Рак кожи: меланома

Oxford Textbook of Oncology. Third edition. 2016. Edited by David J. Kerr, Daniel G. Haller, Cornelis J.H. van de Velde, Michael Baumann


Введение

Меланома является злокачественной, часто агрессивной, потенциально фатальной опухолью, которая развивается вследствие генетических и метаболических аномалий в меланоцитах. Последние представляют пигмент-продуцирующие клетки, которые происходят из нервного гребешка и мигрируют в кожу и другие области в процессе эмбрионального развития. Поскольку меланоциты локализуются преимущественно в коже, большинство меланом являются кутанными по происхождению, и эта глава будет посвящена, главным образом, меланоме кожи. Однако меланома может также возникать из меланоцитов некутанных областей. Клинические особенности и лечение меланомы слизистой будут обсуждаться кратко, и меланомы глаза будут рассматриваться отдельно.

Меланома кожи — перманентно растущая проблема здравохранения развитых стран, преимущественно светлокожих популяций, и скорость ее роста выше, чем любых других солидных опухолей. До недавнего времени лечение всех форм меланомы было прежде всего хирургическим. Однако недавние достижения в молекулярной биологии меланомы и признание факта, что меланома развивается в результате накопления множественных генетических дефектов внутри меланоцитов, а также понимание роли иммунной системы в регуляции меланомы, вели к значительно более эффективному лечению. К счастью, у подавляющего большинства пациентов меланома диагностируется на стадии, когда курабельность может достигаться относительно простой операции. Тем не менее,  у 10-15% больных с первичной меланомой кожи, в конечном итоге возникнут отдаленные метастазы; в настоящее время почти у всех подобных пациентов болезнь в конечном итоге окажется фатальной. Однако медикаментозная терапия распространенной меланомы является быстро развивающейся областью, и есть основания для значительного оптимизма в том, что в течение последующих нескольких лет новые системные методы лечения обеспечат хороший долгосрочный контроль и, возможно, даже курабельность метастатической меланомы отдаленных областей.

Молекулярная биология и патогенез

Солнечная инсоляция является причинным фактором более 80% меланом кожи. Ультрафиолетовая (UV) радиация индуцирует мутации пиримидиновых димеров в ДНК, приводя к характерному профилю УФ-индуцированного повреждения при секвенировании всего экзома в меланомных клетках. UV излучение также промотирирует продукцию факторов роста кератиноцитами и другими клетками кожи, и супрессирует T клетка-опосредованной иммунной защиты кожи. Стимуляция продукции меланина UV радиацией продуцирует реактивные кислородные формы меланина, которые вызывают ДНК повреждение и супрессируют механизмы апоптоза. Формирование меланомы является результатом аккумуляции мутаций в генетических путях меланоцитов, которые способствуют пролиферации клеток и предотвращают нормальные пути гибели клеток в ответ на ДНК повреждение. Таким образом, генетически нестабильный меланоцит предрасположен к последовательногму накоплению ДНК повреждений. Это ведет к быстрому отбору генетических мутаций, которые позволяют и способствуют ангиогенезу и уклонению от иммунного ответа и позволяют быстро отбирать варианты, способные к инвазии и метастазированию. Меланомные клетки демонстрируют устойчивость к механизмам клеточной смерти на нескольких уровнях; это может объяснять большую часть наблюдаемой резистентности меланомных клеток к цитотоксической атаке при использовании химиотерапии, лучевой терапии или иммунотерапии.

Доброкачественные пролиферации меланоцитов (невусы) часто несут мутации в BRAF онкогене, но их можно остановить путем протективного инициирования старения. Меланомы могут происходить из избегающих старения невусных прогениторов, хотя механизмы этого остаются противоречивыми. Первичные соматические генетические мутации в меланоме неизвестны, но прогрессия опухоли обычно включает активацию митоген-активированной протеинкиназы (mitogen-activated protein kinase, MAPK) путем приобретения мутаций в BRAF (50%), NRAS (20%), EGFR (10%) или другие механизмы. Одной из основных мишеней MAPK пути является главный регулятор меланоцитов, микрофтальмический транскрипционный фактор (MITF), мутации которого наблюдаются в 10% меланом. MITF регулирует набор генов, регулирующих пролиферацию, выживание и инвазию клеток. Гены, часто дерегулированные в меланоме, показаны в таблице 49.1.

Сохраняются противоречия относительно роли стволовых клеток в меланоме, но демонстрация того, что большинство клеток в границах развившейся меланомы способны к стволоподобному поведению, свидетельствует в пользу концепции пластичности в онтогенезе меланомы скорее, чем классического иерархического паттерна, наблюдаемого в гематологии.

Генетическая предрасположенность к меланоме

Риск меланомы существенно возрастает у пациентов с семейной историей меланомы. Наличие одного аффективного родственника первой степени удваивает риск, и риск еще более возрастает с дополнительными аффективными близкими родственниками, родственниками с множественными первичными меланомами и родственниками, заболевшими в более молодом возрасте.

Около 2% всех меланом обусловлены идентифицируемыми, наследственными мутациями в высокопенетрантных генах, включая CDKN2A и, очень редко, CDK4 и BAP1 (таблица 49.2). Некоторые, но не все, родственники также демонстрируют фенотип множественных атипичных невусов, в том числе полипоидный атипичный невус Шпица у лиц с герминативными мутациями BAP1. Наличие множественных невусов у индивидуума, атипичных или неатипичных, является сильным маркером риска меланомы независимо от семейной истории. Наличие только невуса не может использоваться для предсказания существования зародышевых мутаций CDKN2A. Некоторые семейства с наследуемыми мутациями CDKN2A также имеют повышенный риск развития рака поджелудочной железы. Носители инактивирующих мутаций в генах имеют риск развития меланомы от 50% до 90% в возрасте 80 лет. Наследственные мутации этого гена обнаружены в 30-40% семей с тремя или более близкими родственниками с меланомой.

Таблица 49.1. Гены, часто измененные соматически в меланоме

Ген Полное имя Функция
MITF MIcropthalmia Transcription Factor Основной транскрипционный фактор меланоцитов
BRAF B-Rapidly Accelerated Fibrosarcoma gene Сигналинг фактора роста
NRAS N-RAt Sarcoma protein Сигналинг фактора роста
EGFR Epidermal Growth Factor Receptor Сигналинг фактора роста
TERT TElomerase Reverse Transcriptase Регенерация теломер, позволяющая уклоняться от клеточной смерти
CDKN2A Cyclin Dependent Kinase iNhibitor 2A Контроль клеточного цикла
PTEN Phosphatase and TENsin homologue Регуляция сигналинга фактора роста
PREX2 Phosphatidylinositol-3,4,5- trisphosphate-dependent Rac EXchange factor 2 Регуляция сигналинга фактора роста

Консультацию по генетике рака следует рассматривать в соответствии с «правилом тройки»: (1) пациенты с тремя или более меланомами у родственников первой или второй степени на одной стороне семьи; (2) семьи с тремя или более случаями меланомы или рака поджелудочной железы на одной стороне семьи; или (3) в странах с более низкой заболеваемостью, например, в  Северной Европе, индивидуумы с тремя или более первичными меланомами.

Некоторые наследуемые варианты гена рецептора меланокортина-1 (MC1R) наделяют повышенной сенситивностью к УФ и 2-4-кратным увеличением риска меланомы. Изменения в других генах, связанных с пигментацией кожи, также немного повышают риск (таблица 49.2).

Эпидемиология и предотвращение

Меланома кожи — это злокачественная опухоль, которая в основном поражает светлокожих людей, особенно лиц с кельтской родословной. Это чаще наблюдается, когда такие индивидуумы подвергаются воздействию солярного УФ излучения высокой интенсивности, особенно в случае  интенсивной и повторяющейся экспозиции, в частности в детстве. Другими ассоциированными с меланомой факторами являются наличие многочисленных невусов, особенно атипичных (диспластических) невусов и более высокий социально-экономический статус. Лица с историей меланомы, с историей немеланомного рака кожи и с семейной историей меланомы.имеют более высокий риск.

Worldwide, the incidence of cutaneous melanoma has been increasing steadily for several decades. It now represents a major health problem for many developed nations, with incidence figures already approaching those of lung cancer, breast cancer, prostate cancer, and bowel cancer in countries such as Australia and New Zealand where the majority of the population is fair-skinned and exposed to high levels of solar UV radiation. Melanoma incidence rates for Australia, the USA, the Netherlands, and the UK are shown in Table 49.3. The table shows that melanoma incidence continues to increase at an alarming rate around the world. In the Netherlands and the UK, melanoma mortality rates continue to rise, but in Australia and the US mortality rates appear to have stabilized since the turn of the century.

Таблица 49.2. Гены, ассоциированные с наследственным риском меланомы

  Хромосома Протеин Функция Пенетрантность Популяционная частота мутаций/вариантов Предиктивное генетическое тестирование
Высокий риск
CDKN2A 9p21 p16INK4A, p14ARF Cell-cycle regulation, apoptosis High Low Consider, by rule of threes
CDK4 12q14 Cyclin-dependent kinase 4 Cell-cycle regulation High Low Very rarely in specific families
BAP1 3p21 BRCA1-Associated Protein 1 Chromatin modulation, transcriptional regulation, ubiquitin-proteasome system High Low Very rarely in specific families
Низкий риск
MC1R 16q24 Melanocortin 1 receptor Pigmentation Low High No
ASIP 20q11 Agouti signalling protein Pigmentation Low High No
TYR 11q14 Tyrosinase Pigmentation Low High No
TYRP1 9p23 Tyrosinase-related protein 1 Pigmentation Low High No
MITF 14q32 Micropthalmia-associated transcription factor Regulation of melanocyte differentiation and stemness Medium Low No
Unknown 1q21 N/A N/A N/A N/A No

Таблица 49.3. Заболеваемость меланомой в Австралии, США, Нидерландах и Великобритании

Age-standardized incidence (105/year) Lifetime risk (incidence) Incidence trend over 10 years Mortality trend Age-standardized mortality (105 year) national Cancer Frequency (ranking)
Australia (2009/2010)
Men 61.7 1 in 14 42% increase

(1991–2009)

No significant increase or decrease (1991–2009) 8.9 3rd
Women 40 1 in 23 18% increase

(1991–2009)

No significant increase or decrease (1991–2009) 3.5 3rd
USA (2009/2010)
Men (whites only) 31.9 1 in 41 19% increase

(2000–2009)

11% increase (2000–2009) 4.6 5th
Women (whites only) 20 1 in 61 20% increase

(2000–2009)

No significant increase or decrease (2000–2009) 2.0 6th
The netherlands (2008)
Men 14.7 1 in 71* 45% increase

(1989–2008)

64% increase (2002–2011) 3.0 12th
Women 18.8 1 in 59* 37% increase

(1989–2008)

52% increase (2002–2011) 2.0 12th
UK (2010)
Men 17.2 1 in 55 63% increase

(2000–2010)

82% increase (2000–2010) 3.1 6th
Women 17.3 1 in 56 67% increase

(2000–2010)

90% increase (2000–2010) 1.8 6th

*Only 2006 estimates of lifetime risk available.

The mutagenic effect of UV light, particularly UVB, on melanocytes has been clearly established, and sun-protection education programs are now conducted in many countries where the incidence of melanoma is high. There are some early indications that attempts to reduce the incidence of melanoma through these programs are proving effective, but because the latent period for melanoma development following UV-induced initiation may be several decades, further time will need to elapse before their value can be fully assessed. The dangers of UV exposure through sunbed use, particularly in teenagers and young adults, have also been recognized and for this form of cutaneous UV exposure the latent period for melanoma development may be short.

Клинический диагноз и подтверждение диагноза биопсией

The diagnosis of cutaneous melanoma is normally straightforward. However, even for experienced dermatologists it can sometimes be challenging to differentiate an early invasive melanoma from a benign naevus, and the clinical differentiation between a dysplastic naevus and an in situ melanoma can also be extremely difficult. Furthermore, up to 10% of melanomas do not have the typical dark pigmentation but are non-pigmented, often pink lesions when examined with the naked eye; these are termed amelanotic melanomas, and they may be confused with non-melanocytic skin cancers such as squamous cell carcinomas or basal cell carcinomas.

The classical diagnostic features of a melanoma, whether it presents as a change in a pre-existing pigmented lesion on the skin or as a new pigmented lesion, are asymmetry, border irregularity, and colour variegation. Transformation of a previously flat lesion into one that is elevated and palpable should always also arouse suspicion, and a larger lesion (more than 6 mm in diameter) is more

likely to be a melanoma than a smaller lesion. To aid diagnosis, these features have been fitted into an ABCDE system (Asymmetry, Border irregularity, Colour variegation, Diameter >6mm, and Elevation). Some have suggested that ‘E’ might also be used for Evolution, i.e., change in appearance. When assessing suspicious skin lesions it must always be borne in mind that up to 50% of cutaneous melanomas do not arise in pre-existing naevi but in apparently normal skin.

Critical to the proper assessment of pigmented skin lesions and the diagnosis of melanomas is careful examination with good lighting, preferably with a magnifying device. A hand-held dermatoscope allows suspicious lesions to be assessed in more detail. Dermoscopy has been shown in several large, carefully conducted studies to improve diagnostic accuracy considerably, particularly for clinicians who are not dermatologists. The technique not only provides the requisite magnification and good lighting but additionally it uses epiluminescence microscopy to assist in differentiating benign from malignant melanocytic lesions. Also useful in melanoma diagnosis is computerized imaging, which if repeated can allow suspicious lesions to be monitored carefully and changes identified. High quality whole-body digital photography is another technology that is useful for monitoring. Careful serial assessment of lesions with photography or computerized imaging has been shown to be of value in patients with many lesions, particularly those with numerous atypical (dysplastic) naevi (the ‘dysplastic naevus syndrome’). An evolving technique for melanoma diagnosis is reflectance confocal laser microscopy, which allows in vivo microscopic examination in a horizontal plane. Confocal microscopy is particularly useful for defining the extent of in situ melanomas. A detailed description of diagnostic techniques for melanoma is beyond the scope of this chapter, but well-illustrated guides are available in both printed and electronic forms.

When careful clinical examination with use of relevant technological aids indicates that a lesion might be a melanoma, a surgical biopsy should be performed. Complete excisional biopsy with 2 mm clearance margins is preferred, and gives the reporting histopathologist the best opportunity to provide an accurate diagnosis. Incision biopsies and shave biopsies often make interpretation difficult for the pathologist, and it is important to note that the majority of cases of litigation related to misdiagnosis of melanomas involve the use of partial biopsies.

The importance of clinical history in melanoma diagnosis cannot be over-emphasized, and if a patient reports that a lesion has appeared only recently, has become larger, itches or has begun to bleed intermittently, the clinician’s level of suspicion must be high and a biopsy performed unless a very confident diagnosis of a benign lesion can be made.

Гистопатологические черты и заключение о меланоме кожи и гистологическая классификация

Патологический диагноз меланомы

To determine whether a pigmented lesion is a melanoma or a benign naevus, the pathologist must assess a range of microscopic features and correlate these with clinical information, including the anatomical site of the lesion, the patient’s age, and more specific details about the lesion such as a history of change or prior trauma. If the clinical features do not correlate with the pathological interpretation, it is usually prudent to review the pathology in the clinical context and, if a partial biopsy has been performed, consider performing a further biopsy of the lesion (preferably complete excision biopsy).

Гистологически неоднозначные опухоли (‘меланоцитарные опухоли неопределенного злокачественного потенциала’)

Whilst the vast majority of melanocytic tumours can be rapidly and accurately classified as naevi or melanomas by routine pathological assessment, it is now well recognized that there exists a small subset of cases which display some benign features and other features suggestive of melanoma. Such lesions have been described using a variety of terms including ‘melanocytic tumour of uncertain malignant potential’ (MelTUMP), histologically ambiguous melanocytic tumour, or borderline melanoma. These terms should not be regarded as specific diagnoses but rather as a means of communicating uncertainty regarding their biological potential. For such problematic tumours, it is now well-documented that the interobserver reproducibility for their pathological classification is poor, and even tumours regarded as benign by a majority of acknowledged experts may on occasion prove lethal.

There is increasing recognition of the likely existence of a poorly-defined intermediate grade of melanocytic neoplasms with low-grade malignant potential that show frequent involvement of sentinel lymph nodes but infrequent spread beyond the regional lymph nodes to distant metastatic sites. The assessment of risk and prognostic factors (and as a consequence, management decisions) for such tumours remains problematic. In recent years, there have been concerted efforts to develop adjunctive diagnostic techniques, particularly molecular techniques that may assist in the more accurate classification of such tumours.

Молекулярная оценка первичных меланоцитарных опухолей

Molecular studies have demonstrated that melanomas are characterized by the presence of numerous chromosomal copy number gains and losses and that in most naevi (apart from Spitz naevi, which may occasionally show chromosomal gains in 11p or 7q) such aberrations are not observed. The classification of difficult melanocytic tumours, in which accurate characterization of the tumour as benign or malignant is difficult based on routine histopathology, may be assisted by assessment for the presence of chromosomal copy number aberrations.

Сравнительная геномная гибридизация

Comparative genomic hybridization (CGH) can be used to detect chromosomal copy number aberrations in formalin-fixed, paraffin-embedded tissue. Although this technique has the advantage of being able to detect any aberrations occurring in the genome, there are a number of technical and practical reasons why it is often not an appropriate adjunct to pathological diagnosis in routine clinical practice.

Флюоресцентная in situ гибридизация

Fluorescence in situ hybridization (FISH) is a technique that can be utilized to directly visualize specific chromosomal copy number changes within individual tumour cells. While it has the limitation of being able to test for only a limited number of changes (compared to CGH, which tests for chromosomal aberrations in the entire genome), FISH is more easily applied in routine clinical practice and can be successfully performed on small tumour samples.

Классификация меланомы

It has long been recognized that melanoma is not a single disease entity but consists of a number of disease subtypes. The traditional clinicopathological classification scheme for melanoma, based on the pioneering work of Clark, McGovern, and others in the late 1960s and the 1970s, includes four main subtypes: superficial spreading melanoma, nodular melanoma, lentigo maligna melanoma, and acral lentiginous melanoma. Other less common melanoma subtypes such as desmoplastic melanoma and naevoid melanoma have been recognized and characterized more recently.

Таблица 49.4. Пример структурированного (синоптического) заключения патолога о первичной меланоме кожи

Specimen type Excision
Site Left thigh
Diagnosis Primary cutaneous melanoma
Classification/main pattern Superficial spreading
Breslow thickness 2.7 mm
Clark level IV
Ulceration

Diameter of ulcer

% of dermal invasive tumour width

Present

5.5 mm

60%

Dermal mitotic rate 12/mm2
Predominant cell type Epithelioid
Intravascular/intralymphatic invasion Absent
Neurotropism Present (perineural)
Satellites Absent
Desmoplastic component Absent
Features of regression

Early (TILs)

Intermediate

Late (fibrosis and loss of rete ridges)

 

Grade 1 (Focal and mild)

Absent

Absent

Associated naevus (type) Dysplastic compound
Actinic/Solar elastosis Moderate
Margins

In situ component—nearest peripheral

Invasive component—nearest peripheral

Invasive component—nearest deep

 

3.2 mm clear of inferior margin

5.2 mm clear of inferior margin

4.4 mm

From a clinical perspective, the major importance of the traditional Clark-McGovern melanoma classification scheme is that it highlights the various clinical and histological appearances of melanoma that must be recognized by clinicians and pathologists in order to avoid misdiagnosis. As detailed below, the prognosis for a patient with apparently localized primary cutaneous melanoma is principally determined by tumour thickness [1], and the melanoma subtype does not have independent prognostic significance.

Молекулярная классификация меланомы

In the past decade, critical molecular alterations in melanomas have been identified, as previously discussed. A comparison of the traditional clinicopathological melanoma classification with a classification based on the somatic mutation status reveals remarkable similarities.

For example, melanomas associated with prominent solar damage (lentigo maligna melanomas) commonly have NRAS and sometimes KIT mutations, while superfi al spreading melanomas that arise in the skin of intermittently sun-exposed areas often have BRAF mutations. BRAF mutant melanoma is also associated with younger patient age, lack of cumulative sun-induced damage at the primary site, truncal location, and a high body naevus count. A recent study reported that of patients with a BRAF mutation, 73% were V600E, 19% V600K, and 8% other genotypes. There was an inverse relationship between BRAF mutation prevalence and age. All patients <30 years and only 25% of patients =70 years had BRAF-mutant melanoma. Amongst BRAF-mutant melanoma, the frequency of non-V600E genotypes (including V600K) increased with increasing age.

Заключение патолога по меланоме

Pathological features of the primary melanoma are strong predictors of outcome for patients with clinically localized primary cutaneous melanomas [2]. Numerous studies have shown that tumour thickness (measured using the method described by Breslow) is the strongest prognostic factor. Multiple recent studies have demonstrated that the mitotic rate of the dermal component of a melanoma is also a strong prognostic factor, as is ulceration.

It has been demonstrated that a structured or ‘synoptic’ format can facilitate the reporting of all relevant histological features in the pathology report, allowing formulation of an appropriate management plan and an accurate estimation of prognosis (Table 49.4).

Различные патологические черты и их значимость

Толщина по Бреслоу (Breslow)

Толщина по Бреслоу является единственным наиболее важным прогностическим фактором для пациентов с клинически локализованной первичной меланомой, которые не имеют патологический региональный лимфоузел. Толщина по Бреслоу измеряется от верхней части зернистого слоя эпидермиса (или, если поверхность изъязвляется, от основания язвы) до самой глубокой инвазивной клетки.

Изъявление

Изъязвление — интегральный компонент стадийной системы American Joint Committee on Cancer (AJCC)/International Union Against Cancer (UICC) и независимый предиктор исхода у пациентов с клинически локализованной первичной меланомой кожи. Протяженность изъязвления (измеренная как диаметр или как процент ширины опухоли) предоставляет более точную прогностическую информацию, чем наличие изъязвления.

Скорость митозов

Multiple recent studies have demonstrated that mitotic rate (of the invasive component of a melanoma) is an important prognostic factor for clinically localized primary melanomas and its routine reporting is recommended by the AJCC (Figure 49.1). Furthermore, the presence or absence of mitotic figures in non-ulcerated thin (=1.0 mm) melanomas is utilized in the seventh (2010) edition of the AJCC Staging System for Melanoma for separating pT1a and pT1b tumours. For consistency and reproducibility, a standardized method for determining the mitotic rate must be used.

Фиг. 49.1. Кривые выживаемости по числу митозов/мм2.

Другие факторы

Other pathological features of the primary melanoma that influence prognosis include the presence of lymphatic or blood vessel invasion, Clark level of invasion, tumour-infiltrating lymphocytes, tumour regression, and the presence of a desmoplastic melanoma component.

Сателлиты

Up to 13% of melanoma patients (with or without a positive sentinel lymph node [SLN]) develop recurrence between the primary tumour site and regional lymph nodes. Depending on their proximity to the primary tumour site, such recurrences have been termed local recurrences, satellites, and intransit metastases (although the definitions used by different investigators have not been consistent). Apart from true local recurrences due to incompletely excised primary melanomas (persistent primary melanomas), all of these terms represent a biologically similar phenomenon (i.e., local metastasis) and the definitions used for them are therefore somewhat arbitrary The presence of satellites or intransit metastases has serious adverse prognostic impact and, in the absence of synchronous nodal metastases, such patients are included in the same prognostic group as those with nodal metastases (N2c) in the seventh (2010) edition of the AJCC Staging System [1].

Патология сторожевых лимфоузлов

A SLN can be defined as any lymph node that receives direct lymphatic drainage from the primary tumour site. At the present time, although the optimal methodology for SLN pathological examination is not uniformly agreed, there is general consensus that both haematoxylin-eosin stained sections and sections stained immunohistochemically for various melanoma-associated antigens (such as S-100 protein, HMB-45, and MelanA/MART1) should be examined.

Multiple recent studies have demonstrated that both the location and extent of tumour deposits within SLNs are not only strong predictors of the presence of positive non-SLNs in completion lymph node dissection (CLND) specimens but also provide important prognostic information. For example, if there are only a few metastatic tumour cells in the SLN subcapsular sinus, the probability of finding additional metastatic disease in a CLND specimen is extremely small and the patient’s prognosis is very good. In contrast, if there are multiple large metastatic foci and the tumour cells extend deeply into the central part of the SLN, the chance of finding metastases in non-SLNs in a CLND specimen is much higher and the prognosis is much worse.

Молекулярное патологическое тестирование мутаций

Molecular genetic testing of melanocytic tumours has the potential to identify subgroups of tumours with specific genetic signatures that may accurately predict their likely clinical course and/ or response to treatment. It is usually performed in the context of patients with advanced stage metastatic disease who are being considered for targeted therapies. Mutation testing can be performed on routinely collected archival formalin-fixed, paraffin-embedded tissue. It can also be performed on fresh tissue, but this is not essential. Specimens containing a high percentage of viable tumour cells are the most suitable (thus SLNs containing micrometastases admixed with numerous lymphocytes are often unsatisfactory). Nevertheless, core biopsies and cell blocks made from fine-needle biopsy cytology specimens can often yield diagnostic results.

An important issue to consider when ordering mutation testing is which is the most appropriate specimen to test. At the current time, only limited data are available regarding the concordance of BRAF and NRAS mutation status between primary and metastatic melanomas from individual patients. In one recent study, the concordance rates ranged from 75–96% in metastases from different locations. Therefore, it would appear most appropriate to perform mutation testing on the most recent distant metastatic melanoma specimen provided sufficient viable tumour cells with minimal admixed non-tumour cells is available. If this is not available, testing of locoregional/in-transit metastases is preferred to testing of the primary melanoma.

Mutation testing assays currently in widespread use in clinical practice include traditional Sanger sequencing, allele-specific reverse transcriptase-polymerase chain reaction (RT-PCR), mass spectroscopy/multiplex assays, and pyrosequencing. Each of these techniques has some advantages and disadvantages, and as a consequence no single testing methodology is ideal. Sanger sequencing, usually supplemented by pre-screening with high-resolution melting curve analysis to select only abnormal specimens for further analysis, has traditionally been considered the gold standard. While it detects all known and new mutations (i.e., it is comprehensive), it has only moderate technical sensitivity (about 25%). Hence, careful macrodissection by pathologists to enrich for tumour cells is an important pre-analytical step with this technique. Allele-specific RT-PCR tests (e.g., the Roche cobas 4800 BRAF V600 mutation test) offer high sensitivity but will only detect specific targeted mutations. For example, the Roche cobas test was designed to detect BRAFV600E mutations and does not detect other BRAF mutations (including a significant proportion of BRAFV600K mutations). This may have important clinical consequences because BRAFV600K mutations have been reported to occur in 19–30% of BRAF-mutant melanomas and may not be identified using some testing methodologies. Pyrosequencing and mass spectroscopy assays offer high sensitivity and the ability to test for the presence of a range of mutations in a single test.

Immunohistochemistry (IHC) may also be used for molecular testing. Recent studies showed high correlation of IHC expression of the BRAFV600E-specific antibody VE1 with the presence of the BRAFV600E mutation and, in fact, appeared to be more accurate than testing with traditional molecular techniques in one study. The ability to detect mutations by immunochemistry has a number of potential advantages over traditional molecular techniques including faster turnaround times, cost savings, and availability in most pathology laboratories. Potentially, this may facilitate the rapid triage of patients into appropriate treatment pathways at a time when a delay in initiating treatment may result in an adverse outcome.

Стадийность и прогноз меланомы

The earliest melanoma staging system had three stages, based on each patient’s primary tumour (T stage), regional lymph node status (N stage), and the presence or absence of distant metastases (M stage). This staging system, however, was primarily clinical and did not involve microstaging, and it was not until the AJCC Staging System was published in 1977 and 1978 that microstaging was integrated into the staging system for cutaneous melanoma. The AJCC Melanoma Staging System has since been reviewed and updated several times, most recently in 2009 [1]. The current AJCC Staging System, also used by the European-based UICC, is based on assessment of the primary tumour (with Breslow thickness, ulceration, and mitotic rate as the major prognostic factors), evaluation of the regional lymph nodes (with size of metastatic deposits and number of involved nodes having prognostic significance) and evaluation of distant metastatic sites as well as serum lactose dehydrogenase (LDH) levels. Based on the large AJCC melanoma database, prognostic models were able to be developed by the Melanoma Staging Committee of the AJCC and clear differences in survival outcome based on AJCC staging and substaging were demonstrated (see Figure 49.2). Electronic tools that provide prognostic estimates for individual patients are now available and are often helpful both to patients and to their treating clinicians.

Начальные исследования

For patients who present with a primary cutaneous melanoma of any thickness and who have no clinical evidence of regional node metastasis, there is no evidence that investigations such as blood tests, X-rays, or scans are of benefit. For patients found to have micrometastatic disease in regional lymph nodes on SLN biopsy (i.e., with Stage IIIA disease), there is likewise currently no evidence that staging with blood tests, X-rays, or scans is of value. For patients first presenting with Stage IV disease, however, it is appropriate to perform full staging with either whole body CT scans or a PET/CT scan and a CT or MRI scan of the brain. Serum LDH should be checked in those with Stage IIB, Stage IIIC, or Stage IV disease, and if systemic therapy is contemplated the presence or absence of a BRAF mutation in the patient’s melanoma should be determined.

Хирургическое лечение первичной меланомы

Any lesion thought to be a primary cutaneous melanoma is best removed by complete excision-biopsy in the first instance, with 2 mm clearance margins, as previously discussed. This allows full histological assessment and rational treatment planning. Immediate performance of a wide excision is not recommended, even if a confident diagnosis of melanoma is made, because clinical estimates of Breslow thickness are notoriously unreliable. If an immediate wide excision is performed, not only might an inappropriate wide excision margin be taken but the opportunity to perform accurate lymphatic mapping and a SLN biopsy (SLNB) procedure might be lost if the melanoma proves to be thicker than anticipated or to have adverse features such as a high mitotic rate.

Wide excision margins

Having established a diagnosis of primary cutaneous melanoma, definitive treatment can be planned. Currently recommended excision margins for primary melanomas are shown in Table 49.5. They are based on the results of a number of prospective randomized trials.

Менеджмент региональных лимфатических узлов

It is well established that the presence or absence of metastatic disease in regional lymph nodes is the most significant prognostic factor in patients with clinically localized cutaneous melanoma. In the late nineteenth century, Snow advocated routine prophylactic CLND for all patients with cutaneous melanoma who had no clinical evidence of metastatic disease in their regional lymph nodes. The rationale was to remove clinically occult metastatic disease in the regional nodes before spread to distant sites occurred.

Fig. 49.2. Survival curves from the American Joint Committee on Cancer Melanoma Staging Database comparing (A) the different T categories and (B) the stage groupings for Stages I and II melanoma. For patients with Stage III disease, survival curves are shown comparing (C) the different N categories and (D) the stage groupings.

However, no prospective randomized trial has shown a convincing overall survival benefit for elective lymph node dissection (ELND), although some studies have suggested a benefit for patients with intermediate thickness melanomas.

Биопсия сторожевых лимфоузлов

In the early 1990s, Morton et al. introduced the concept of lymphatic mapping and SLNB as a minimally invasive alternative to ELND [3]. The SLNB concept was simple. Lymphatic drainage from a primary melanoma site is initially to a sentinel lymph node in the regional node field, with subsequent onward passage of lymph to other nodes in that field. If melanoma cells spread via lymphatics to the regional lymph node field, they will lodge initially in the sentinel lymph node. Thus, if this node can be identified and removed, which is possible using preoperative lymphoscintigraphy and intraoperative localization with blue dye and a gamma probe, the presence or absence of metastatic disease in the regional lymph node field can be determined with very great accuracy. After the initial report by Morton et al., several validation studies confirmed that this hypothesis was correct.

 

Таблица 49.5. Края хирургического иссечения (рекомендованные большинством национальных руководств)

The common practice of sentinel lymph node (SLN) biopsy in patients with melanoma does not improve their long-term survival, according to the final results of a landmark international trial published in the New England Journal of Medicine [4]. The investigators of the Multicenter Selective Lymphadenectomy (MSLT-I) trial compared SLN biopsy with a watch-and-wait approach (only removing nodes once palpable) in melanoma. The 10-year, disease-specific survival in the overall study population was the primary outcome and was not significantly different between the biopsy and observation arms (81.4% vs 78.3%; p = .18).

Today, SLNB is a standard staging procedure in most melanoma treatment centres around the world; in 2012, an evidence-based guideline produced by the American Society of Clinical Oncology and the Society of Surgical Oncology recommended its use in all patients with intermediate thickness melanomas. SLNB allows these patients to be accurately staged according to the AJCC/UICC staging system. As well, it appears to provide a substantial survival benefit for those found to be SLN-positive, if an immediate CLND is performed (as outlined above) [5]. In patients with thick (T4) melanomas SLNB is considered unlikely to improve survival outcome, but does reduce very considerably the risk of highly morbid regional node field recurrence and provides useful staging, as it does for intermediate thickness melanomas.

There are also sound reasons to recommend SLNB for patients with melanomas in the 0.75–1.0 mm thickness range, if adverse prognostic features are present (e.g., ulceration, a mitotic rate >1/mm2 in a subset of T1b tumours), or if the patient is <45 years of age.

Some authors have suggested that preoperative examination of regional nodes with high-resolution ultrasound will identify metastatic disease in regional nodes with an accuracy approaching that of SLNB. However, several large studies have shown very low sensitivity rates for preoperative ultrasound, and there is general agreement that ultrasound cannot replace SLNB for accurate staging of melanoma patients with clinically negative regional nodes.

Техника биопсии сторожевых лимфоузлов

A SLNB procedure involves preoperative lymphoscintigraphy, then injection of blue dye intradermally at the primary melanoma site immediately preoperatively, and SLN localization surgically-based on blue staining of the SLN with a high gamma count.

Major melanoma treatment centres around the world have now accumulated considerable experience with the procedure, and false-negative SLNB results are less common than they were when the technique was first introduced.

Менеджмент позитивных сторожевых лимфоузлов

The standard treatment recommendation for patients found to have metastatic disease in a SLN is an immediate CLND, but whether this is always necessary is being tested in a second Multicenter Selective Lymphadenectomy Trial (MSLT-II). In this trial, patients found to be SLN-positive are randomized either to have a CLND or to have the residual nodes in the regional node field monitored carefully using regular high-resolution ultrasound, with CLND only if metastatic disease in a node field becomes apparent (ClinicalTrials. gov Identifier: NCT00297895). A registration trial in Europe (the MINITUB study) is also examining this question in a prospective fashion. However, it will be several years before the results of these studies are available, and until then CLND must remain the standard therapy for patients found to be SLN-positive.

Менеджмент клинически вовлеченных региональных лимфатических узлов

Standard management of patients with clinically involved regional lymph nodes involves full regional lymph node dissection. For the axilla this means complete clearance of lymph node levels I, II, and III. For the neck, however, selective node dissections may be performed, depending on the site of the primary tumour. For involved groin lymph nodes, a complete clearance of nodes in the femoral triangle (i.e., below the level of the inguinal ligament) is standard, but whether pelvic nodes need clearance is a matter of ongoing debate. In most centres, an iliac and obturator node clearance is recommended if there are multiple involved nodes below the inguinal ligament, or if these nodes are large. Involvement of Cloquet’s node is also regarded by many as an indication to perform an ilio-inguinal node clearance rather than an inguinal node clearance only. The presence of macroscopic disease in regional lymph nodes has serious prognostic implications, because up to 50% of these patients will ultimately die of melanoma [1]. A detailed consideration of surgical techniques for dealing with clinically apparent metastatic melanoma in regional lymph nodes is beyond the scope of this book, but full descriptions are available elsewhere.

Адъювантная системная терапия и адъювантная лучевая терапия для резецированной болезни III стадии

Адъювантная системная терапия

Because patients with resected AJCC Stage IIIB and IIIC disease are at high risk of dying of melanoma (with <50% 10-year survival) they should be considered for adjuvant systemic therapy. Those at intermediate levels of risk (Stage IIA, IIB, and IIIA) (51–64% 10-year survival) may also be considered for clinical trials of adjuvant therapy. The only drug with demonstrated efficacy as adjuvant therapy for high-risk melanoma is interferon-alpha2b. Phase III clinical trials have compared high-dose interferon (20 MU/ m2), intermediate-dose interferon (5–10 MU), intermediate-dose pegylated interferon, and low-dose interferon (1–3 MU) regimens with observation. Multiple trials have shown that adjuvant high-dose interferon improves relapse-free survival by approximately 10% at five years, but initially reported benefits in overall survival have disappeared with longer follow-up periods. Individual patient data meta-analyses of observation-controlled trials of various dosing regimens showed a statistically significant benefit of interferon for event-free survival, and an absolute overall survival benefit of 3% (CI 1–5%) at five years. There was no evidence of any difference according to dose or duration of therapy. Individual Phase III trials of intermediateand low-dose interferon have not shown a clear advantage for interferon over observation. Long-term pegylated interferon improved four-year relapse-free survival by 7% but had no effect on distant metastasis-free survival or overall survival. High-dose interferon-alpha remains the only FDA-approved systemic adjuvant therapy for melanoma. The toxicity of high-dose interferon-alpha is substantial but reversible and requires experienced medical oncology management, aggressive supportive measures including the use of prophylactic antidepressants, and careful monitoring and dose-reduction strategies, particularly for hepatotoxicity. Because of the toxicity of high-dose interferon and the uncertain benefits of lower dosing regimens, patient participation in clinical trials of new adjuvant therapies is strongly encouraged and observation remains an appropriate comparator in Phase III trials. Experimental approaches undergoing current investigation with prospective randomized placebo-controlled double-blind clinical trials include immunotherapy with anti-MAGE-A3 vaccine, ipilimumab, or PEG-interferon (in patients with ulcerated primary melanomas and microscopic lymph node involvement). Drugs targeting the MAP kinase pathway are also in placebo-controlled adjuvant clinical trials using vemurafenib (GO27826, ‘BRIM-8’) or the combination of dabrafenib and trametinib (BRF115532, ‘Combi-AD’).

Адъювантная лучевая терапия

Following surgical clearance of macroscopic (clinically detectable) disease in regional lymph nodes, recurrence in the node field is most common when at least one involved node is large (>3 cm), where multiple nodes are involved, or if there is histological evidence of extranodal spread. To reduce this risk of node field recurrence, adjuvant postoperative radiotherapy to the node field may be given. In the only large prospective trial that has examined the value of this adjuvant radiotherapy following regional node clearance in high-risk melanoma patients, the rate of node field recurrence was 33% in the control group and 18% in the group that received adjuvant radiotherapy, with acceptably low morbidity.

Локальные и транзитные рецидивы

True local recurrence of a primary melanoma, i.e., within a previous wide excision scar, is rare if adequate margins are achieved. Thus most recurrences adjacent to a previous melanoma wide excision site, like in transit metastases that occur between the primary site and the draining regional lymph node field, are probably due to intralymphatic metastasis. The term ‘satellitosis’ is frequently used for microscopic or macroscopic recurrences that are within a few centimetres of the primary site. These, too, are likely to be due to the same pathophysiological process, i.e., intralymphatic metastasis.

When local or in transit metastasis occurs, the patient’s prognosis becomes much worse. Up to 50% of patients who develop even a single local or in transit metastasis ultimately die of melanoma. The treatment modality employed to deal with local and in transit metastases does not appear to have any effect on ultimate outcome, and the goal of treatment is therefore to deal with the problem of loco-regional disease in the most efficient but least invasive and least morbid way possible. The recent introduction of effective forms of systemic therapy may improve the outcome for patients with in transit metastases not able to be treated by any of the methods outlined below.

Простое иссечение, абляционная техника, внутри-повреждения и топическая терапии

If local or in transit metastases are small and few in number, simple surgical excision is the best treatment option. If the disease is superficial but more extensive, simple ablative techniques such as diathermy-fulguration or CO2 laser ablation are effective. When the disease is unable to be controlled by simple measures such as those just outlined, consideration may need to be given to intralesional therapy (e.g., with BCG, IL-2 or Rose Bengal) and radiotherapy may also be employed if the disease is localized.

Extensive but superficial disease can also be treated with topical agents. One of the most promising of these is topical diphencyprone, which enhances local skin immunity and leads to tumour involution in many patients, even after other forms of treatment, including surgery and radiotherapy, have failed.

Изолированная перфузия конечности и изолированная инфузия конечности с цитотоксическими препаратами

When locally recurrent or in transit disease is not suitable for treatment with any of the modalities described above and the disease is confi ed to a limb, regional chemotherapy with vascular isolation, using the techniques of isolated limb perfusion (ILP) or isolated limb infusion (ILI), is often effective. Both these techniques involve the administration of high-dose chemotherapy to a limb when its blood supply is isolated from the general circulation with a tourniquet. Isolated limb perfusion has been used for more than 50 years, and was developed shortly after the technique of cardiopulmonary bypass was introduced, using similar equipment and based on similar principles. Large bore cannulas are placed by open operation into the major vein and artery of the affected limb, and the cannulas are connected to an extracorporeal circuit through which circulation is maintained with a pump that incorporates an oxygenator and a heat exchanger, as for cardiopulmonary bypass. The limb is isolated from the vasculature of the body by placing a tourniquet around the root of the limb to occlude all blood vessels, and high-dose cytotoxic agents are perfused through the limb, usually for a period of 60–90 minutes. The drug most commonly used is melphalan, and its effi acy is enhanced by adjusting the temperature in the perfusion circuit so that mild to moderately hyperthermic limb temperatures (39–41°C) are achieved.

Even for patients with extensive in transit disease in a limb, complete response rates of 40–50% are reported after ILP and partial response rates of 30–40%, resulting in good disease control in 80–90% of patients who are treated in this way. Better results for patients with very bulky disease have been reported when TNF has been used with melphalan, but there are significant risks associated with systemic leakage of the TNF, and there has been no clinical trial evidence of superior efficacy of ILP with melphalan and TNF over ILP with melphalan alone.

An alternative but much simpler technique of regional chemotherapy with vascular isolation is isolated limb infusion. This technique was conceived as a method of achieving the benefits of ILP more simply and more safely. In a large experience of the ILI technique in Sydney, where it was developed, complete response rates of 38% and partial response rates of 46% were achieved. An ILI procedure is performed via small calibre catheters that are inserted percutaneously by a radiologist into the axial vessels of the affected limb via the opposite groin. Having applied a pneumatic tourniquet to the root of the limb, cytotoxic drugs in high concentration (normally melphalan and actinomycin D) are infused and circulated in the limb using a hand-held syringe via a three way stopcock in the external circuit (which also contains a blood warmer) for a period of 30 minutes. At the end of this time the limb vasculature is flushed with an electrolyte solution, the venous effluent is discarded, the tourniquet is deflated and the catheters are withdrawn.

Both ILP and ILI inevitably produce an inflammatory reaction in the normal tissues of the treated limb, and occasionally more severe reactions in the limb can occur, with skin and muscle necrosis. The tumour deposits in the limb usually begin to undergo involution within a week of the procedure, but the full effect of the treatment may not be apparent for up to three months.

Ампутация конечности

When all the above forms of treatment fail to control disease in a limb, amputation is very occasionally required. Even when this is necessary, some patients remain disease-free indefinitely, although the majority go on to develop systemic metastases and eventually die of melanoma.

Наблюдение для новых меланом и метастатической болезни

There are two distinctly separate reasons for periodic review of patients with melanoma. The fi st is to identify recurrent disease and the second is to diagnose new primary melanomas at an early stage. It is well documented that any patient who has had a primary melanoma is at greatly increased risk of developing another primary melanoma in the future. The risk of recurrence of the original primary depends on its thickness and other histological features (such as ulceration and mitotic rate). This means that more intensive follow-up schedules are usually recommended for patients with thick melanomas and less intensive schedules for those with thin melanomas. There are, however, no good prospective clinical trial data to indicate the optimal frequency of follow-up visits, and most follow-up schedules are based on very low level evidence. Nevertheless, it is commonly recommended that patients with thin (<1 mm) melanomas be checked at least annually following their definitive melanoma treatment, while patients with intermediate thickness (1–4 mm) and thick (>4 mm) melanomas be checked every three to four months for the fi st two years, and less frequently thereafter.

In considering follow-up strategies, however, it must be borne in mind that the great majority of melanoma recurrences and new primary melanomas are detected not by doctors at routine visits but by the patient or their partner. In most series where this has been examined, no more than 15–20% of recurrences and new primary melanomas have been detected by doctors at routine visits. A very useful part of melanoma patient care is, therefore, to provide adequate education which will help early recognition of recurrent disease or new primary tumours. Such programs already exist in many major melanoma treatment centres.

The value of routine follow-up blood tests, X-rays, and scans is controversial. Until recently, many clinicians involved in the care of patients with melanoma considered that early diagnosis of systemic metastatic disease in asymptomatic patients was of little benefit because there was no effective therapy. The advent of systemic agents that are effective, at least in the shortto medium-term, means that this nihilistic approach to follow-up investigations may need to be reappraised. With the ready availability of CT and PET/ CT scanning in most countries where melanoma incidence is high, it would seem reasonable to offer whole body imaging (either CT or PET/CT scans) at least annually to patients considered to be at high risk of systemic metastasis (e.g., those with treated Stage IIC, IIIA, IIIB, and IIIC disease, as well as those with Stage IV disease following apparently successful surgical treatment).

Хирургическое лечение болезни IV стадии согласно American Joint Committee on Cancer

For patients with AJCC Stage I, Stage II, and Stage III melanoma, surgery is the standard treatment. For patients with Stage IV disease, however, the role of surgery is less well defined. Resection of metastatic melanoma at distant sites may be considered appropriate if complete removal of all identifiable disease appears to be possible, with potentially curative intent. It may also be considered for patients with resectable disease that is causing troublesome symptoms, or is considered likely to cause troublesome symptoms before the patient dies of the disease. In each patient, the potential benefits of the proposed surgery should outweigh the risks. If surgical excision of metastases can be accomplished with low morbidity, quick and effective palliation (or expectant palliation) is possible.

Хирургия с куративными целями пациентов с меланомой IV стадии

Many studies have demonstrated that complete surgical resection of metastatic disease gives patients the greatest chance of prolonged survival with a good quality of life. Five-year survival rates of 20–30% are reported after complete surgical resection of visceral metastases, compared with five-year survival rates of around 10% in patients treated with the best available systemic therapies. In assessing the results of surgical treatment for distant metastatic disease, it must be borne in mind that the outlook for patients with involvement of distant skin, subcutaneous tissues, or distant lymph nodes is substantially better than the outlook for patients with metastatic disease at visceral sites (see Figure 49.3).

With present day sophisticated imaging techniques, particularly PET/CT and MRI scanning, the identifi ation of patients with metastatic disease that is completely resectable has become easier and more reliable. Even if there is residual metastatic melanoma in the body, not detected by conventional imaging techniques, there is some evidence that the cytoreductive surgery may allow the patient’s cellular and/or humoral immunity to more effectively control the growth of residual occult tumour cells. Even when further distant metastases become apparent following previous surgical excision of apparently isolated distant melanoma metastases, salvage by repeated surgical excision may be possible. In one study, a 90% five-year survival rate was reported after complete resection for recurrence after initial metastasectomy.

Fig. 49.3. Survival curves of 7635 patients with metastatic melanomas at distant sites (Stage IV) grouped by (A) the site of metastatic disease and (B) serum lactose dehydrogenase (LDH) levels. LDH values are not used to stratify patients. Curves in (A) are based only on site of metastasis. The number of patients is shown in parenthesis. SQ, subcutaneous.

Исходы резекции метастазов меланомы в специфических областях

Кожа, подкожная ткань и лимфатические узлы

These are the most common sites for non-loco-regional metastatic melanoma. When only a few lesions exist in distant skin, subcutaneous tissues, or lymph nodes, excellent results have been reported after surgical excision. Repeated excisions are often necessary, but appear to be worthwhile if there is no evidence of visceral disease. There is no evidence that excision of metastatic disease at these sites with very wide margins is necessary, but it is clearly important that they be removed with a cuff of apparently normal tissue so that histologically clear margins are achieved.

Легкие

Melanoma metastases in the lung are diagnosed more frequently than metastases at other visceral sites, perhaps because they are more readily identified with modern imaging techniques than metastases elsewhere. The lung metastases are usually asymptomatic, and they are associated with longer survival (median 10–11 months) than metastases in other viscera. Reports from a number of single institutions and the International Registry of Lung Metastases have demonstrated prolonged survival in appropriately selected patients who have had lung metastases resected. As is the case for patients with melanoma metastases in other viscera, patients with lung metastases are likely to have the best outcome if there is no evidence of metastatic disease at any other site.

Головной мозг

Cerebral metastases account for 20–54% of deaths from melanoma, and post-mortem studies have shown that the great majority of patients who die of melanoma have brain metastases. Without treatment, the median survival for a patient with a symptomatic brain metastasis is only approximately one month without treatment and two months with palliative corticosteroid therapy alone. In the past, the active treatment options for patients with brain metastases were surgical resection or whole brain radiotherapy (WBRT). In more recent times stereotactic radiotherapy has been shown to have similar efficacy to surgery, and is particularly appropriate when multiple lesions require treatment. Several studies have shown that symptoms are relieved and survival times are increased in the great majority of patients whose cerebral melanoma metastases are treated. Symptoms due to cerebral metastases are improved in more than two-thirds of melanoma patients treated with WBRT; however, the median survival after WBRT alone is only 3.5 months. The role of WBRT after surgical resection of cerebral metastases has been controversial.

Гастроинтестинальный тракт

Melanoma metastases in the gastrointestinal tract are also very common in post-mortem studies, but are less frequently symptomatic during life. The most common symptoms are abdominal pain, bleeding (and associated anaemia), and bowel obstruction. In any patient with a history of melanoma who presents with anaemia, the possibility of one or more metastases in the gastrointestinal tract, most commonly small bowel, must be considered. Melanoma metastases in the oesophagus and stomach are best treated by surgical resection if they isolated; as well as achieving good relief of symptoms, long-term survival is sometimes achieved. Patients with small bowel metastases often present with small bowel obstruction due to intussusception. Even when there is disease at other sites, surgery to resect the segment of small bowel containing the intussuscepting metastasis is worthwhile, as it produces immediate relief of symptoms, restores good quality of life, and often extends survival considerably.

Печень и билиарный тракт

Patients with melanoma metastases in their liver generally have a very short life expectancy (2–4 months). However, patients who have apparently isolated liver metastases that are able to be resected surgically occasionally achieve long-term survival. In recent times, ablative techniques for multiple liver metastases have been introduced, such as cryotherapy and radiofrequency ablation. These have extended the therapeutic options for patients who have multiple hepatic metastases. Regional therapy via the hepatic artery (using agents such as fotemustine and radioactive spheres) is now quite widely used with palliative intent, but has not been shown in clinical trials to improve survival outcome.

Селезенка

Isolated melanoma metastases in the spleen are uncommon, and there are usually synchronous metastases at other intra-abdominal sites. For patients in whom the splenic disease is apparently isolated or symptomatic, however, surgery should be considered.

Кости

It is unusual for patients to have melanoma bone metastases without metastatic disease at other sites, and the main role of surgery is to prevent or relieve symptoms. This may involve bone resection, enucleation of the tumour (then filling the resulting cavity with bone cement), joint replacement, operative bone fixation, or the use of external braces or a cast. Many bone metastases can be treated effectively with radiotherapy, and radiation is often given as adjuvant therapy following a surgical procedure for a bone metastasis. Metastases involving the spinal vertebrae have potentially serious implications, because pathological fractures or tumour expansion may cause spinal cord compression. When this occurs, urgent decompressive laminectomy may be required with adjuvant postoperative radiotherapy. If there is judged to be no imminent risk of spinal cord compression, most vertebral metastases can be treated effectively with external beam radiotherapy.

Системная терапия болезни IV стадии

Таргетные препараты

BRAF ингибиторы

The MAPK pathway is strongly activated in 90% of melanomas. In approximately 50% of cases this is caused by activating mutations in BRAF; the most common of these is substitution of glutamic acid for valine at amino acid position 600 (V600E), which locks the kinase in activated conformation. Other activating mutations also occur, including V600K, V600D, and V600R. Vemurafenib and dabrafenib are potent and selective inhibitors of mutant BRAF. They induce tumour regression in the majority of patients who have V600-mutant BRAF melanoma, with overall response rates of 50–60%. Responses occur in all sites, including brain. In a Phase 3 trial of vemurafenib in treatment-naive patients there was a statistically significant improvement in overall survival from 9.6 months with the standard comparator, dacarbazine (DTIC), to 13.2 months with vemurafenib. The true benefit of vemurafenib was underestimated in this trial, however, because 50 dacarbazine-treated patients crossed over to receive vemurafenib 12 months after trial commencement when the clear benefits of the test drug became obvious at interim data monitoring. Vemurafenib and dabrafenib have both been approved by the FDA for treatment of V600-mutant BRAF melanoma.

Median progression-free survival with vemurafenib and dabrafenib is 5–6 months, and this has prompted vigorous examination of mechanisms of emergent resistance to therapy with BRAF inhibitors [6]. Most clinically relevant mechanisms involve reactivation of the MAPK pathway by upstream activation, including NRAS mutation and RTK over-expression, amplification of mutant BRAF, and emergence of active splice variants of BRAF which are unaffected by BRAF inhibitors. Approaches to overcome resistance to BRAF inhibitors include combining BRAF and MEK inhibitors (see below), adaptive trial design using other combinations of targeted drugs, and the use of pulsed therapy, which has shown remarkable efficacy in an animal model.

BRAF inhibitors are well tolerated. The most common side effects are skin rashes, including Grover’s disease, papillomas and verrucas, and other keratopathies. Vemurafenib, but not dabrafenib, is severely photosensitizing, an effect unrelated to BRAF inhibition. Paradoxical activation of the MAPK pathway may occur in keratinocytes carrying upstream activators like RAS mutations. In the presence of BRAF inhibition this results in heterodimer formation between RAF family members and downstream MAPK stimulation. In 10–20% of treated patients this may result in the formation of keratoacanthomas or squamous cell carcinomas. These are readily treated by surgical excision, but regular skin surveillance is essential for patients on BRAF inhibitors. This paradoxical oncogenesis has also been associated with an increased incidence of second primary melanomas and induction of acute leukaemia.

MEK ингибиторы

MEK inhibitors are active in patients with mutant BRAF melanoma, presumably because of the high level of stimulation of the pathway downstream of BRAF in these tumours. A number of drugs in this class are undergoing clinical development. Trametinib confers benefits in both progression-free and overall survival compared to standard chemotherapy, with an overall response rate of 22%. Some MEK inhibitors such as MEK162 show some evidence of activity in mutant NRAS melanoma, for which there are currently no other established targeted systemic treatment options, and clinical trials are proceeding with these drugs.

The dominant toxicities of MEK inhibitors are acneiform rashes, diarrhoea, nausea, oedema, and fatigue. Central serous retinopathy and retinal vein occlusion are rare side effects which mandate careful ophthalmological monitoring of all patients treated with these agents.

Комбинированное BRAF и MEK ингибирование

The demonstration that MAPK reactivation was responsible for most cases of emergent resistance to BRAF inhibition, together with in vitro demonstrations of synergy and reduced toxicity, led to clinical trials of combined BRAF and MEK inhibition. In a randomized Phase 2 study the combination of dabrafenib plus trametinib in patients naпve to BRAF inhibitors showed an overall response rate of 63% in the maximally dosed cohort, with a median progression-free survival of 9.4 months compared with 5.8 months in the single-agent dabrafenib arm and 12-month progression-free survival of 41% vs 9%. The combination also rescued some patients refractory to BRAF inhibitors, with an overall response rate of 19% and median progression-free survival of 3.6 months. Phase 3 trials have commenced comparing the doublet with single-agent dabrafenib or vemurafenib, but these early results suggest that dual MAPK blockade with BRAF and MEK inhibitors is likely to become standard therapy for BRAF-mutant melanoma. The impressive activity of this combination has led to the dabrafenib/trametinib doublet being tested in the adjuvant setting in the ‘Combi-AD’ trial. Some of the more notable toxicities of the MAPK inhibitors cancel each other out when used in combination. The presence of a MEK inhibitor appears to block paradoxical MAPK activation in keratinocytes, reducing SCC incidence to near-background levels, and BRAF inhibition appears to block the acneiform rash of MEK inhibitors. Drug-induced fever occurs, however, in more than 50% of patients on the dabrafenib/trametinib combination.

Other BRAF/MEK inhibitor combinations being assessed in early clinical trials include LGX818/MEK162 and vemurafenib/ cobimetinib.

KIT ингибирование

A small subset of mucosal, acral, and chronic sun-damaged skin melanomas carry activating mutations in the KIT oncogene. Some, but not all, of these mutations are sensitive to inhibition with imatinib, sunitinib, or nilotinib. The likelihood of response correlates with the ratio of mutated:wild-type KIT alleles in the melanoma cell. Response duration is generally measured in months.

Другие молекулярные мишени

Approximately 20% of cutaneous melanomas carry NRAS mutations. These are nearly always reciprocal to BRAF mutations, unless the tumour has been previously exposed to the selective environment of BRAF inhibition. NRAS is a difficult target for designing small molecule inhibitors, and preclinical and early clinical focus is on downstream effectors including MEK and PI3K.

There is evidence for activation of the AKT/PI3K pathway in many melanomas, and in a subset of tumours resistant to BRAF inhibitors. Multiple PI3K inhibitors are being assessed in clinical trials both as single agents and in combination with MAPK inhibitors.

The high frequency of CDKN2A/p16 alterations in melanoma and amplification of cyclin D1 both point to the importance of this for regulation of the melanoma cell cycle, and drugs targeting this axis are in early clinical development.

Иммунотерапия

Вакцины

Despite the presence of detectable immune responses in 30–60% of patients, tumour regression occurs in onlya minority of vaccine-treated metastatic melanoma patients. Vaccine therapy remains under intense investigation in the adjuvant setting, and may have a role in combination with other immunotherapies in metastatic disease.

Адоптивная иммунотерапия

In carefully selected patients, high rates of disease control are reported with adoptive immunotherapy programs. These involve harvesting, then ex vivo expansion and sometimes genetic manipulation, of tumour infiltrating lymphocytes (TIL). Typically, patients are conditioned with lymphodepleting cytotoxic chemotherapy, with or without cytokines and whole body radiotherapy, before reinfusion of expanded TIL. The best series response rates were 50–70%, with small numbers of patients remaining disease-free at over four years. Inpatient support is required following immunoconditioning and toxicity includes febrile neutropaenia in 12–16% of patients. Several centres internationally are developing simplified and less toxic protocols of adoptive immunotherapy, including the use of genetically-engineered T cells expressing chimeric antigen receptors (CAR-T cells).

Интерлeйкин-2 и интерферон-α

Interleukin-2 (IL-2) is FDA-approved for treating metastatic melanoma based on a retrospective series showing sustained disease control in a small subset of treated patients. Although the overall response rate was just 16%, one quarter of responding patients had sustained disease control, most beyond five years. Gene expression profiles may assist in identifying those who may benefit from IL-2. The toxicity of IL-2 therapy is high and includes hypotension in 64% of patients and treatment-related mortality in 2.2%.

Single agent interferon-alpha has a response rate of approximately 20% in metastatic melanoma in Phase 2 trials but response duration is brief and use is restricted by the high incidence of influenza-like toxicity including fatigue and fever. Routine use is not recommended by most international guidelines except in the adjuvant setting and in clinical trials.

Регуляторы иммунных чекпоинтов

Activation of the immune response is kept in check at both induction and effector phases by complex molecular interactions inducing feedback inhibition of T cell proliferation and cytokine release to dampen down the immune response and prevent autoimmunity. Melanoma cells subvert this system to induce immunological tolerance. Molecules which target checkpoint regulation induce potent immune responses against melanoma cells and are active in the treatment of metastatic disease.

CTLA4 ингибиторы

Ipilimumab is a monoclonal antibody which binds to CTLA4 on regulatory T cells, inhibiting its interaction with B7 on antigen-expressing cells, and removing a regulatory brake on T cell activation. In a phase 3 clinical trial of metastatic melanoma patients refractory to prior systemic therapy, ipilimumab (3 mg/kg) with or without a gp100 vaccine proved superior to vaccine control in overall survival. In first-line therapy of metastatic melanoma, the combination of ipilimumab (10 mg/kg) with the cytotoxic drug dacarbazine proved superior in overall survival to dacarbazine/placebo control. Notable in this trial was a 10% improvement in landmark absolute overall survival benefit at two years (28.5% vs 17.9%) and three years (20.8% vs 12.2%).

Tumour response rates to ipilimumab are low (~10%), and grade 3–4 autoimmune toxicity occurs in more than one half of all treated patients. Dermatitis and colitis are the most common toxicities, but are readily reversible with corticosteroids. Biopredictors of the subgroup of metastatic melanoma patients who respond to CTLA4 inhibition are eagerly sought, as they are for all forms of immunotherapy of this disease. Ipilimumab is FDA approved for the treatment of metastatic melanoma.

A second anti-CTLA4 monoclonal antibody, tremelimumab, showed similar promise to ipilimumab in Phase 2 clinical trials, but failed to show superiority over chemotherapy as first-line therapy. The reasons for the failure of tremelimumab to replicate the benefits of ipilimumab are not clear but may relate to dosage schedules or pharmacokinetic and pharmacodynamic factors.

Препараты, таргетирующие PD-1 и PD-1 лиганд

Pro-death receptor-1 ligand 1 (PD-L1) is expressed on many melanoma cells. PD-1 is an immune checkpoint regulator expressed on cytotoxic T lymphocytes which dampens the immune response and induces immune tolerance. Phase I trials of the monoclonal antibodies nivolumab and lambrolizumab, which target the interaction between PD-1 and its ligand, show promising activity with remissions in around 20–50% of patients. Autoimmune toxicity seems much lower than that seen with ipilimumab. Expression of PD-L1 on tumour and stromal tissue is being investigated as a possible biomarker predicting response to anti-PD-1 therapy. Monoclonal antibodies against PD-L1 also have activity against metastatic melanoma and are in clinical trials.

Combined use of nivolumab with ipilimumab provides synergistic benefit in patients with metastatic melanoma, with tumour remissions that are frequent, rapid and durable, with median two-yearly survival close to 80% and with manageable toxicity [7].

Химиотерапия

Melanoma has formidable defences against the induction of apoptosis and this probably accounts for its relative resistance to cytotoxic chemotherapy. Single-agent dacarbazine (DTIC), temozolamide, and fotemustine are used as systemic therapy of metastatic melanoma because of their relatively low toxicity and simplicity of administration, and because of the failure of more toxic combination therapies to show superiority in terms of survival outcomes. However, response rates to dacarbazine and temozolamide in recent randomized trials have been less than 10%, the median duration of response is brief, and the median overall survival nine months. The small group of patients who benefit cannot be reliably predicted by tumour biomarkers. Chemotherapy response is more likely in subcutaneous, lymph node, and pulmonary metastases than in other visceral sites, and in those with better performance status. A Phase III Trial of three-agent chemotherapy versus the same drugs plus interferon-alpha and interleukin-2 (‘biochemotherapy’) produced a slightly higher response rate and progression-free survival for biochemotherapy, but this was not associated with either improved quality of response or better overall survival. NAB-paclitaxel shows improved progression-free survival over dacarbazine and the combination of paclitaxel and carboplatin also produces slightly higher response rates (18%). However, these small gains are not matched by overall survival benefits and are only achieved at the cost of higher haematological and neural toxicities.

Роль лучевой терапии для меланомы IIIC и IV стадии

Sixty years ago it was suggested that melanoma was a tumour type that was particularly resistant to radiation therapy. However, this perception was based on the results of radiotherapy techniques that have long since been superseded.

Today radiation therapy is widely used to treat metastatic melanoma at distant sites. It is usually given with palliative intent, and in some patients prolonged disease control is achieved. A detailed consideration of the clinical radiobiology of melanoma is beyond the scope of this chapter, but is discussed in detail elsewhere.

Метастазы в кожу и подкожную область

When surgical excision of troublesome cutaneous or subcutaneous metastases at distant sites is not possible, radiotherapy may be an effective treatment option.

Метастазы в лимфатические узлы

Extensive metastatic lymph node disease that is not amenable to surgical treatment and has failed to respond to systemic therapy can often be effectively palliated with radiotherapy. A commonly used treatment schedule involves the administration of 20 Gy in five daily fractions. A bolus dose may be required for nodal masses that have fungated.

Метастазы в головной мозг

Cerebral metastases frequently cause significant morbidity and without treatment the prognosis of patients who develop cerebral metastases is bleak; their median survival is only three to four months, and up to 95% of them die as a direct result of their brain metastases. Although it is difficult to separate out the effects of case selection, there is persuasive evidence that treatment involving surgery and/or radiotherapy can extend survival times considerably. There is also evidence that stereotactic radiosurgery (SRS) is as effective as surgical excision of single brain metastases, but several metastases may be readily treated by SRS, whereas surgery is rarely considered feasible under these circumstances. Control rates reported after SRS for the treatment of melanoma metastases in the brain are high, with individual treatment centres reporting local control rates of 80–90%.

The role of WBRT after surgical resection of cerebral metastases or following their treatment with SRS remains controversial. The main deterrent to the use of WBRT has been the perception that there is a treatment-related decline in neurocognitive function following its use. A large prospective, multicentre randomized trial assessing the value of WBRT following treatment of melanoma cerebral metastases by surgery or SRS is currently in progress.

Компрессия спинного мозга вследствие метастазов меланомы

This problem usually arises as a result of extra-dural compression from an expanding vertebral metastasis. Occasionally, however, the compression arises from a metastasis within the spinal cord itself or as a result of diffuse meningeal involvement. The classical clinical picture is of progressively severe back pain in a patient known to have disseminated melanoma. This is followed by the typical clinical signs and symptoms of spinal cord compression, with loss of bladder and bowel control, loss of strength in the lower limbs, with paresthesiae or numbness, and ultimately paraplegia. Malignant spinal cord compression constitutes an oncological emergency. The definitive investigation is an MRI scan of the spine, and high-dose corticosteroids should be commenced immediately if the condition is suspected. Treatment options are surgical decompression or urgent radiotherapy. A decision about which treatment to offer the patient depends on numerous factors, not only the location and extent of the metastasis that is causing the problem, but also the patient’s general condition, the presence of systemic metastases at other sites, and the extent of spinal involvement. There is general consensus that patients with isolated vertebral lesions causing spinal cord compression who are considered to have a reasonable life expectancy should be offered decompressive surgery followed by post-operative radiotherapy. In patients who are not considered to require urgent surgery, radiotherapy should be offered. Steroid therapy is continued throughout the treatment course and then slowly tapered when it is complete. If neurological deterioration is observed during the course of palliative radiotherapy to the spine, urgent surgical decompression must be considered to avoid paraplegia. However, relief of symptoms after palliative radiotherapy for threatened spinal cord compression has been reported in two-thirds of patients.

Метастазы в кости

Метастазы в кости (за исключением позвоночника) часто наблюдаются у пациентов с распространенной меланомой. Пациенты с костными метастазами, как правило, испытывают боль, с прогрессированием в патологический перелом вовлеченной кости во многих случаях, если поражение не лечится. Метастазы в кости часто распространяются на окружающие ткани, что визуализируется на КТ или МРТ сканах. Костные метастазы часто хорошо поддаются курации паллиативной лучевой терапией, которая обеспечивает облегчение боли более чем в 65% случаев. Угрожающие или фактические патологические переломы требуют внутренней фиксации с последующей лучевой терапией.

Другие области, которые поддаются лечению радиотерапией

Другие показания к лечению метастатической меланомы лучевой терапией включают метастазы в мягкие ткани, которые вызывают боль как результат локальнойинвазии, поражения, которые вызывают потерю крови, например, в бронхиальном древе, и поражения, которые вызывают обструктивные симптомы, например, метастатические узлы в средостении или метастатические депозиты в ротоглотке, глотке, трахее или бронхиальном дереве. Другая ситуация, когда радиотерапия может быть полезна, — это метастазы в орбиту с результирующим проптозом, диплопией и ухудшением остроты зрения.

Метастатическая меланома из неизвестного первичного сайта

In approximately 10% of patients in whom metastatic melanoma is diagnosed in lymph nodes, there is neither evidence of nor any prior history of a primary melanoma. This phenomenon is attributed either to complete regression of a previously existing unrecognized primary melanoma, or to de novo development of melanoma in naevus cells within a lymph node (which are commonly observed). Whatever the aetiology of the condition, the prognosis for the patient is somewhat better than for a patient with equivalent nodal disease from a known primary site. Much less frequently, systemic metastases are diagnosed when there is no known primary melanoma site. In both situations, treatment should be the same as for metastatic disease from a known primary site.

Меланома некожной локализации

Although the majority of melanomas arise in the skin, melanomas can also develop at mucosal sites. Ocular melanomas are considered in Chapter 57, Tumours of the eye and orbit. Mucosal melanomas are rare. Sites at which they can develop include the oropharynx, oesophagus, lung, stomach, gall bladder, small bowel, large bowel, rectum, anus, urethra, vagina, and cervix. The principles of treatment for primary melanomas arising in all of these sites are similar, i.e., by complete surgical excision whenever possible. There may be a role for radiotherapy as definitive therapy in the management of mucosal melanoma.

Руководства по менеджменту меланомы и важность мультидисциплинарного леченебного подхода

Over the past twenty years, the surgical management of primary cutaneous melanoma has changed substantially. Whereas elective dissection of regional lymph node fields was routine in many melanoma treatment centres until the early 1990s, the introduction of SLNB has meant that the great majority of patients have been spared the morbidity of that approach, and only those found to have metastatic disease in a SLN (around 20% of those with melanoma >1mm in thickness) are subjected to CLND. The recommended width of excision for a primary cutaneous melanoma has reduced progressively, after clinical trials indicated that 1–2cm margins were adequate for most patients, with very low rates of local recurrence and no adverse effect on melanoma-specific survival compared with wider excision margins. More recently, the introduction of several forms of effective systemic therapy has changed management strategies for patients with Stage IV disease; these may be quite complex, depending on drug availability and eligibility for clinical trials. What this proliferation of treatment options means for patients with Stage III and Stage IV disease is that he or she is best served if a management plan is discussed by a multidisciplinary team. This approach will ensure that all treatment options are canvassed, and an appropriate management strategy devised for each patient. It is also important for patients to be offered participation in clinical trials whenever possible, so that new options for adjuvant therapy (in patients with surgically resected Stage III and Stage IV disease) and for definitive therapy (in patients with unresectable Stage IV disease) can be properly assessed and outcomes further improved. A particular multidisciplinary challenge is posed by brain metastases. Targeted drugs and immunotherapy have activity in brain metastases, so careful clinical planning is required, involving neurosurgeons, radiation oncologists, and medical oncologists. For patients with straightforward Stage I and Stage II disease, management according to nationally-agreed guidelines will ensure that optimal treatment outcomes are achieved.

Литература

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