34. Меланома

The American Cancer Society’s Oncology in Practice: clinical management (2018)

Edited by American Cancer Society


Заболеваемость и смертность

Melanoma incidence is rising faster than that of almost all other cancer in the United States (US), and in 2017 there were an estimated 87,110 new cases of invasive melanoma [1]. Annual incidence rate increases of 2–3% per year have been noted in many European countries. In Australia and New Zealand, the two countries with the greatest burden of melanoma incidence, rates have doubled nearly every 10 years. Melanoma incidence has increased steadily over the past 30 years, and since 2004, by 3% annually in Caucasians [2]. Bimodal increases are apparent, with incidence rates rising more than twofold among young women (ages 20–29) and increasing even more sharply among middle-aged and older men.

The increase in melanoma incidence has been attributed to many factors: primarily, increased intermittent ultraviolet radiation (UVR) exposure among fair-skinned populations, via travel to sunny locales and through past wartime service. Several alternative factors have been proposed to contribute to the dramatically increased melanoma incidence in developed countries over the past 70 years, including higher rates of skin biopsies and screening resulting in the detection of thinner, more indolent lesions, and changes in the histologic interpretation of early evolving lesions.

Approximately 9,730 individuals in the US [1] and 23,000 Europeans die from melanoma each year, comprising about 75% of the world’s melanoma deaths [3]. In the US and elsewhere, mortality rates for most cancers are dropping, whereas mortality rates of melanoma have only recently stabilized or continue to rise slightly. From 1969 through 2008, mortality declined among men and women aged 20–44. However, the mortality rate among men over age 65, who comprise 36% of all deaths but only 20% of all cases, rose by more than 150% during the same period [2]. These US mortality patterns are evident in most developed countries.

Прогностические факторы

Толщина опухоли

Survival rates decline steadily as the tumor thickness and disease stage increase. Over 95% of individuals diagnosed with melanoma ≤1 mm in thickness (T1) can expect prolonged survival and even cure, while individuals with thicker, later stage lesions (>4 mm) are more likely to die from metastatic disease (5-year survival rates ranging from 50 to 75% depending on other staging parameters) [4]. While a 5-year period is typically used to measure survival, a 2012 study in Queensland found 96% 20-year survival for individuals diagnosed with thin melanoma (≤1 mm) [4].

Many developed countries such as Australia, the US, and Sweden have 5-year survival rates exceeding 90%. In contrast, a number of countries in Eastern Europe have 5-year survival rates of 60%, similar to what was seen in advanced countries nearly 50 years ago. Of the more than 20,000 deaths from melanoma in Europe in 2008, Central and Eastern Europe comprise 35.5% of the total, although they have the smallest population in the region [3].

Возраст и пол пациентов и локализация первичной опухоли

A number of clinical factors affect patient prognosis including age, gender, and anatomic location of the primary tumor. In general, men, older individuals, and those with melanoma on the head and neck tend to fare worse. A population-based study in France during 2004–2008 showed that male patients had thicker and more frequently ulcerated tumors. Anatomic location varied between genders, involving the trunk in 47% of male patients and the legs in 48% of female patients. Older patients had thicker and more advanced melanomas, more frequently on the head and neck [5].

Подтипы меланомы

There is increasing evidence that the nodular subtype of melanoma accounts for a disproportionate number of melanoma deaths. In an Australian study, the median thickness of nodular melanoma (NM) at diagnosis was 2.6 mm compared with 0.6 mm for superficial spreading melanoma (SSM). A third of patients who died from melanoma during the follow-up period had thick tumors (>4 mm), most of which were NM (61%). Nodular melanoma accounted for 14% of invasive melanoma, but was responsible for 43% of melanoma deaths [4]. By comparison, SSM comprised 56% of invasive melanoma and 30% of deaths. A retrospective population-based cohort study of SEER data from 1978 to 2007 similarly demonstrated that among melanomas of known subtype, SSM comprised 66% of incident melanomas and 46% of ultimately fatal melanomas; in contrast, NM comprised only 14% of incident melanomas but 37% of fatal cases [6].

Этиология, факторы риска и предотвращение

Факторы риска и модели меланомы

Established risk factors for melanoma are discussed in The American Cancer Society’s Oncology in Practice: Clinical Management, Chapter 10, and include: (i) increased numbers of common/typical melanocytic nevi (“moles”), presence of clinically atypical/dysplastic nevi; (ii) fair-complexion phenotype, often seen in tandem with red hair, light eye color, and increased sun sensitivity; (iii) personal history of non-melanoma skin cancer (NMSC), including basal cell and squamous cell carcinomas; (iv) family history of melanoma; and (v) excessive sun exposure through either natural or artificial ultraviolet light. Several risk assessment models have been used to target individuals who are at high risk for melanoma [7], though there are no available models to identify those at highest risk of developing lethal melanoma. Preliminary components of such a model include targeting white middle-aged and older (>65 years) men and those without partners or significant others, who play an instrumental role in early detection through examination of the skin, prompting or arranging physician skin examinations, and assisting in treatment and diagnostic decisions. Thorough skin examination of high-risk areas such as the back and scalp is warranted given the disproportionate number of fatal melanomas in these locations.

One current risk assessment model has been derived from a large case-control study of 718 non-Hispanic White patients and 945 controls that provided data for primary care clinicians and patients alike [7]. This tool involves inspection of the back for suspect moles and asks two questions about complexion and history of sun exposure. Mild freckling and light complexion were risk factors for both men and women. In addition, >17 small moles and =2 large moles in men or =12 small moles on the backs of women were also significant risk factors. These data led to the Melanoma Risk Assessment Tool, which is available from the National Cancer Institute (http://www.cancer. gov/melanomarisktool/). The tool calculates absolute risk of melanoma over the next 5 years up to age 70.

Новые факторы риска меланомы

Screening and educational efforts can be more readily targeted to those with more established and identifiable risk factors. While individuals with the following risk factors are not as numerous as those noted earlier, jointly they represent a growing burden of risk thus requiring innovative behavioral strategies.

MC1R

The contribution of melanocortin-1 receptor (MC1R) gene variants to the development of early-onset melanoma is unknown. In an Australian population-based, case-control family study, MC1R sequencing of 565 young (18–39 years) patients with invasive cutaneous melanoma, 409 unrelated controls, and 518 sibling controls demonstrated that some MC1R variants were important determinants of early-onset melanoma, with strong associations in men and those with no or few nevi or with high childhood sun exposure [8].

История рака детства

History of cancer in childhood is a risk factor for subsequent malignancy, including melanoma. An analysis of childhood cancer survivors for subsequent melanoma risk demonstrated a standardized incidence ratio (SIR) of 2.42 (1.77, 3.23) [9]. The childhood cancer cases were generally those in the radiation field [9, 10].

Трансплантация органа

Organ transplant recipients receive long-term immunosuppression to prevent graft rejection. While transplant populations are at far greater risk of squamous cell carcinomas, they also develop more melanomas compared to the general population [11]. The age-adjusted incidence rate of melanoma among renal transplantation recipients was 55.9 diagnoses per 100,000 population representing a 3.6 times greater risk in age-adjusted, standardized risk from the SEER population [12].

Болезнь Паркинсона

A large systematic meta-analysis reviewed the association of Parkinson disease (PD) and melanoma and demonstrated increased relative risk (RR) of 1.56 (1.27, 1.91) [13]. A more recent publication showed a significant relationship in cases where PD preceded melanoma, with OR 3.61 (1.49, 8.77) Conversely, if melanoma preceded PD, the OR was reported as 1.07 (0.62, 1.84). Many limitations exist, thus there is a need for well-conducted prospective studies that can also attempt to develop biological plausibility for a PD and melanoma association.

Несолнечный загар/искусственные ультрафиолетовые лампы

Indoor tanning is thought to be the major contributor to the increasing incidence of cutaneous melanoma among young women. Increased risk of melanoma has been associated with increasing years, hours, and sessions of tanning behavior [14]. A 2011 review found that ever-users of sunbeds had a 41% increased melanoma risk compared with never-users [15]. When further subdivided, those who used sunbeds >10 times had a higher risk (OR 2.01: 1.22, 3.31), as did those with earlier age of first use [15]. Alarmingly, 76% of melanomas in fairskinned participants were attributed to tanning bed use at young ages. A meta-analysis of 27 studies found an overall summary RR for melanoma of 1.20 (1.08, 1.34) for “ever use” of sunbeds compared to those without this exposure. The RR for this exposure was even higher among individuals <35 years of age – 1.87 (1.41, 2.48) [16].

Патология

Молекулярная патология и патогенез

Despite the explosion in understanding of the molecular mechanisms driving melanoma, the sequence of events in which normal melanocytes transform into melanoma cells, referred to as melanomagenesis, remains poorly understood. It likely involves a multistep process of genetic mutations that (i) alter cell proliferation, differentiation, and death, and (ii) impact susceptibility to the carcinogenic effects of UVR [17].

The traditional Clark model of the progression of melanoma emphasized the stepwise transformation of melanocytes to melanoma, from the formation of nevi to the subsequent development of dysplasia, hyperplasia, invasion, and metastasis. However, this stepwise progression from melanocyte to mole to melanoma is relatively uncommon. In fact, fewer than 20–30% of melanomas are believed to arise from precursor nevi, though a higher proportion may be associated with histologically dysplastic nevi [18, 19]. The fact that most cutaneous melanomas arise de novo from normal-appearing skin suggests alternative pathways that bypass the nevus as a biologic intermediate, or that melanoma derives from transformed melanocyte stem cells or de-differentiated mature melanocytes [20]. This concept is supported by recent data suggesting difference in survival for patients with nevus-associated melanoma versus de novo melanoma, which may be more biologically aggressive [21]. However, Shain et al. defined the succession of genetic alterations during melanoma progression, suggesting an intermediate category of melanocytic neoplasia that may be defined by the controversial category of dysplastic nevi [22]. This study also underscored UVR as a major factor in both the initiation and progression of melanoma.

Сигнальные пути в меланоме

A number of cellular pathways have been identified in the development of melanoma. These span signal transduction to developmental and transcriptional pathways and cell cycle deregulation. Understanding of signaling events involved in melanomagenesis may allow for more nuanced differentiation of subsets of melanoma and define molecular signatures and subtypes associated with response and resistance to targeted therapy.

One growth factor pathway that has garnered considerable attention as related to melanoma is the RAS–RAF–MAPK– ERK signal transduction cascade. Oncogenic lesions introduce changes in the primary sequence of RAS so that the protein is constitutively active. Much of the attention surrounding this pathway in human melanoma focuses on the fact that, in virtually all cases, there is an alteration at some level in the RAS signaling cascade [23]. Specifically, NRAS and BRAF mutations occur in about 80% of the most common subtypes of melanoma.

Activating mutations in BRAF are found in approximately half of all melanomas, with the majority arising in intermittently sun-exposed skin, as compared with melanomas from chronically sun-exposed areas, acral, mucosal, and uveal melanomas, suggesting an inverse association with high levels of cumulative UV exposure [24, 25]. The most common BRAF mutation is the T1799A point mutation, BRAF V600E, which results in the protein taking on a constitutive active configuration. Since BRAF mutations are common in both benign and dysplastic nevi, it is likely that such mutations are not sufficient for malignant transformation of melanocytes [26]. However, the high frequency of these mutations suggests a role in the earliest stages of neoplasia. The etiologic factors resulting in the BRAF mutation remain unclear, specifically the role of UVR.

The c-KIT receptor tyrosine kinase has been shown to be amplified or mutated in a subset of melanomas, specifically those that develop on body sites with little to no UV exposure, such as acral and mucosal melanomas, or on chronically sundamaged skin [27]. Activation of this tyrosine kinase results in the stimulation of the MAPK and PI3K–AKT pathways, producing both proliferative and survival advantages [28].

None of the oncogenes or tumor suppressor genes identified in melanoma are thought to be solely responsible for melanoma pathogenesis. For instance, NRAS, as mentioned above, activates Raf kinases in response to growth factor receptor activation and harbors activating mutations in 15–20% of melanomas [29]. The loss of the p16 tumor suppressor is a relatively frequent event in melanoma, and there is significant overlap with BRAF mutation [30]. PTEN mutations and deletion have been described in a minority of melanomas and appear to coincide with BRAF mutation.

Клинико-патологические подтипы

Four major clinicopathologic subtypes of primary cutaneous melanoma have been identified: superficial spreading melanoma, nodular melanoma, lentigo maligna melanoma, and acral lentiginous melanoma (Table 34.1, Figures 34.1, 34.2, 34.3, 34.4, and 34.5). In addition, there are rare variants (accounting for <5% of melanomas) including: (i) desmoplastic/neurotropic melanoma, (ii) mucosal (lentiginous) melanoma [31], (iii) malignant blue nevus, (iv) melanoma arising in a giant/large congenital nevus, and (v) melanoma of soft parts (clear cell sarcoma). Distinction among the subtypes is based on histologic growth pattern, anatomic site, and degree of sun damage. The pattern of sun exposure varies between the types (chronic in lentigo maligna; intermittent in superficial spreading and nodular subtypes; and non-contributory in acral lentiginous and mucosal subtypes). Whether the melanoma subtype affects the overall prognosis remains controversial [17].

Desmoplastic melanoma is a relatively rare but important melanoma subtype, given its predilection for older-age individuals and clinical features similar to NMSC. 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. Lack of pigmentation and clinical features more suggestive of keratinocytic 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.

Таблица 34.1. Характеристика основных подтипов меланомы.

Подтип меланомы Клинические черты и анатомическая область Гистологические черты Вклад UV экспозиции Молекулярные черты
Поверхностно распространяющаяся Nearly 70% of cutaneous melanoma. Most common on the trunk in men and legs in women. Flat to slightly raised lesion that commonly displays the ABCD warning signs Radial in situ growth phase of atypical melanocytes arranged haphazardly at the dermoepidermal junction, prominent upward (pagetoid) migration Intermittent, high‐intensity exposure BRAF мутации наиболее часты
Нодулярная 15–30% of cutaneous melanoma. Most commonly on the legs and trunk in men and women. Dark brown to black papule or nodule demonstrating rapid growth over weeks to months No preceding radial growth phase, direct vertical extension of population of melanoma cells demonstrating proliferation and nuclear pleomorphism into the dermis Intermittent, high‐intensity exposure NRAS мутации наиболее часты
Злокачественное лентиго Typically located on the head, neck, and arms (chronically sun‐damaged skin) of fair‐skinned older individuals (average age 65 years). Slowly growing over years to decades. Large brown macule (in situ component) with development of raised blue‐black nodules (invasive component) Radial in situ growth at the dermoepidermal junction with little tendency for pagetoid scatter, background Chronic exposure KIT мутации наиболее часты
Акральная лентигинозная Least common subtype in White persons, most common subtype in African American, Asian, and Hispanic persons. Occurs on the palms, on the soles, or beneath the nail plate. Often delayed diagnosis as can mimic subungual hematoma, subungual wart, or fungal infection of the nail Radial in situ growth at the dermoepidermal junction with little tendency for pagetoid scatter Non‐contributory KIT, CDK4 и CDKN2A мутации наиболее часты

Figure 34.1. Superficial spreading melanoma on the right upper back of a middle-aged man.

Figure 34.2. Nodular melanoma on the lower mid-back of a middle-aged man.

Amelanotic melanoma is an uncommon clinical presentation (<5% of melanomas) and can be seen in any subtype. It is nonpigmented and clinically appears pink or flesh-colored, often mimicking basal cell or squamous cell carcinoma, dermatofibroma, or a ruptured hair follicle. Amelanotic melanoma occurs most commonly in the setting of the nodular or desmoplastic melanoma subtypes or melanoma metastasis to the skin, presumably because of the inability of these poorly differentiated cancer cells to synthesize melanin pigment (Figure 34.6).

Figure 34.3. Lentigo maligna melanoma, left cheek.

Figure 34.4. Acral lentiginous melanoma, sole of left foot.

Figure 34.5. Subungual melanoma, left great toe.

Figure 34.6. Amelanotic melanoma, right cheek.

Гистопатологические находки

With the exception of nodular melanoma, the growth patterns of the other clinicopathologic 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. Superficial spreading melanoma has an in situ (radial growth) phase characterized by increased numbers of atypical intraepithelial melanocytes arranged haphazardly at the dermoepidermal junction and demonstrates upward migration of cells through the epidermis (pagetoid spread). Lentigo maligna melanoma and acral lentiginous melanoma demonstrate predominant in situ growth at the dermoepidermal junction and little tendency for pagetoid spread.

Dermal invasion confers metastatic potential, although the greatest risk occurs in the setting of a vertical growth (tumorigenic) phase [32]. Immunohistochemical staining for lineage (S-100, homatropine methylbromide 45 (HMB-45), melan-A/Mart-1) or proliferation markers (proliferating cell nuclear antigen, Ki-67) may be helpful in some cases for histologic differentiation from histologic melanoma simulators such as melanocytic nevi, Spitz nevi, cellular blue nevus, clear cell sarcoma, or malignant peripheral nerve sheath tumor [33].

Диагноз

Диагноз меланомы кожи

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. Melanoma occurs most commonly on the trunk in White males and the lower legs in White females [34]. In African American, Hispanic, and Asian persons, the most common subtype of melanoma occurs on non-sunexposed areas including plantar foot, subungual, palmar, and mucosal sites.

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 [35].

From a clinical standpoint, a new or changing “mole” or other skin lesion 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 also warrant evaluation. Again, because the majority of cutaneous melanoma arise de novo and not in association with a precursor nevus, mass removal of melanocytic nevi is not warranted for melanoma prevention.

Clinician and patient education regarding the warning signs of early melanoma (particularly the superficial spreading subtype) has been enhanced through the use of the ABCDE clinical warning signs criteria [36] (Table 34.2). Lesions exhibiting these features should be evaluated for 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 ABCD criteria (e.g., nodular, amelanotic, or desmoplastic melanomas) [37].

Table 34.2. ABCDEs: clinical features of melanoma.

A Asymmetry – the two halves of the lesion do not match each other
B Border irregularity – may appear ragged, notched, or scalloped
C Color variation – color is not uniform or lesion may be many colors displaying shades of tan, brown, or black. White, reddish, or blue-gray discoloration is of particular concern
D Diameter – usually greater than 6 mm (roughly the diameter of a pencil eraser) although melanomas may be smaller in size; any growth in a nevus warrants an evaluation
E Evolving lesion – changes in size or color; critical for nodular or amelanotic melanoma, which may not exhibit the ABCD criteria above

The standard for melanoma diagnosis is histopathologic examination of the suspicious skin lesion. An excisional biopsy with narrow margins (1–3 mm) of normal-appearing skin around the lesion is preferred when possible to provide accurate diagnosis and histologic microstaging. Acceptable excisional biopsy techniques include a punch biopsy around the visible pigmented lesion, saucerization shave (extending into the deep reticular dermis or subcutaneous fat), or fusiform excision [38, 39]. Superficial shave biopsies for suspicious pigmented lesions should be avoided because partial removal of the primary melanoma may compromise measurement of tumor thickness, which remains the most important histologic prognostic factor for cutaneous melanoma [40].

An important exception to this rule is the lentigo maligna subtype of melanoma in situ, in which the risk of misdiagnosis is high if 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 [38, 39].

Стадийность

Tumor thickness, or 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. Importantly, the Eighth Edition of the AJCC Cancer Staging Manual records thickness to the nearest 0.1 mm, rather than the nearest 0.01 mm, due to the lack of precision in measurement beyond the 1/10th decimal point [41]. Increased tumor thickness confers a higher metastatic potential and a poorer prognosis [43]. 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, up-stages both cutaneous and nodal disease [44].

Clark level has been used for more than 40 years and provides a measurement of tumor invasion anatomically. However, analysis of the worldwide American Joint Committee on Cancer/ Union for International Cancer Control (AJCC/UICC) 2008 collaborative melanoma database 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 no longer included the Clark level in T1 melanomas (=1 mm depth), except in cases when mitotic rate could be assessed [44]. The Eighth Edition of the AJCC Cancer Staging Manual excludes Clark level from staging, noting its lack of predictive value for survival, compared with other prognostic variables [41].

In contrast, cellular proliferation within the primary tumor, as reflected by the mitotic rate (measured per mm2), emerged as an important predictor of survival [45]. Dermal mitotic rate ≥1/mm2 was used to up-stage T1a melanoma to T1b melanoma in the 2009 AJCC/UICC staging system [44]. However, tumor mitotic rate was removed as a staging criterion from the Eighth Edition of the AJCC Cancer Staging Manual, although histopathologic measurement of mitotic rate (#/mm2) is recommended across all tumor thicknesses given its impact on prognosis [41].

The AJCC/UICC Melanoma Staging System recommends sentinel lymph node (SLN) – biopsy be performed as a staging procedure in patients for whom the information will have clinical relevance in planning subsequent treatment and follow-up. The procedure is currently recommended by the National Comprehensive Cancer Network (NCCN) for patients who have T2, T3, or T4 melanomas and clinically uninvolved regional lymph nodes (clinical stages IB and II), as well as for patients with T1 melanomas and secondary features associated with increased risk for nodal micrometastases, including ulceration, lymphovascular invasion, and elevated mitotic rate (proposed as =2/mm2), especially when the primary melanoma is greater than 0.75 mm (now =0.8 mm, T1b) in thickness [44]. However, due to AJCC changes in the staging of T1a/b melanoma (effective January 2018), which recognize Breslow thickness =0.8 mm as the most reliable predictor of SLN positivity (regardless of histologic ulceration of dermal mitotic rate), current NCCN recommendations (www.nccn.org) utilize this tumor thickness as a threshold for SLNB consideration. Discussion of SLNB may also be appropriate in T1a melanoma (<0.8 mm without ulceration) when adverse histologic features are present, particularly in younger age patients [41, 42].

Лечение

Хирургия

Иссечение меланомы кожи

Wide local excision is the primary treatment for cutaneous melanoma (AJCC/UICC stages 0, I, and II). The goals of surgery are to achieve histopathologically clear margins and a low likelihood of local recurrence, including both true local recurrence at the margin (from inadequately excised primary melanoma) and metastatic local recurrence (i.e., satellites from intralymphatic spread of melanoma). Surgical margins of 5 mm were recommended for melanoma in situ by the National Institutes of Health (NIH) Consensus Development Conference on Diagnosis and Treatment of Early Melanoma in 1992, though this guideline was not based on prospectively controlled trials data [46]. In addition, certain melanoma in situ subtypes (e.g., lentigo maligna and acral lentiginous) often demonstrate subclinical extension and skip areas, making the use of histologically controlled margins through Mohs micrographic surgery or staged excision (e.g., “slow-Mohs”) potentially more effective compared to conventional wide local excision [17, 47]. Mohs micrographic surgery is generally not recommended for treatment of invasive melanoma, though it has been successfully used in the management of thinner tumors. Studies have shown no increased local recurrence for Mohs surgery compared with historical controls, although much of the currently published data stem from thinner tumors with a lower risk of local recurrence and metastasis [48, 49].

Clinical margins of 1 cm are generally recommended for T1 melanoma [46, 50] and may be acceptable for tumors between 1.01 mm and 2.0 mm thickness (T2), although 2-cm margins are also deemed appropriate for T2 melanoma [51, 52]. Margins of 2 cm are recommended for cutaneous melanomas >2 mm (T3, T4) to prevent potential local recurrence in or around the scar site. In a recently concluded multicenter randomized controlled trial in nine European countries from 1994 to 2002, 936 patients with clinical stage IIA–IIC cutaneous melanoma >2 mm were randomized to wide excision with either 2or 4-cm resection margins. 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 [53]. Both the NCCN and American Academy of Dermatology (AAD) melanoma practice guidelines recommend surgical margins of at least 1 cm and no greater than 2 cm for invasive melanoma, depending on tumor thickness [38, 39, 42].

Биопсия сторожевых лимфоузлов

Pathologic staging of the regional nodes via sentinel lymph node biopsy (SLNB) allows a selective approach to identifying cutaneous melanoma patients with occult regional nodal metastasis, thereby up-staging the melanoma to AJCC/UICC stage III.

Preoperative lymphatic mapping (lymphoscintigraphy) and vital blue dye injection around the primary melanoma or biopsy scar at the time of wide local excision is performed to identify and remove the sentinel lymph node(s), which are then examined histopathologically for the presence of micrometastasis using both routine histology and immunohistochemistry. If present, a completion lymph node dissection (CLND) has traditionally been performed, though as yet no difference in overall survival (OS) has been observed for SLN-positive patients who underwent CLND compared to those who did not [54, 55]. Approximately 8–20% of CLND patients will have non-sentinel nodal metastases. Current NCCN guidelines recommend that CLND be discussed and offered in the setting of a positive SLNB, although active nodal basin surveillance, typically with ultrasound, is an alternative to CLND. However, CLND may be recommended in the setting of higher SLN tumor burden, greater number of positive SLNs, and/or adverse histologic features in the primary melanoma [42]. Surveillance regional nodal ultrasound is increasingly recognized for its role in monitoring the regional nodal basin in patients who are eligible for SLNB or CLND but do not undergo these procedures or in whom SLNB is technically not successful, although ultrasound is not considered a replacement for either SLNB or CLND at this point [56].

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. Current NCCN and AAD clinical practice guidelines advocate pathologic staging of the regional lymph nodes with SLNB for cutaneous melanoma >1 mm depth and for thinner tumors with adverse features (e.g., ulceration, lymphovascular invasion, high mitotic rate) [39, 57]. A comprehensive systematic review of SLNB literature published from January 1990 through August 2011 was conducted by the American Society of Clinical Oncology and Society of Surgical Oncology and concurred with these recommendations [58]. As previously noted, NCCN guidelines stratify risk of SLN metastasis based on a Breslow depth cut-off point of 0.8mm (e.g. T1a/b), with recommendations to forego SLNB staging in patients with nonulcerated tumors 0.8 mm, unless other adverse histologic features are evident, for example lymphovascular invasion and/or very high mitotic index (particularly in younger age patients) [42].

While SLNB provides the most reliable and accurate means of staging appropriate patients with primary melanoma, its impact on overall survival has yet to be demonstrated. The final results of the first Multicenter Selective Lymphadenectomy Trial (MSLT-1), Florida Melanoma Trial, and Sunbelt Melanoma Trial have not shown a therapeutic benefit of SLNB in patients with cutaneous melanoma, although low rates of SLN positivity in these analyses limit their power to detect an overall survival difference [59]. Incorporation of novel molecular techniques may eventually aid in the selection of the most appropriate patients for SLNB and/or CLND.

Хирургическое лечение метастатической болезни

Surgery may consist of excision of dermal recurrences or intransit metastases, lymphadenectomy of nodal disease, and/or resection of visceral metastases. Distant metastases typically involve primarily the lung, liver, brain, gastrointestinal tract, and bone. Surgical treatment is generally offered for palliation of widespread metastases, although some data have suggested that metastasectomy of isolated visceral metastasis may result in improved survival for some patients with stage IV melanoma [60]. Candidates for operative intervention are generally those with isolated lung or brain metastases, although the role of metastasectomy for limited metastasis at other visceral sites has also been proposed. In rare cases, long-term survival may be achieved.

Терапия

Адъювантная системная терапия для резецированной меланомы

Numerous adjuvant therapies have been investigated for the treatment of cutaneous melanoma following surgical resection. High-dose interferon (IFN) alfa-2b and high-dose ipilimumab are currently approved by the US Food and Drug Administration (FDA) for adjuvant use in patients with melanoma at high risk for relapse (generally defined as resected stage III disease). Other immune checkpoint inhibitors, molecularly targeted agents (e.g., BRAF inhibitors), biologic response modifiers (e.g., granulocyte macrophage colony-stimulating factor (GM-CSF)), and various melanoma vaccines are currently being studied in the adjuvant setting for resected stage III and IV melanoma.

High-dose IFN alfa-2b was approved by the US Food and Drug Administration (FDA) in 1995 as an adjuvant therapy for resected primary tumors >4 mm in Breslow depth (AJCC stage IIB) and regional lymph node metastasis (stage III). High-dose pegylated IFN was FDA-approved as an adjuvant therapy for patients with resected stage III melanoma in 2011. Most trials of low-dose IFN have shown no benefit in disease-free survival (DFS) or OS rates, though a benefit in both DFS and OS was suggested in a study of low-dose IFN in resected stage III patients in a German Dermatologic Cooperative Oncology Group study [61]. A more recent 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 macrometastastic nodes did not reveal differences in DFS, distant metastasis free survival (DMFS), or OS [62].

In the US, three prospective, multicenter, randomized, controlled trials were 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) and have supported a consistent benefit in RFS but not OS [63].

A European Organisation for Research and Treatment of Cancer (EORTC) randomized, phase 3 trial of adjuvant high-dose pegylated interferon alfa-2b (PEG-IFN) in patients with resected stage III melanoma similarly showed no OS benefit but almost 12% improvement in RFS, though this was mostly limited to patients with microscopic lymph node involvement [64]. Longterm 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 SLN metastasis have appeared to show the most consistent benefit from adjuvant treatment with PEG-IFN [65].

More recent systematic reviews and meta-analyses have demonstrated conflicting findings. A meta-analysis of 14 randomized controlled trials of IFN-αlfa in varying doses (low, intermediate, and high) involving 8122 patients demonstrated significant improvement in DFS (hazard ratio (HR) for disease recurrence = 0.82; 95% confidence interval (CI) 0.77 to 0.87; P <0.001) and OS (HR for death = 0.89; 95% CI 0.83–0.96; P = 0.002), although the optimal IFN-α dose and treatment duration remain unclear [66]. However, an updated systematic review of seven trials comparing high-dose IFN-αlfa with observation demonstrated benefit in only DFS (HR 0.77; 95% CI 0.6500.92; P = 0.004) and not OS (HR 0.93; 95% CI 0.78–1.12; P = 0.45) [67]. In any case, the potential benefits of high-dose IFN (whether administered for 1 year, or up to 5 years in the pegylated form), must be weighed against its substantial tolerability and toxicity issues, including the duration of therapy, commonly associated flu-like symptoms, and potential for significant adverse reactions.

Новейшая адъювантная иммунотерапия/режим для резецированной меланомы III стадиии

Ipilimumab, an immune checkpoint inhibitor of cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), was FDA approved in 2015 for adjuvant treatment of patients with cutaneous melanoma with pathologic involvement of regional lymph nodes (>1 mm) who have undergone CLND. Approval was based on results from the EORTC 18071 trial of 951 stage III patients that showed significantly increased RFS in the ipilimumab group compared with the placebo group at 1–3 years (46.5% vs 34.8% at 3 years) [68]. Patients in the ipilimumab group were 25% less likely to experience melanoma recurrence than those in the placebo group. However, the FDA-approved regimen for adjuvant ipilimumab is >3 times higher (10 mg/kg every 3 weeks for 4 doses then every 3 months for up to 3 years) and longer than that approved for patients with unresectable stage III and IV disease. Improved RFS was again demonstrated at median follow-up of 5.3 years (HR 0.76; 95% CI 0.64–0.89; P = 0.0008) [69].

However for the first time, ipilimumab significantly reduced the risk of death – by 28% compared with placebo (11% absolute gain in OS at 5 years; HR 0.72; 95% CI 0.58–0.88; P = 0.001), and distant metastasis-free survival by 24% versus placebo (HR 0.76; 95% CI 0.64–0.92; P = 0.002), though rates of grade 3 or 4 immune-related adverse events (irAEs) remained high (41.6% vs 2.7%). Because irAEs are both dose and duration dependent, high-dose ipilimumab should be used with caution in the adjuvant setting. Results from a phase 3 cooperative group trial (ECOG E1609) assessing the use of lowversus 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. Adjuvant trials utilizing anti-programmed-death receptors (PD-1 inhibitors) are underway with promising results [70].

Adjuvant biochemotherapy is also a consideration for resected stage III melanoma, based on results from a phase 3 SWOG S0008 trial utilizing a 9-week regimen consisting of cisplatin, vinblastine, dacarbazine, IL-2, and IFN, compared with the standard 52-week regimen of high-dose IFN alfa-2b in patients with resected stage III melanoma. Improved RFS survival was noted in biochemotherapy-treated patients compared with those on high-dose IFN (4.0 years vs 1.9 years, respectively, 95% CI 0.58–0.97), although median and 5-year OS rates did not significantly differ between the treatment groups [71]. However, substantial toxicity associated with the biochemotherapy regimen limits its use in clinical practice.

Меланомные вакцины

Melanoma vaccines are a type of specific active immunotherapy based on melanoma cell expression of certain HLA- and tumor-associated antigens. Their appeal lies in lower toxicity (e.g., fatigue, myalgias, local inflammatory skin reactions) compared with other agents. Numerous melanoma-associated antigens have been identified, but it remains unclear which are the most important in eliciting the necessary cytotoxic and humoral responses to eradicate melanoma cells. 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. To date, no large, phase 3 randomized trial has demonstrated an OS advantage for vaccine-treated melanoma patients. However, a phase 3 trial of the glycoprotein peptide vaccine gp100:209-217(210 M) in combination with high-dose interleukin-2 (IL-2) showed significant improvement in response rate and progression-free survival (PFS) compared with IL-2 alone and provided the first evidence of clinical benefit for vaccine strategies in patients with melanoma [72].

Системное лечение распространенной меланомы

Improved survival in patients with unresectable AJCC/UICC stage III and IV melanoma has been an elusive goal for the past several decades, with effective systemic therapies only recently becoming widely available. Following the FDA approval of IL-2 in 1998, a 13-year period elapsed with no new drugs approved for the treatment of advanced disease until ipilimumab and vemurafenib in 2011, heralding a new era of immunotherapy and molecularly targeted therapy for treatment of patients with advanced disease (Figure 34.7).

Figure 34.7. Schematic demonstrating therapeutic targets in the melanoma pathway. ERK, extracellular-signal-regulated kinase; MEK, MAPK/ERK kinase; mTOR, mechanistic target of rapamycin; PTEN, phosphatase and tensin homolog; RTK, receptor tyrosine kinase.

Химиотерапия

While no chemotherapeutic agent has demonstrated improved OS, chemotherapy may provide palliation for patients with unresectable melanoma. Dacarbazine (DTIC) was the first drug approved for the treatment of metastatic melanoma in 1975, with overall response rates ranging from 8 to 20%, although responses are typically partial, short-lived (4–6 months) and limited to skin, soft tissue, lymph node, and lung metastasis. The objective response rate (ORR) in a pooled analysis of 23 randomized controlled trials assessing the use of DTIC alone in 1,390 patients was 15.3%, the majority of which were partial (11.2%,) with complete response rates of only 4.2% [73]. In a phase 3 study of dacarbazine compared with its oral analog, temozolomide, the response rates were similar (12% vs 13%, respectively), although temozolomide has improved central nervous system penetration over DTIC [74]. To date, no combination chemotherapy or biochemotherapy regimen (incorporating IFN or IL-2 with combination chemotherapy) has demonstrated a survival advantage over single-agent DTIC, although combination regimens are associated with higher ORRs and longer PFS [75, 76]. Some data have demonstrated promising results for albumin-bound paclitaxel (nab-Paclitaxel) combined with carboplatin in chemotherapy-naпve patients with unresectable stage IV melanoma [77].

Иммуномодулирующие агенты

Interleukin-2 is a recombinant, T-cell-derived growth factor that was FDA approved in a high-dose bolus regimen in 1998 for the treatment of metastatic melanoma, due to the potential for durable complete responses in a small subset of patients. A pooled analysis of 270 patients treated with 600,000–720,000 units/kg administered every 8 hours for 5 days demonstrated an ORR of 16%, and complete response of 6%, mostly in patients with soft tissue and lung metastasis [78]. Forty-four percent of responders were long-term survivors beyond 5 years (range, >70 months to >150 months). Approximately 4% of responders will have durable remission after treatment [79]. However, treatment with high dose IL-2 requires hospitalization and intensive monitoring due to significant toxicities, including hypotension, fever, chills, vomiting, diarrhea, increased capillary permeability, cardiac arrhythmias, oliguria, and volume overload. Thus, treatment is often limited to specialized centers with experience in the management of this regimen and to younger patients with excellent performance status and organ function.

Ингибиторы иммунных чекпоинтов

Ipilimumab is a monoclonal antibody against cytotoxic Tlymphocyte-associated antigen 4 (CTLA-4) which inhibits T-cell inactivation, allowing expansion of naturally developed melanomaspecific cytotoxic T cells. Ipilimumab was the first drug to demonstrate an OS advantage in stage IV melanoma and was FDA approved in 2011 for patients with unresectable stage III and IV melanoma. In the pivotal phase 3 trial, ipilimumab (given at 3 mg/kg every 3 weeks for 4 treatments) was shown to enhance the 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; HR for death 0.66; P = 0.003). Durable responses were observed for over 2 years in 9/15 (60%) of ipilimumab responders, suggesting a durable response benefit that has been demonstrated to be independent of HLA status [80]. Results of a phase 3 trial comparing DTIC plus ipilimumab (administered at 10 mg/kg) versus DTIC 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 or follow-up [81]. However, the use of both lowand high-dose ipilimumab is tempered by potential severe irAEs, primarily enterocolitis and hypophysitis, which require prompt initiation of high-dose corticosteroids and/or other immune response modifiers, as well as hormone replacement for pituitary axis 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 with lower toxicity was demonstrated with human monoclonal antibodies against the programmed death-1 (PD-1) protein, a T-cell coinhibitory receptor, or its ligand, PD-L1. Objective responses, durable tumor regression, and prolonged stabilization of disease were initially observed in patients with a variety of advanced cancers, including nonsmall cell lung cancer, renal cell carcinoma, and melanoma following treatment with the anti-PD-L1 antibody BMS-936559, with reduced toxicity compared to ipilimumab. The PD-1 inhibitor pembrolizumab was FDA approved in 2014 for patients with advanced or unresectable stage III and IV melanoma and demonstrated efficacy in ipilimumab-refractory advanced melanoma [82]. An additional PD-1 inhibitor, nivolumab, was approved in 2015, and both PD-1 blockers are considered first-line monotherapy in patients with advanced melanoma [83].

Accelerated FDA approval of the PD-1 inhibitor pembrolizumab was granted in 2014 for patients with advanced or unresectable melanoma following progression on prior therapies, including ipilimumab and BRAF inhibitors [84]. Demonstration of superior survival and lower toxicity compared with ipilimumab in the phase 3 KEYNOTE-006 trial resulted in approval as first-line therapy in 2015.

Concurrent studies of the PD-1 inhibitor nivolumab showed similar durable tumor remission and long-term safety, with median OS of 16.8 months and 1and 2-year survival rates of 62% and 43%, respectively, in patients with advanced, treatment-refractory melanoma [85]. In previously untreated BRAF wild-type melanoma patients, nivolumab was associated with significantly improved OS at 1 year compared with dacarbazine (72.9% vs 42.1%, respectively), with ORR of 40% versus 13.9%, respectively, resulting in FDA approval in 2015 [86]. Subsequent documented superior PFS over ipilimumab in the CheckMate 067 trial resulted in FDA approval of nivolumab as first-line monotherapy in metastatic melanoma.

The combination of CTLA-4 and PD-1 inhibitors showed even greater efficacy in patients with advanced melanoma but is associated with increased toxicity (grade 3 or 4 events) [87]. Combined nivolumab plus ipilimumab showed median PFS of 11.5 months compared with 2.9 months with ipilimumab and 6.9 months with nivolumab, and even higher responses in patients with tumors positive for the PD-1 ligand [88]. The nivolumab/ipilimumab combination was FDA approved in 2015 for previously untreated patients with BRAF V600 wild-type unresectable or metastatic melanoma [89]. Three-year OS analysis in the CheckMate 067 trial demonstrated superiority of combination therapy with nivolumab plus ipilimumab (58%) and nivolumab monotherapy (52%) over ipilimumab monotherapy (34%) [90]. Similar to BRAF/MEK inhibition, combination checkpoint blockade tends to work rapidly. However, significant immune-related adverse events occur on the dual regimen, making appropriate patient selection critical, along with careful monitoring during treatment, and prompt initiation of appropriate therapy for side effects.

In 2015, the FDA approved talimogene laherparepvec, commonly known as T-vec. This genetically modified, liveattenuated herpes simplex virus is programmed to replicate within tumors and produce the immune stimulatory protein GM-CSF. T-vec is indicated for the local treatment of unresectable cutaneous, subcutaneous, and nodal lesions in patients with melanoma recurrence after initial surgery but has demonstrated efficacy against visceral metastasis as well.

Approval of T-vec was based on the OPTiM randomized controlled trial in patients with unresectable regional or distant metastasis [91]. 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 <0.001). Overall response rate was also higher (26.4% vs 5.7%; P <0.001), with 32 (10.8%) patients demonstrating a complete response, although median OS was not statistically significant. Combination immunotherapies with T-vec and checkpoint inhibitors are now being studied for synergistic and/or abscopal immune responses [92].

BRAF и MEK ингибиторы

The mitogen-activated protein kinase (MAPK) signaling pathway (RAS–RAF–MEK–ERK) is constitutively activated in up to 80–90% of melanomas, with the most common mutations in either NRAS (15–30% of melanomas) or BRAF (50–66% of melanomas). Drugs that target this pathway, including multikinase inhibitors which decrease BRAF activity, have revolutionized treatment for patients with unresectable melanoma, although drug resistance is frequently encountered over time.

Vemurafenib is a selective small molecule inhibitor of some mutated forms of BRAF serine-threonine kinase, including BRAFV600E and BRAF-V600K. In the pivotal phase 3 study, vemurafenib markedly improved PFS and OS compared with DTIC as a firstline agent in patients with advanced melanoma [93]. Vemurafenibtreated patients had a 74% reduction in the risk for disease progression or death compared with patients receiving DTIC (hazard ratio, 0.26; P <0.001). Mean PFS was 5.3months in the vemurafenib group, compared with 1.6months in the DTIC group. At 6 months, the estimated overall survival rate was 84% (95% CI, 78–89) in the vemurafenib group and 64% (95% CI, 56–73) in the DTIC group. Vemurafenib was FDA approved in 2011 for the treatment of unresectable or metastatic melanoma with the BRAFV600 mutation. It is not indicated for patients whose tumors do not harbor the V600 mutation (i.e., wild-type BRAF melanoma).

Side effects from vemurafenib are mainly cutaneous in nature and include photosensitivity, 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 believed to be related to paradoxical activation of the MAPK pathway. Recent 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 by a dermatologist in treated individuals [94]. Dabrafenib is another BRAF inhibitor that inhibits the mutant BRAF protein in melanomas with either the V600E or V600K genotype. A phase 3 study demonstrated high clinical response rates and improved PFS in BRAF(V600E) metastatic melanoma patients who received dabrafenib compared with DTIC [95]. 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 is associated with less phototoxicity; it was FDA approved in May 2013 [96].

A phase 3 open-label trial assessing the use of an oral selective MEK inhibitor, trametinib, versus dacarbazine in 322 patients with metastatic melanoma (unresectable stage IIIC or IV) demonstrated improved rates of PFS and OS in patients with the BRAFV600E or V600K mutation [97]. Rash, diarrhea, and peripheral edema were the most common toxic effects in the trametinib group, though secondary skin neoplasms, including cutaneous SCC, were not noted. Trametinib was FDA approved in May 2013 as a single agent, but is seldom used as monotherapy.

Two phase 3 trials (COMBI-v and coBRIM) demonstrated that combination BRAF and MEK inhibition is more efficacious than BRAF inhibitor monotherapy. Improved PFS resulted in FDA approval in 2014 for vemurafenib/dabrafenib as first-line therapy and for vemurafenib/cobimetinib in 2015. Combination therapy is considered standard of care for patients with high volume and/or rapidly progressing BRAF-mutant melanoma, and is also being investigated on the adjuvant therapy front [98].

Наблюдение/выживаемость

The key components to melanoma follow-up are careful physical examination (with attention to skin and lymph nodes) 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 lymph node self-examinations.

Лабораторные и образные исследования

Baseline and surveillance laboratory studies (e.g., lactate dehydrogenase (LDH) level, liver function tests, chemistry panel, CBC count), chest radiography (CXR), and other imaging studies (e.g., CT scanning, positron emission tomography (PET) scanning, bone scanning, magnetic resonance imaging (MRI)) are not typically beneficial for stage I/II (cutaneous) melanoma patients without signs or symptoms of metastasis [99–101].

A metastatic workup should be initiated if physical findings or symptoms suggest disease recurrence. Screening CT or PETCT may be considered if the patient has documented nodal metastasis based on results from the SLNB, although the yield is low in this setting (0.5–3.7%) and positive findings tend to correlate with increased tumor thickness, ulceration of the primary tumor, and/or large tumor burden in the sentinel lymph node(s) [102]. A meta-analysis of 74 studies comprising over 10,000 melanoma patients demonstrated that ultrasonography was superior for detection of lymph node metastasis and PET-CT for detection of distant metastasis for both staging and surveillance in clinically appropriate patients [103].

Current NCCN guidelines recommend against surveillance laboratory or imaging studies for asymptomatic patients with stage IA, IB, and IIA melanoma (i.e., tumors =4 mm depth), unless clinically indicated for workup of signs or symptoms that suggest disease recurrence. Imaging studies (CT, PET-CT, or brain MRI) should be for confirmation of suspected metastasis or to delineate the extent of disease and may be considered to screen for recurrent/metastatic disease in asymptomatic patients with stage IIB–IV disease, although this latter recommendation remains optional. Routine laboratory or radiologic imaging in asymptomatic melanoma patients of any stage is not recommended after 3–5 years of follow-up [39, 42].

While abnormal laboratory test results are rarely the sole indicator of metastatic disease, serum LDH levels were incorporated into the AJCC melanoma staging in 2002 for the classification of stage IV (distant) disease, and they remain a key prognostic factor for this subgroup of patients. Elevated LDH levels are associated with worse survival in this subgroup, but routine testing is not recommended for patients with lower stage disease

Физикальный осмотр

Cutaneous melanoma patients should be monitored regularly following diagnosis, particularly in the setting of tumors at increased risk of recurrence (e.g., >2 mm thickness, with ulceration, lymphovascular invasion, and/or high mitotic rate). While most metastases occur in the first 1–3 years after treatment of the primary tumor, skin examinations are recommended for life. An estimated 4–8% of patients with a history of melanoma develop a new primary melanoma, generally within the first 3–5 years following diagnosis. The risk of new primary melanoma is higher 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 subtypes of melanoma; and male sex [104].

The frequency of dermatologic, surgical, and oncologic surveillance depends on individual patient risk for new primary melanoma as well as for recurrent disease.

Обучение пациентов

Patients with a history of melanoma should be educated regarding sun-protective measures (including sun-protective clothing, hats, eyewear, and the use of sunscreen); skin self-examinations for new primary melanoma, which is particularly important in patients with numerous nevi (common or atypical) and/or a strong family history of melanoma; possible local recurrence within the melanoma scar; and screening of first-degree relatives for melanoma, particularly if they have a history of atypical moles. In addition, referral to a cancer genetics clinic for discussion of genetic testing for the CDKN2A (P16) mutation should be considered 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) [105]. However, a negative p16 mutation result does not preclude the need for ongoing dermatologic surveillance in patients with a history of melanoma.

Выживаемость

As of 2012, an estimated one million Americans were living with a melanoma diagnosis, 21% of whom were under 50 years of age [106]. Delineating survivorship issues among melanoma survivors is vital to reducing the long-term social burden of this disease and improving quality of life. However, little survivorship research has been conducted to date among the growing population of melanoma survivors. Most melanoma survivors (74%) report fears of disease recurrence, and 33% report elevated levels of general distress and anxiety [107, 108]. In a recent analysis of 48 melanoma survivors of diverse ages, younger survivors expressed very specific concerns about insurability, career prospects, and family planning that differed from those reported by older survivors [109]. As melanoma becomes a more treatable disease in patients with advanced stages, attention to survivorship issues will be even more important.

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