergroup trials (with median follow-up ranging from 2.1-12.6 y) revealed that RFS, but not OS, was significantly prolonged for patients treated with high-dose IFN versus observation.[73] A subsequent systematic review and meta-analysis showed a modest benefit in OS in four of 14 comparisons but combined multiple low-, intermediate-, and high-dose regimens.[74] However, a more recent systematic review of seven randomized controlled trials demonstrated no OS benefit between adjuvant high-dose IFN and observation, although a meta-analysis of disease-free survival showed a significant benefit for high-dose IFN over control.[75]

A European Organization for Research and Treatment of Cancer (EORTC) randomized, phase III trial of adjuvant pegylated IFN alfa-2b (Peg-Intron) (PEG-IFN) in patients with resected stage III melanoma similarly showed no OS benefit but almost 12% improvement in RFS, although largely restricted to patients with microscopic lymph node involvement.[76] Long-term results of this trial at 7.6 years median follow-up demonstrated a slightly diminished impact on RFS, with a 7-year RFS rate of 39.1% in the PEG-IFN arm compared with 34.6% in the observation arm; however, no difference was observed in OS with longer follow-up. The subgroup of patients with ulcerated primary tumors and sentinel lymph node metastasis appeared to show the most consistent benefit from adjuvant treatment with PEG-IFN.[77]

The potential benefits of high-dose IFN (given in either the pegylated form or standard year-long regimen) must be weighed against its substantial tolerability and toxicity issues, including commonly associated flulike symptoms and potential for significant adverse reactions.

New adjuvant immunotherapies/regimens for resected stage III melanoma

Ipilimumab (Yervoy), an immune checkpoint inhibitor of cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), was approved in October 2015 for the adjuvant treatment of patients with cutaneous melanoma with pathologic involvement of regional lymph nodes larger than 1 mm who have undergone complete resection, including total lymphadenectomy. Approval for adjuvant therapy was based on results from the EORTC 18071 study that was conducted in 951 high-risk patients with stage III melanoma who had undergone a complete lymph node dissection.[78] Recurrence-free survival was significantly higher in the ipilimumab group compared with the placebo group at 1 year (63.5% vs 56.1%), at 2 years (51.5% vs 43.8%), and at 3 years (46.5% vs 34.8%). Patients in the ipilimumab group were 25% less likely to experience melanoma recurrence than those in the placebo group (P = .0013). Median recurrence-free survival was also improved in the ipilimumab group (26.1 vs 17.1 months). The FDA-approved regimen for adjuvant ipilimumab (10 mg/kg q3wk for 4 doses then every 3 months for up to 3 y) for provides significantly higher dosing and duration than that approved for patients with unresectable stage III and IV melanoma. Since immune-related adverse events are dose-related with CTLA-4 antibody therapy,[79] the risks of high-dose adjuvant ipilimumab must be weighed against its improvement in RFS alone, with no improvement in OS demonstrated thus far. Pending analysis of the phase 3 ECOG E1609 trial assessing the use of low (3 mg/kg) versus high-dose ipilimumab compared with high-dose IFN in patients with resected stage IIIB and IV melanoma will help to establish the efficacy of low-dose ipilimumab in the adjuvant setting. CTLA-4 single-nucleotide variants may be predictive of the biologic response.[80]

The anti–programmed-death-receptor-1 (PD-1) agent pembrolizumab was approved in September 2014 for unresected stage III and IV melanoma and has demonstrated efficacy in ipilimumab-refractory advanced melanoma.[81, 82, 83, 84] An additional PD-1 inhibitor, nivolumab, was approved in October 2015, and both PD-1 blockers are now considered first-line monotherapy in patients with advanced (unresectable stage III and IV) melanoma and are now being studied for adjuvant therapy in resected, earlier-stage melanoma.[85] Known adverse effects include induction of immunobullous disease, especially pemphigoid, as well as eruptive keratoacanthomas similar to those seen with BRAF therapy.[86, 87, 88, 89]

Adjuvant biochemotherapy is also a consideration for resected stage III melanoma, based on results from a phase 3 SWOG S0008 trial using a 9-week regimen consisting of cisplatin, vinblastine, dacarbazine, interleukin (IL)–2, and IFN, compared with the standard 52-week regimen of high-dose IFN alfa-2b in patients with resected stage III melanoma.[90] Patients with the lowest risk category, with a single regional nodal micrometastasis and no ulceration of the primary melanoma (N1a), were excluded from the study. Improved RFS was noted in biochemotherapy-treated patients compared with those on high-dose IFN (4 years vs 1.9 years, respectively, 95% confidence interval [CI], 0.58-0.97), although median and 5-year OS rates did not significantly differ between the treatment groups. However, substantial toxicity associated with the biochemotherapy regimen is expected to limits its use in clinical practice.

Melanoma vaccines

Melanoma vaccines are a theoretically attractive alternative to chemotherapy or immunotherapy with systemic cytokines because they are typically associated with relatively little toxicity (eg, fatigue, myalgias, local inflammatory skin reactions). Melanoma vaccines are a type of specific active immunotherapy based on melanoma cell expression of certain HLA- and tumor-associated antigens. Numerous melanoma-associated antigens have been identified, and which of these are the most important in eliciting the necessary cytotoxic and humoral responses to kill melanoma cells remains unclear. In addition, HLA haplotype restriction (mainly to the A2 allele) limits the use of peptide vaccines in many patients. Most current trials for melanoma vaccines are for advanced disease (stages III and IV); trials aimed at prevention are not yet available.

Vaccine types include whole cell preparations, cell lysates, gangliosides, peptides/proteins, dendritic cell vaccines, and DNA vaccines. Melanoma vaccines may be (1) autologous (killed cell and recombinant types), allogeneic, shed from tumor, defined antigen-directed, or genetically engineered and (2) either polyvalent or univalent in nature. Enhanced delivery systems, such as dendritic cell preparations, DNA-plasmid vectors, and intranodal infusion, are under active study to enhance immunogenicity and host response. Biologic response modifiers such as granulocyte macrophage colony-stimulating factor, IL-2, IL-12, and IFN gamma are often integrated into vaccine strategies.

As yet, no large, phase III randomized trial has demonstrated an OS advantage for vaccine-treated melanoma patients. However, a phase III trial of gp100:209-217(210M) peptide vaccine in combination with high-dose IL-2 showed significant improvement in response rate and progression-free survival compared with IL-2 alone and provides the first evidence of clinical benefit for vaccine strategies in patients with melanoma.[91, 92, 93] Vaccine strategies remain challenging in melanoma but continue to be studied.

BRAF and MEK inhibitors for advanced melanoma (unresectable stage III and IV)

The mitogen-activated protein kinase (MAPK) signaling pathway (RAS/RAF/MEK/ERK) has been found to be constitutively activated in up to 80-90% of melanomas, with the most common mutations in either NRAS (15-30% of melanomas) or BRAF (50-70% of melanomas). Drugs that target this pathway, including multikinase inhibitors, which decrease BRAF activity, are highly effective in treating metastatic melanoma.[94, 95, 96]

Vemurafenib (Zelboraf) was approved by the FDA in August 2011. It is an inhibitor of some mutated forms of BRAF serine-threonine kinase, including BRAF(V600E). The drug is indicated for the treatment of unresectable or metastatic melanoma with BRAF(V600) mutation as detected by the cobas 4800 BRAF V600 Mutation Test (Roche Molecular Systems). Vemurafenib and other BRAF inhibitors are contraindicated in patients with wild-type BRAF melanoma.

The BRAF Inhibitor in Melanoma (BRIM)–3 study results showed vemurafenib improved progression-free and overall survival compared with standard chemotherapy in patients with advanced melanoma with no previous treatment. Results found vemurafenib had a 74% reduction in the risk for progression (or death) compared with patients receiving dacarbazine chemotherapy (hazard ratio, 0.26; P< .001). Mean progression-free survival was 5.3 months in the vemurafenib group, compared with 1.6 months in the dacarbazine group. At 6 months, the estimated OS rate was 84% (95% CI, 78-89) in the vemurafenib group and 64% (95% CI, 56-73) in the dacarbazine group.[95]

Adverse effects from vemurafenib monotherapy are largely cutaneous and include photosensitivity, which appears to be driven by UV-A light,[97] alopecia, xerosis, follicular hyperkeratosis (keratosis pilaris‒like), rash, and potential development of cutaneous squamous cell carcinoma (SCC), particularly the keratoacanthoma type. The keratinocyte proliferations observed with BRAF inhibition, ranging from benign papillomas to SCC, tend to appear early in the course of treatment and are likely driven by paradoxical activation of the MAPK pathway. Reports of atypical melanocytic proliferations in patients on selective BRAF inhibitors, including new primary melanomas and dysplastic nevi, highlight the need for routine skin examination in all treated individuals.[98]

Dabrafenib (Taflinar) is a newer BRAF inhibitor that inhibits the mutant BRAF protein in melanomas with either the V600E or V600K genotype. A phase III study demonstrated high clinical response rates and improved progression-free survival in BRAF(V600E) metastatic melanoma patients who received dabrafenib compared with dacarbazine.[99] Efficacy has also been demonstrated in BRAF(V600K) patients and in those with brain metastasis. Dabrafenib appears similar to vemurafenib in terms of efficacy but may be associated with less photosensitivity, although it is associated with increased pyrexia; it was FDA approved in May 2013.[100]

A subsequent phase III open-label trial assessing the use of an oral selective MEK inhibitor, trametinib (Mekinist), versus dacarbazine in 322 patients with metastatic melanoma (unresectable stage IIIC or IV) demonstrated improved rates of progression-free and OS in patients with the BRAF(V600E) or BRAF(V600K) mutation.[101] At 6 months, OS was 81% in the trametinib group and 67% in the chemotherapy group, despite allowances for cross-over from the chemotherapy group to the trametinib group following disease progression (hazard ratio for death, 0.54; 95% CI, 0.32-0.92, P = .01). Rash, diarrhea, and peripheral edema were the most common toxic effects in the trametinib group, although secondary skin neoplasms, including cutaneous SCCs, were not noted.

Trametinib was FDA approved in May 2013 as a single agent. The combination of BRAF and MEK inhibitors (dabrafenib/trametinib) has shown higher response rates and more durable clinical benefit than monotherapy[102, 103] and was FDA approved in January 2014. Combination BRAF/MEK inhibition is now considered first-line therapy over BRAF monotherapy.

Two phase III trials (COMBI-v and coBRIM) demonstrated that combination therapy with a BRAF inhibitor and a MEK inhibitor is more efficacious than therapy with a BRAF inhibitor alone, with longer progression-free survival, resulting in FDA approval in 2014 for vemurafenib/dabrafenib as first-line therapy over BRAF inhibitor monotherapy, and for vemurafenib/cobimetinib in 2015. Combination therapy is the standard of care for BRAF mutant advanced melanoma, particularly in the setting of rapidly progressing and/or high-volume metastasis.[104]

Immune checkpoint inhibitors for advanced melanoma (unresectable stage III and IV)

Ipilimumab is a monoclonal antibody against CTLA-4, which inhibits T-cell inactivation, allowing expansion of melanoma-specific cytotoxic T cells. Ipilimumab, a CTLA-4 blocker, was the first drug to demonstrate an OS in stage IV melanoma and was FDA approved in 2011 for patients with unresectable stage III and IV melanoma.

In the pivotal phase III trial, ipilimumab (3 mg/kg q3wk for 4 treatments) was shown to enhance T-cell response in HLA-A2–positive patients and prolong OS in patients with metastatic melanoma compared with a glycoprotein 100 (gp 100) peptide vaccine (median OS, 10.1 vs 6.4 months, respectively; hazard ratio for death 0.66; P = .003). Durable responses were observed for over 2 years in 9 (60%) of 15 of ipilimumab responders, suggesting a durable response benefit that has been demonstrated to be independent of HLA status.[105] Results of a phase III trial comparing dacarbazine plus ipilimumab (administered at 10 mg/kg ) versus dacarbazine alone also demonstrated improved median OS in the ipilimumab-treated group (11.2 vs 9.1 months), with a consistent survival benefit noted at years 1, 2, and 3 of follow-up.[106]

However, the use of both low- and high-dose ipilimumab is tempered by potential severe immune-related adverse events, primarily enterocolitis and hypophysitis, which require prompt initiation of high-dose corticosteroids and/or other immune response modifiers, as well as hormone replacement for hypophysitis (including hypopituitarism and adrenal insufficiency) alteration. Dermatitis, pruritus, and potential vitiligo may also be seen with ipilimumab therapy, emphasizing the importance of dermatologic consultation for management of associated skin conditions.

Enhanced antitumor activity has also been demonstrated with human monoclonal antibodies against the programmed death-1 (PD1) protein, a T-cell co-inhibitory receptor, or its ligand, PD-L1. Objective responses, durable tumor regression, and prolonged stabilization of disease were demonstrated in patients with a variety of advanced cancers, including non–small-cell lung cancer, renal cell cancer, and melanoma following treatment with the anti–PD-L1 antibody BMS-936559, with reduced toxicity in comparison to ipilimumab. Objective responses (complete or partial) were observed in 9 (17%) of 52 of melanoma patients, generating enthusiasm for these agents in patients with metastatic disease.[107, 108]

Accelerated FDA approval of the PD1 inhibitor pembrolizumab (Keytruda) was granted in September 2014 for patients with advanced or unresectable melanoma following progression on prior therapies, including ipilimumab and BRAF inhibitors.[109] , although it was approved as first-line therapy in December 2015, based on demonstrated superior survival and lower toxicity compared with ipilimumab in the phase 3 KEYNOTE-006 trial.[110]

Concurrent studies of the PD1 inhibitor nivolumab (Opdivo) showed similar durable tumor remission and long-term safety, with median OS of 16.8 months and 1- and 2-year survival rates of 62% and 43%, respectively, in patients with advanced, treatment-refractory melanoma.[111] The use of nivolumab in previously untreated BRAF wild-type melanoma patients showed significantly improved OS at 1 year compared with dacarbazine (72.9% vs 42.1%, respectively), with objective response rates of 40% versus 13.9%, respectively, resulting in FDA approval of nivolumab in March 2015.[112] Subsequent documented superior progression-free survival over ipilimumab in the CheckMate 067 trial has resulted in similar FDA approval as a first-line agent for metastatic melanoma.

The combination of ipilimumab and PD1 inhibitors has shown even greater efficacy in patients with advanced melanoma, but it is associated with increased toxicity.[113] The FDA approved the combination regimen of nivolumab plus ipilimumab in September 2015 in previously untreated patients with BRAF V600 wild-type unresectable or metastatic melanoma.[114] Since increased immune-related adverse events occur on the combined regimen, appropriate patient selection, careful monitoring during treatment, and prompt initiation of appropriate therapy are warranted.

In October 2015, the FDA approved talimogene laherparepvec, commonly known as T-vec (Imlygic), a genetically modified, live-attenuated herpes simplex virus programmed to replicate within tumors and produce the immune stimulatory protein granulocyte macrophage colony-stimulating factor (GM-CSF).[115] It is indicated for the local treatment of unresectable cutaneous, subcutaneous, and nodal lesions in patients with melanoma recurrence after initial surgery. It is administered by injection into cutaneous, subcutaneous, and/or nodal lesions that are visible, palpable, or detectable by ultrasound guidance.

Approval was based on results from the OPTiM study, a randomized, controlled trial conducted in adults with unresectable regionally or distantly metastatic melanoma.[116] The study enrolled 436 patients, of which 295 patients treated with talimogene laherparepvec were compared with 141 patients treated with GM-CSF. The primary endpoint was the durable response rate, defined as the rate of complete response plus partial response continuously lasting at least 6 months and beginning within the first 12 months. Secondary endpoints included OS and the overall response rate.

The durable response rate was significantly higher among patients who received talimogene laherparepvec compared with those given GM-CSF (16.3% vs 2.1%; odds ratio, 8.9; P< .001). Of the patients who experienced a durable response, 29.1% had a durable complete response and 70.8% had a durable partial response. The median time to response was 4.1 months (range, 1.2-16.7 months) in the arm receiving talimogene laherparepvec.

The overall response rate was also higher with talimogene laherparepvec (26.4% vs 5.7%; P< .001). In all, 32 (10.8%) patients receiving talimogene laherparepvec experienced a complete response, compared with just one (< 1%) patient receiving GM-CSF. The median time to treatment failure was 8.2 months with talimogene laherparepvec and 2.9 months with GM-CSF (hazard ratio, 0.42). Median OS was 23.3 months and 18.9 months, respectively (hazard ration, 0.79; P = .051), which just missed being statistically significant.

Surgical Care

Surgery is the primary mode of therapy for localized cutaneous melanoma.

Surgical margins for primary melanoma

The narrowest efficacious margins for cutaneous melanoma have yet to be determined. Surgical margins of 5 mm are currently recommended for melanoma in situ, and margins of 1 cm are recommended for melanomas less than or equal to 1 mm in depth (low-risk primaries).[117] In some settings of melanoma in situ, tissue sparing may be critical, and Mohs margin-controlled excision may be appropriate. A 2012 prospective study of 1120 melanoma in situ cases revealed that Mohs surgery, with 9-mm margins of normal-appearing skin around the melanoma, resulted in complete removal of almost 99% of lesions and was superior to 6 mm margins, which cleared only 86% of all tumors.[118] However, Mohs surgery is not recommended in either the NCCN or AAD melanoma guidelines for surgical resection of invasive cutaneous melanoma.

Randomized prospective studies show that 2-cm margins are appropriate for tumors of intermediate thickness (1-4 mm Breslow depth), although 1-cm margins have been proven effective for tumors of 1- to 2-mm thickness.[119, 120] Margins of 2 cm are recommended for cutaneous melanomas greater than 4 mm in thickness (high-risk primaries) to prevent potential local recurrence in or around the scar site.

A 2004 prospective study of melanoma greater than or equal to 2 mm thickness (median depth 3 mm) from the United Kingdom suggested that narrower margins (1 cm) result in higher locoregional recurrence compared with wider margins (3 cm), although no difference was noted in melanoma-specific survival between the two groups.[121] However, this study was criticized for combining satellite, in-transit, and regional nodal recurrences as the primary endpoint and by excluding SLNB (which would have demonstrated existing occult regional nodal metastasis at the time of wide local excision). Likewise, because a 2-cm margin is as efficacious as a 4-cm margin for melanomas of 1-4 mm depth, a 3-cm margin has been deemed unlikely to prove more beneficial than a 2-cm margin.

A retrospective study of high-risk primary melanomas (>4 mm thickness, median depth 6 mm) showed that excisional margins greater than 2 cm have no effect on local recurrence, disease-free relapse, or OS rates; therefore, a 2-cm margin is likely appropriate in this subgroup.[122]

In a recently concluded multicenter randomized controlled trial in 9 European countries from 1994 to 2002, 936 patients with clinical stage IIA–C cutaneous melanoma thicker than 2 mm were allocated 1:1 for wide excision with either 2- or 4-cm resection margin. With median follow up of 6.7 years, the overall 5-year survival in both groups was 65%, suggesting that a 2-cm resection margin is sufficient and safe for patients with cutaneous melanoma thicker than 2 mm.[123]

Mohs micrographic surgery has also been proposed for cutaneous melanoma and has the advantage of providing visualization of 100% of peripheral and deep margins microscopically. While studies have shown no increased local recurrence for Mohs surgery compared with historical controls, much of the data stem from thinner tumors with a lower risk of local recurrence and metastasis.[124] Mohs surgery may have certain "niche" indications, including melanomas located the head, neck, hands, or feet. Mohs surgery may prove useful in completely removing subclinical tumor extension in certain subtypes of melanoma in situ, such as lentigo maligna and acral lentiginous melanoma in situ.

Elective lymph node dissection

Prophylactic lymph node dissection for primary cutaneous melanoma of intermediate thickness initially was believed to confer a survival advantage on patients with tumors of 1-4 mm in depth. However, subsequent prospective randomized clinical trials have shown no survival benefit for elective lymphadenectomy for melanomas of varying thicknesses on the extremities and marginal, if any, benefit for nonextremity melanomas.[125, 126]

The 10-year follow-up data from two of the trials conducted by the World Health Organization and the Melanoma Intergroup suggested a survival benefit for certain subsets of patients studied. Patients with occult metastasis detected at the time of wide local excision who underwent immediate elective lymph node dissection had a significantly better 5-year survival rate (48%) compared with those who underwent delayed (therapeutic) lymph node dissection when lymphadenopathy became apparent clinically (27%).[127] However, the differences in OS rates for all patients who had delayed lymph node dissection were not statistically significant compared with the immediate node dissection group.

SLNB

Lymphatic mapping and sentinel node biopsy serve as the most effective and accurate means of staging the regional lymph node basin(s) in patients with melanoma greater than 1 mm in depth and in those less than or equal to 1 mm in depth with adverse features (eg, ulceration, lymphovascular invasion, high mitotic rate—particularly for tumors 0.76-1 mm in thickness).

SLNB for cutaneous melanoma was developed in the early 1990s to allow a selective approach to identifying individuals with occult regional nodal metastasis through localization of the first-draining, or sentinel, node. The success of the technique is based on the concept that cutaneous lymphatic flow is well-delineated in melanoma and that the histology of the sentinel node is characteristic of the entire lymph node basin (ie, a negative sentinel node obviates the need for further lymph node dissection). Both of these concepts were borne out in initial and subsequent studies of the staging technique.[128]

Preoperative radiographic mapping (lymphoscintigraphy) and vital blue dye injection around the primary melanoma or biopsy scar (at the time of wide local excision/reexcision) is performed to identify and remove the initial draining regional node(s).

The sentinel node is examined for the presence of micrometastasis using both routine histology and immunohistochemistry; if present, a therapeutic or completion lymph node dissection (CLND) has traditionally been performed, although recent data have shown no evidence of improved OS in patients who underwent CLND versus clinical observation following SLNB. A negative sentinel node biopsy result prevents the morbidity associated with an unnecessary lymphadenectomy.

Sentinel node status (positive or negative) is widely regarded as the most important prognostic factor for recurrence and the most powerful predictor of survival in melanoma patients. In a study of 612 patients with cutaneous melanoma (stage I/II), negative results from SLNB were associated with a nearly 60% increase in 3-year disease-free survival compared with positive SLNB results.[129]

Current AJCC melanoma staging and National Comprehensive Cancer Network clinical practice guidelines advocate pathologic staging of the regional lymph nodes for cutaneous melanoma of greater than 1 mm depth along with microstaging of the primary melanoma as the most complete means of staging.[54, 67]

SLNB provides the most reliable and accurate means of detecting occult regional nodal micrometastasis in clinically appropriate patients with primary melanomas and provides a more accurate determination of patient prognosis compared to clinical staging. However, its impact on overall survival has yet to be determined.[130] The results of the Multicenter Selective Lymphadenectomy Trial (MSLT), the Florida Melanoma Trial, and the Sunbelt Melanoma Trial have not demonstrated that SLNB provides a therapeutic benefit in patients with cutaneous melanoma, although low rates of sentinel lymph node positivity in all studies limit their power to detect an overall survival difference.

The final analyses of the MSLT-1 was published in 2014.[131] This analysis of the subset of 1270 patients with intermediate-thickness melanoma (1.2-3.5 mm) demonstrated no overall (melanoma-specific) survival differences in the group that underwent SLNB at the time of primary excision of the melanoma versus the group that underwent wide local excision alone. However, immediate lymphadenectomy in the setting of a positive sentinel lymph node was associated with improved 10-year survival compared with delayed  lymph node dissection in patients who developed macroscopic nodal metastasis following primary excision alone (62.1% vs 41.5%, respectively). The risk of death was reduced by nearly one half in this subset (hazard ratio, 0.56; 95% CI, 0.37-0.84; P = .0006) in the node-positive subset of patients who underwent immediate versus delayed lymph node dissection for regional nodal metastasis. The treatment-related difference persisted when patients with false-negative SLNB results were included in the final analysis (10-year melanoma-specific survival 56% vs 41.5%, respectively, hazard ratio, 0.67; 95% CI, 0.46-97; P = .04), However, OS rates did not differ in the subset of patients with thick melanoma (>3.5 mm).

The potential therapeutic benefit of early removal of micrometastasis in the regional nodal basin as well as the merits of CLND following a positive SLNB continue to be analyzed in various studies worldwide. Incorporation of newer molecular techniques, such as gene expression profiling, may aid in determining the therapeutic benefit and selection of the most appropriate patients for both SLNB and CLND. See the Medscape article The Role of Sentinel Node Biopsy in Skin Cancer for further information.

Consultations

Dermatologist, as follows:

  • For clinical assessment and biopsy of suspicious skin lesions to diagnose melanoma

  • For long-term follow-up of most patients with cutaneous melanoma

  • For surveillance of individuals at increased risk of melanoma based on mole phenotype, family history, sun sensitivity, and other factors

  • For early detection of suspicious pigmented lesions, particularly in patients at increased risk of melanoma

  • For surgical or topical treatment of cutaneous melanoma

  • For lifelong skin surveillance to detect possible new primary melanoma

Surgical oncologist, as follows:

  • For sentinel node biopsy, typically performed at the time of wide local excision and following preoperative lymphoscintigraphy

  • For surgical treatment of regional lymph node disease and soft tissue and/or in-transit recurrence (stage III disease)

  • For palliative surgical treatment of visceral and CNS metastasis

Medical oncologist, as follows:

  • To discuss adjuvant systemic therapy with approved agents or clinical trials: Patients with high-risk resected melanoma who are eligible for adjuvant therapy (usually stage III melanoma) should be referred to a medical oncologist or melanoma specialist soon after surgery in order to optimize the chances for appropriate adjuvant therapy or clinical trial entry. Patients with unresectable stage III or IV melanoma should be referred primarily to medical oncologists for initiation of first-line therapy with targeted agents, immune checkpoint inhibitors, or clinical trial consideration.

  • To discuss and initiate treatment of metastatic melanoma (stage IV) with chemotherapy, high-dose IL-2, concurrent biochemotherapy, or clinical trials, as indicated clinically

Nuclear medicine specialist, as follows:

  • For preoperative lymphoscintigraphy if SLNB is performed

  • For PET-CT scan interpretation

Pathologist/dermatopathologist, as follows:

  • For accurate histologic microstaging of primary melanoma

  • For evaluation of nodal tissue from SLNB for micrometastasis

  • For confirmation of the diagnosis of disseminated disease

Radiation oncologist, as follows:

  • For consideration of local adjuvant therapy for high-risk desmoplastic melanoma for improved local control, as detailed in current NCCN guidelines

  • For consideration of adjuvant treatment of resected regional nodal metastasis with extracapsular extension per current NCCN guideline recommendations

  • For palliative treatment of distant metastatic disease, particularly bony metastasis or brain involvement (whole brain radiotherapy or stereotactic radiosurgery)

Neurosurgeon, as follows:

  • For evaluation for resectable brain metastasis

Long-Term Monitoring

Patients should be monitored regularly after a diagnosis of cutaneous melanoma, particularly in the setting of thicker tumors, because most metastases occur in the first 1-3 years after treatment of the primary tumor. Annual skin examinations are recommended for life because an estimated 4-8% of patients with a history of melanoma develop new primary melanoma, generally within the first 3-5 years following diagnosis.[132] The risk of new primary melanoma increases in the setting of increased nevus count; multiple clinical atypical/dysplastic nevi; family history of melanoma; fair skin/sun sensitivity; prior in situ, nodular, and lentigo maligna melanoma; and male sex.[133] Additionally, individual patient risk factors should be taken into account in the determining the frequency of dermatologic surveillance.

The diagnosis of recurrent/metastatic disease and new primary melanoma depends on a routine evaluation schedule that varies according to the following:

  • Tumor depth

  • The presence of histologic ulceration

  • Mitotic rate in the primary tumor

  • Regional lymph node status

  • Results of the examination of the melanoma scar

  • Results of the examination of regional and distant lymph node basins

  • The presence of hepatosplenomegaly upon abdominal examination

  • Mole pattern and examination findings from the entire cutaneous surface for new primaries

 

Guidelines

Clinical Practice Guidelines

American Academy of Dermatology clinical practice guidelines

Guidelines have been released by the American Academy of Dermatology on the evaluation and management of primary cutaneous melanoma.[134]

Evidence strongly indicates that Breslow thickness, ulceration, and dermal mitotic rate are important predictors of patient outcome in primary cutaneous melanoma.

The recommended first-line treatment for any-thickness primary cutaneous melanoma, as well as for melanoma in situ, is surgical excision with histologically negative margins; tumor thickness should dictate the margins.

Surgical margins for invasive cutaneous melanoma, as measured clinically around the primary tumor, should be a minimum of 1 cm and a maximum of 2 cm, although narrower margins can be used to accommodate function and/or anatomic location. It is recommended that the excision be as deep as, but not inclusive of, the fascia.

It is not recommended that asymptomatic patients with newly diagnosed stage 0-II primary cutaneous melanoma undergo baseline radiologic imaging and laboratory studies.

For cutaneous melanoma at baseline, radiologic imaging and laboratory studies should be conducted only to assess the specific signs or symptoms of synchronous metastasis (regional nodal or distant).

At baseline or when physical examination of lymph nodes is equivocal and requires surveillance, the use of lymph node ultrasonography is encouraged. Surveillance with such imaging is also encouraged in the following patients:

  • Those who meet criteria for sentinel lymph node biopsy (SLNB) but do not undergo the procedure
  • Patients in whom SLNB is not possible or is technically unsuccessful (eg, because lymphoscintigraphic dye migration has failed and a draining sentinel lymph node cannot be identified)
  • Those in whom, despite a positive SLNB, complete lymph node dissection is not performed

Regular clinical follow-up represents the most important strategy for detecting cutaneous melanoma recurrence. The need for further radiologic or laboratory studies to detect local, regional, or distant metastatic disease should be determined via history (review of systems) and physical examination findings.

Patients should be taught self-examination of the skin and lymph nodes in order to detect recurrent disease or new primary cutaneous melanoma.

For the first 3 months of BRAF inhibitor monotherapy, patients with numerous squamoproliferative neoplasms should undergo dermatologic evaluation every 2-4 weeks, although less skin toxicity is associated with the standard treatment, combination BRAF/MEK inhibition.

Patients being treated with immune checkpoint inhibitors should undergo dermatologic evaluation within the first month of therapy, with such assessment being continued as needed to manage dermatologic adverse effects.

National Comprehensive Cancer Network clinical practice guidelines

Guidelines on systemic therapy for metastatic or unresectable cutaneous melanoma and recommendations for adjuvant systemic therapies were released in April 2019 by the National Comprehensive Cancer Network.[135]

Systemic therapy for metastatic or unresectable disease

Recommended first-line therapy (metastatic or unresectable disease):

  • Anti–programmed cell death protein 1 (PD1) monotherapy: Pembrolizumab, nivolumab

  • Combination targeted therapy for BRAF V600–activating mutation (preferred if clinically necessary for early response): Dabrafenib/trametinib, vemurafenib/cobimetinib, encorafenib/binimetinib

  • Useful in certain circumstances: Nivolumab/ipilimumab

Recommended second-line or subsequent therapy (disease progression or maximum clinical benefit from BRAF-targeted therapy):

  • Preferred regimens: Anti-PD1 monotherapy (pembrolizumab, nivolumab); nivolumab/ipilimumab; combination targeted therapy for BRAF V600–activating mutation (dabrafenib/trametinib, vemurafenib/cobimetinib, encorafenib/binimetinib)

  • Other regimens: Ipilimumab; high-dose interleukin 2 (IL-2)

  • Useful in certain circumstances: Ipilimumab/intralesional talimogene laherparepvec (T-VEC); cytotoxic agents; imatinib for tumors with activating mutations of KIT; larotrectinib for NTRK gene fusion–positive tumors

Recommended adjuvant systemic therapies

For stage III (sentinel lymph node positive) disease:

  • Primary treatment: Wide local excision of primary lesion and sentinel lymph node biopsy, followed by complete lymph node dissection or nodal ultrasound surveillance

  • Recommended options: Observation, nivolumab, pembrolizumab, combination dabrafenib/trametinib

For stage III (clinically positive nodes [no in-transit or satellite metastases]) disease:

  • Primary treatment: Wide local excision of primary lesion and complete lymph node dissection

  • Recommended options: Observation, nivolumab, pembrolizumab, combination dabrafenib/trametinib

For stage III (clinical or microscopic satellite/in-transit) disease:

  • Primary treatment: Complete surgical excision to clear margins

  • Recommended options: Observation, nivolumab, pembrolizumab, combination dabrafenib/trametinib

For stage IV resectable disease:

  • Primary treatment: Complete resection

  • Recommended options: Observation, high-dose ipilimumab (recommended only if patient has prior exposure to anti-PD1 therapy), nivolumab, pembrolizumab

For local satellite/in-transit disease recurrence:

  • Primary treatment: Complete surgical excision to clear margins

  • Recommended options: Observation, nivolumab, pembrolizumab, combination dabrafenib/trametinib

For nodal recurrence:

  • Primary treatment: Excise nodal metastasis and complete lymph node dissection (if incomplete or no prior complete lymph node dissection)

  • Recommended options: Observation, high-dose ipilimumab (recommended only if patient has prior exposure to anti-PD1 therapy), nivolumab, pembrolizumab, combination dabrafenib/trametinib

 

Medication

Medication Summary

High-dose interferon (IFN) alfa-2b was the first  adjuvant therapy approved by the US Food and Drug Administration (FDA) for high-risk resected melanoma, defined as deep primaries greater than 4 mm in Breslow depth (AJCC stage IIB) and regional lymph node metastasis (stage III). Various trials of low-dose IFN have shown no benefit in disease-free relapse or overall survival (OS) rates,[136] although a benefit in both disease-free and OS was suggested in a study of low-dose IFN in resected stage III patients in a German Dermatologic Cooperative Oncology Group study.[137] A 2012 analysis of adjuvant therapy with low-dose pegylated IFN (PEG-IFN) administered for 36 months versus low-dose IFN for 18 months in melanoma patients with macrometastatic nodes did not reveal differences in disease-free survival, distant metastasis-free survival (DMFS), or OS, suggesting lack of superiority of adjuvant low-dose PEG-IFN.[138] Similarly, multiple melanoma vaccine trials are in progress, predominantly for stage III and IV disease, but they have not demonstrated an OS advantage to date.

Ipilimumab, a CTLA-4 blocker, was FDA approved in 2015 for resected stage III melanoma, although the risk of immune-related adverse events have tempered enthusiasm for the high-dose regimen in the adjuvant setting.[79, 106]

Talimogene laherparepvec (Imlygic) was approved in 2015. It is a genetically modified, live-attenuated herpes simplexvirus programmed to replicate within tumors and produce the immune-stimulatory protein granulocyte macrophage colony-stimulating factor (GM-CSF). It is indicated for the local treatment of unresectable cutaneous, subcutaneous, and nodal lesions in patients with melanoma recurrence after initial surgery.

Immunomodulatory Agents

Class Summary

Immunomodulatory agents enhance host immunity for cancer surveillance and eradication.

Interferon alfa-2b (Intron A)

Interferon alfa-2b is a protein product manufactured by recombinant DNA technology. It is produced naturally by cells in the body to combat infections and tumors. Its mechanism of antitumor activity is not clearly understood; however, direct antiproliferative effects against malignant cells and modulation of host immune response may play important roles.

Interferon alfa-2b is generally initiated within 56 days of surgery and typically administered by medical oncologists.

Antineoplastics, Monoclonal Antibodies

Class Summary

Monoclonal antibodies are considered second-line treatment for unresectable or metastatic melanoma. The agents also include inhibitors of programmed death-1 (PD1) protein, a T-cell co-inhibitory receptor, pembrolizumab and nivolumab.

Ipilimumab (Yervoy)

Ipilimumab is a targeted T-cell antibody. It is a recombinant, human cytotoxic T-lymphocyte antigen 4 (CTLA-4)–blocking antibody indicated for unresectable or metastatic melanoma. CTLA-4 is a negative regulator of T-cell activation. Ipilimumab binds to CTLA-4 and blocks the interaction of CTLA-4 with its ligands, CD80/CD86. Blockade of CTLA-4 has been shown to augment T-cell activation and proliferation. The proposed mechanism of action is indirect, possibly through T-cell–mediated antitumor immune responses. Ipilimumab is an IgG1 kappa immunoglobulin with an approximate molecular weight of 148 kd. It is produced in mammalian (Chinese hamster ovary) cell culture.

It is indicated for the treatment of unresectable or metastatic melanoma. Additionally, it is indicated for the adjuvant treatment of patients with cutaneous melanoma with pathologic involvement of regional lymph nodes >1 mm who have undergone complete resection, including total lymphadenectomy. It is also indicated in previously untreated patients with BRAF V600 wild-type, unresectable or metastatic melanoma in combination with nivolumab.

Pembrolizumab (Keytruda)

Pembrolizumab is indicated for unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor

Nivolumab (Opdivo)

Nivolumab is indicated for unresectable or metastatic melanoma and disease progression following ipilimumab treatment and, if BRAF V600 mutation positive, a BRAF inhibitor.

Antineoplastics, Other

Class Summary

Some mutations in the BRAF gene including V600E result in constitutively activated BRAF proteins, which can cause cell proliferation in the absence of growth factors that would normally be required for proliferation. Mitogen-activated extracellular signal regulated kinase (MEK) inhibitors are used in combination with BRAF inhibitors or in single-agent therapy.

Vemurafenib (Zelboraf)

Vemurafenib is a BRAF inhibitor indicated for unresectable or metastatic melanoma with BRAF-V600 mutation as detected by an FDA-approved test. It is not recommended for use with wild-type BRAF melanoma.

Trametinib (Mekinist)

Trametinib is a MEK inhibitor indicated as a single agent or in combination with dabrafenib for unresectable or metastatic melanoma with BRAF V600E or V600K mutations.

Dabrafenib (Taflinar)

Dabrafenib is a BRAF protein kinase inhibitor indicated as a single agent for unresectable or metastatic melanoma with BRAF V600E mutation, or in combination with trametinib for BRAF V600E or V600K mutations.

Oncolytic Immunotherapy

Class Summary

These agents are used adjunctively following the resection of lesions.

Talimogene laherparepvec (Imlygic)

The exact mechanism of action is unknown. Talimogene laherparepvec is a genetically modified, live-attenuated herpes simplex virus programmed to replicate within tumors and to produce the immune stimulatory protein GM-CSF. It causes lysis of tumors, followed by the release of tumor-derived antigens, which together with virally derived GM-CSF may promote an antitumor immune response. It is a solution for intralesional injection that may be considered for local treatment of unresectable cutaneous, subcutaneous, and nodal lesions in patients with melanoma recurrence after initial surgery.

 

Questions & Answers

Overview

What is cutaneous melanoma?

What is the pathophysiology of cutaneous melanoma?

What causes cutaneous melanoma?

What are primary risk factors for cutaneous melanoma?

What are universal risk factors for cutaneous melanoma?

What is the prevalence of cutaneous melanoma in the US?

What is the global prevalence of cutaneous melanoma?

What are the racial predilections of cutaneous melanoma?

What are the sexual predilections of cutaneous melanoma?

Which age groups have the highest prevalence of cutaneous melanoma?

Which factors affect the prognosis of cutaneous melanoma?

What is the prognosis of stage I and II cutaneous melanoma?

What is the prognosis of stage III cutaneous melanoma?

What is the prognosis of stage IV cutaneous melanoma?

What are the morbidity rates for cutaneous melanoma in the US?

What are the global mortality rates for cutaneous melanoma?

What is included in patient education about cutaneous melanoma?

Presentation

Which clinical history findings are characteristic of cutaneous melanoma?

What are the ABCDE criteria for a changing mole in the diagnosis of cutaneous melanoma?

Which physical findings are characteristic of amelanotic melanoma?

Which physical findings are characteristic of cutaneous melanoma?

Which physical findings are characteristic of superficial spreading melanoma?

Which physical findings are characteristic of nodular melanoma?

Which physical findings are characteristic of lentigo maligna melanoma?

Which physical findings are characteristic of acral lentiginous melanoma?

What are the rare melanoma variants?

Which physical findings are characteristic of desmoplastic melanoma?

Where does metastasis occur in cutaneous melanoma?

DDX

Which conditions are included in the differential diagnoses of cutaneous melanoma?

What are the differential diagnoses for Cutaneous Melanoma?

Workup

What is the role of lab testing in the workup of cutaneous melanoma?

What are the components of cutaneous melanoma surveillance?

What is the role of lab testing in cutaneous melanoma staging?

What is the role of imaging studies in the workup of cutaneous melanoma?

What is the role of biopsy in the diagnosis of cutaneous melanoma?

Which histologic findings are characteristic of cutaneous melanoma?

How is cutaneous melanoma staged?

Treatment

What is the role of pembrolizumab in the treatment of cutaneous melanoma?

What is the efficacy of adjuvant therapies for the treatment of cutaneous melanoma?

What is the role of high-dose IFN in the treatment of cutaneous melanoma?

What is the role of ipilimumab (Yervoy) in the treatment of cutaneous melanoma?

What is the role of biochemotherapy in the treatment of cutaneous melanoma?

What is the role of melanoma vaccines in the treatment of cutaneous melanoma?

What is the role of BRAF inhibitors in the treatment of cutaneous melanoma?

What is the role of ipilimumab in the treatment of cutaneous melanoma?

What is the role of PD1 inhibitors in the treatment of cutaneous melanoma?

What is the role of T-vec (Imlygic) in the treatment of cutaneous melanoma?

What is the role of surgery in the treatment of cutaneous melanoma?

What are the recommended surgical margins in the surgical treatment of cutaneous melanoma?

What is the role of lymph node dissection in the treatment of cutaneous melanoma?

What is the role of sentinel lymph node biopsy (SLNB) in the treatment of cutaneous melanoma?

What is the role of a dermatologist in the treatment of cutaneous melanoma?

What is the role of a surgical oncologist in the treatment of cutaneous melanoma?

What is the role of a medical oncologist in the treatment of cutaneous melanoma?

What is the role of a nuclear medicine specialist in the treatment of cutaneous melanoma?

What is the role of a dermatopathologist in the treatment of cutaneous melanoma?

What is the role of a radiation oncologist in the treatment of cutaneous melanoma?

What is the role of a neurosurgeon in the treatment of cutaneous melanoma?

What is included in the long-term monitoring of patients with cutaneous melanoma?

How is recurrent/metastatic cutaneous melanoma diagnosed?

Guidelines

According to the American Academy of Dermatology guidelines, what the prognostic factors for primary cutaneous melanoma?

What are the American Academy of Dermatology first-line treatment recommendations for primary cutaneous melanoma?

What are the American Academy of Dermatology recommendations for baseline and surveillance imaging of primary cutaneous melanoma?

What are the American Academy of Dermatology recommendations for long-term monitoring following treatment of primary cutaneous melanoma?

What are the American Academy of Dermatology recommendations for monitoring patients receiving BRAF inhibitor monotherapy for primary cutaneous melanoma?

What are the American Academy of Dermatology recommendations for monitoring patients receiving immune checkpoint inhibitors for primary cutaneous melanoma?

What are the NCCN guidelines on first-line treatment for metastatic or unresectable cutaneous melanoma?

What are the NCCN guidelines on second-line treatment for metastatic or unresectable cutaneous melanoma?

What are the NCCN guidelines on adjuvant therapies for stage III melanoma?

What are the NCCN guidelines on adjuvant therapies for stage IV melanoma?

What are the NCCN guidelines on adjuvant therapies for melanoma recurrence?

Medications

What is the role of medications in the treatment of cutaneous melanoma?

Which medications in the drug class Oncolytic Immunotherapy are used in the treatment of Cutaneous Melanoma?

Which medications in the drug class Antineoplastics, Other are used in the treatment of Cutaneous Melanoma?

Which medications in the drug class Antineoplastics, Monoclonal Antibodies are used in the treatment of Cutaneous Melanoma?

Which medications in the drug class Immunomodulatory Agents are used in the treatment of Cutaneous Melanoma?