43. Саркома мягких тканей

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

Edited by American Cancer Society

Заболеваемость и смертность

Статистические данные, касающиеся сарком мягких тканей, компилированы в рамках SEER (National Cancer Institute’s Surveillance, Epidemiology, and End Results) программы в категории рака «мягких тканей (включая сердце)», который включает несколько типов канцера, происходящих из мягких тканей, забрюшинного пространства. брюшины, плевры, сердца, средостения и селезенки [1,2]. Большинство, но не все, раковые заболевания в этой категории являются саркомами. Наиболее распространенными гистологиями сарком мягких тканей являются «саркома, не указанная иным образом» (20,6%), липосаркома (16,8%), лейомиосаркома (13,3%), фибросаркома (7,6%) и злокачественная фиброзная гистиоцитома (7,4%) [2]. Рак мягких тканей представляет только 0,7% всех новых диагнозов рака; приблизительно 12 390 новых случаев наблюдаетя в Соединенных Штатах (США) ежегодно. Ежегодно от STS умирает около 4990 человек, что составляет 0,8% всех случаев смерти от рака в США [1]. Инцидент STS, в целом на основе случаев, диагностированных в 2009–2013 годах, составлял приблизительно 3,4 на 100 000 человек в год. В этот же период смертность с поправкой на возраст составляла 1,3 на 100 000 человек в год. Средний возраст на момент постановки диагноза и на момент смерти для этой категории составлял 59 лет и 65 лет соответственно [2].

Этиология

Хотя саркомы классифицируются согласно соединительной ткани их происхождения, неизвестно, нормальные клетки или мезенхимальные стволовые клетки ответственны за неоплазию; последние, тем не менее, наиболее вероятны. В иллюстрации этого, большинство рабдомиосарком возникает в местах отсутствия скелетных мышц. Так же хорошо дифференцированные и дедифференцированные липосаркомы находятся в одной и той же ткани и имеют сходные молекулярные признаки, однако неясно, является ли дедифференцированная липосаркома клональной эволюцией хорошо дифференцированной липосаркомы или представляет собой уникальную форму. Приблизительно в 20% случаев STS, клетка происхождения не может быть определена, несмотря на обширный иммуногистохимический или молекулярный анализ [3]. Большинство сарком являются спорадическими, а генетические или средовые причины идентифицированы лишь в меньшинстве гистологий [3].

Ионизирующая радиация

Внешняя лучевая терапия ассоциирована с повышенным инцидентом сарком мягких тканей в нескольких областях, хотя абсолютный риск, по-видимому, относительно низок. Избыточный инцидент, связанный с лучевой терапией, выше среди выживших детей с раковыми заболеваниями, особенно с генетическими синдромами (такими как наследственная ретинобластома, ассоциированная с RB1 геном), которые могут повышать восприимчивость к радиационному саркомагенезу (RAS) [4]. Хотя нет точного определения RAS, для постановки диагноза необходимо несколько факторов. Саркома должна развиваться в области предыдущего облучения, гистология нового поражения должна отличаться от первоначально облученной опухоли, и обычно между первым курсом облучения и развитием новой опухоли должен быть интервал около 3 лет [5,6]. Злокачественная фиброзная гистиоцитома или недифференцированная плеоморфная саркома (MFH/UPS), ангиосаркома и лейомиосаркома (LMS) являются наиболее распространенными RAS, обычно возникающими после облучения выживших с раком молочной железы, раком головы и шеи и с наследственной ретинобластомой [6].

Воздействия химических веществ

Недавний обзор интерпретировал имеющиеся данные как наводящие на размышления о связи между STS риском и воздействием хлорфенолов и некоторых гербицидов (особенно в профессиональной среде) и выбросами от мусоросжигательных заводов [7,8]. Другие исследования «случай-контроль» не нашли сильной связи.

Хронический лимфоотек

Хронический лимфоотек является предрасполагающим фактором для ангиосаркомы, которая классически наблюдается у женщин, перенесших радикальную мастэктомию по поводу рака молочной железы, и называется синдромом Стюарта-Тревеса (Stewart–Treves). В областях, где филяриозные инфекции являются эндемичными, лимфангиосаркома является редким осложнением филярной лимфедемы. Механизмы сосудистого и лимфатического стаза и последующего развития лимфангиосаркомы не изучены, однако амплификация c-Myc отмечена.

Травма

Есть отдельные сообщения, что тупая травма или хирургическое иссечение могут спровоцировать STS. Многие пациенты с недавно диагностированным STS сообщают о недавней травме в анамнезе, но нет доказательств, подтверждающих, что травма является предрасполагающим фактором [3,9]. Вероятно, травматические эпизоды привлекают внимание к определенной части тела, а последующий осмотр акцентируется на асимптоматическом поражении. Например, травма или хирургическое вмешательство часто упоминаются как фактор, провоцирующий агрессивный фиброматоз или десмоидные опухоли. Тем не менее, открытие рекурентных соматических CTNNB1 (кодирующий β-катенин) мутаций и APC мутаций в спорадических и FAP-ассоциированных десмоидах ослабляют связь между десмоидальными опухолями и травмой. В скандинавском исследовании 100 000 пациентов, перенесших тотальное эндопротезирование тазобедренного или коленного сустава, не сообщалось о более высокой частоте саркомы в хирургической или нехирургической области [9].

Генетические синдромы

Несколько генетических синдромов предрасполагают людей к различным типам STS. STS, ассоциированые с генетическими синдромами, составляют <3% всех случаев. К ним относятся нейрофиброматоз 1 типа (NF1) со злокачественными опухолями оболочек периферических нервов и желудочно-кишечными стромальными опухолями (GIST), синдром Ли-Фраумени (Li–Fraumeni) (TP53 или CHEK2) с рабдомиосаркомой и другими саркомами мягких тканей [10], семейный GIST с зародышевой мутацией в KIT или PDGFR [11], синдром Карни – Стратакиса (Carney–Stratakis) и GIST с мутациями в сукцинатдегидрогеназе (SDHB) [12], семейный аденоматозный полипоз / синдром Гарднера (Gardner) (APC) с десмоидными опухолями [13], наследственная ретинобластома (RB1) с фибросаркомой, синдром Вернера (Werner)/прогерия у взрослых (WRN) с различными саркомами мягких тканей, синдром Горлина (Gorlin)/синдром невоидной базальноклеточной карциномы (PTCH1) и рабдомиосаркома, комплекс туберозного склероза (TSC1 и TSC2) со злокачественными периваскулярными эпителиоидно-клеточными опухолями и хордомой [14].  Секвенирование следующего поколения (NGS) пациентов с саркомой выявило новые зародышевые мутации в генах, задействованных в путях гомологичной репарации, таких как ERCC2, ATM, ATR и BRCA2. Интересно, что не все пациенты, которые имели зародышевые мутации, определенные с помощью NGS, были идентифицированы традиционными методами, такими как тщательный семейный анамнез, полученный генетическими консультантами, что подчеркивает растущую важность NGS платформ для менеджмента пациентов [15].

Клиническая картина

Анатомическое, возрастное и гендерное распределение

Саркомы мягких тканей могут развиваться в любой области организма. Наиболее распространенными местами являются конечности (40%), абдоминальное пространство (35%), туловище (10%), голова и шея (5%) и другие сайты (10%) [3,16]. Инцидент STS возрастает с возрастом, средний возраст составляет 65 лет. Некоторые типы, такие как опухоль Юинга, рабдомиосаркома и остеосаркома, преобладают у детей и подростков, тогда как синовиальная саркома, десмоидные опухоли и десмопластическая мелкоклеточная опухоль (DSRCT) в основном встречаются в медианном возрасте 30 лет. STS, имеющие рекуррентные, неслучайные хромосомные транслокации, наблюдаются рано, на третьем и четвертом десятилетии жизни, тогда как опухоли со сложными геномными аберрациями возникают в более позднем периоде. STS поражают в равной степени оба пола; однако некоторым исключением являются DSRCT, которая преобладает у молодых мужчин (9: 1), саркома Капоши у мужчин, десмоидные опухоли у женщин (2: 1) и ангиосаркома у женщин, вторичная к облучению и / или лимфедеме, при лечении рака молочной железы.

История болезни и паттерны нарушения

Естественная история STS широко варьирует и зависит от гистологии, злокачественности, объема опухоли и анатомического расположения. Всестороннее обсуждение выходит за рамки этой главы. STS растут центробежно вдоль продольной оси, вызывая компрессию окружающих нормальных структур [3,16]. Некоторые STS создаают псевдокапсулу в результате неспецифической воспалительной реакции. Однако при микроскопической оценке часто обнаруживаются пальце-подобные разрастания, которые пересекают псевдокапсулу и инвазируют в нормальные ткани. Когда это возможно, предпринимаются широкие хирургические резекции с отрицательными краями с учетом дополнительного неоадъювантного или адъювантного облучения для снижения риска локального рецидива. Опухоли подразделяются на доброкачественные (нерецидивные), промежуточные (локально агрессивные, редко метастазирующие) и злокачественные. Высоко злокачественные опухоли метастазируют в 20% случаев, и до 50% при размере опухоли свыше 5 см. Любопытно, что даже в границах определенной гистологии могут быть подтипы с широким клиническим поведением. Например, липосаркома имеет четыре отличительных подтипа (хорошо дифференцированные, дедифференцированные, миксоидные/круглоклеточные и плеоморфные) с широко отличающимися анамнезом, лечением и прогнозом. Доброкачественные поражения, такие как липома или лейомиома, не инвазируют в окружающие структуры, не рецидивируют после хирургической резекции и не дают метастазы. Примеры промежуточных STS, которые могут иногда метастазировать, включают одиночные фиброзные опухоли, микофибросаркому и хорошо дифференцированную липосаркому. Для опухолей средней злокачественности частота метастазов составляет 3%, увеличиваясь до более чем 20%, когда объем опухоли превышает 5 см. Например, десмоидные опухоли имеют промежуточную злокачественность, являются локально агрессивными опухолями, которые часто рецидивируют после хирургической резекции, но не имеют метастатического потенциала. Гематогенная диссеминация ведет к отдаленным метастазам, причем наиболее распространенной метастатической областью (50%) являются легкие, за которыми следуют печень, кости/позвоночник, кожа и брюшина. Метастазы в головной мозг крайне редки, за исключением прогрессирующей альвеолярной мягкотканевой саркомы и ангиосаркомы [3].  Микоидная липосаркома обладает уникальной склонностью к метастазированию в позвоночник. На лимфатическую диссеминацию приходится 2% от общего числа метастазов, однако некоторые опухолевые тапы предпочитают этот путь распространения, включая светлоклеточную саркому (28%), эпителиоидную саркому (23%), ангиосаркому (12%), синовиальную саркому (12%) и рабдомиосаркому (12%) [17].

Клиническое обследование и стадийность

Диагноз

Most STS arise in the extremities and patients often describe a slow-growing painless mass and less frequently a localized painful swelling [16]. Retroperitoneal (15%) and visceral (15%) sarcomas can present with vague abdominal pain or increase in abdominal girth. Laboratory studies including tumor markers are not helpful. For extremity, head and neck, and pelvic lesions, magnetic resonance imaging (MRI) provides excellent visualization of neurovascular structures, muscle, bone, and fascial planes. For truncal, visceral, and retroperitoneal structures, computed tomography (CT) of chest, abdomen, and pelvis with contrast (when possible) provides high-quality images of the primary tumor and also serves for staging studies. CT of the lung (preferred over X-ray) should be part of initial staging as this is the most common site for metastatic spread. MRI of the thorax and abdomen may be limited by movement artifacts. Imaging of the brain should be performed if clinically indicated. A total spine MRI is indicated in myxoid/round cell liposarcoma. Positron emission tomography (PET) scans are useful when the above modalities do not provide adequate staging information. PET may also be useful in the neoadjuvant setting where a difference in maximum standardized uptake value (SUV max) of greater than 35% is correlated with chemotherapy response and improved recurrence-free survival (RFS).

Биопсия

The histology of extremity lesions varies widely and, in patients with a subset of sarcoma histologies, multimodality treatment is necessary to optimize outcomes; patients with certain types of STS may benefit from neoadjuvant chemotherapy or radiation. For this reason, most extremity tumors are biopsied prior to surgery. Exceptions to this rule include tumors consistent with well-differentiated liposarcoma on imaging or small (<2 to 3 cm in diameter), superficial lesions. The former have a pathognomonic appearance on CT and MRI (atypical lipomatous tissue with enhancing septa), obviating the need for biopsy, and the latter can be managed with excision alone [18].

In cases where biopsy of a soft tissue lesion is performed, it is essential that this procedure is carefully planned to minimize complications and to facilitate definitive treatment of a sarcoma. At the time of surgical resection, the biopsy site should ideally be resected en bloc with the specimen, and placement of the biopsy tract can significantly affect the ease with which this can be accomplished. Soft tissue tumors of the extremity were historically sampled with incisional biopsy. When performing a biopsy in this manner, care is taken to orient the incision along the axis of the limb to facilitate subsequent resection. Excision of an improperly, transversely-oriented scar en bloc with the specimen often requires removal of large islands of skin, preventing primary closure and necessitating reconstruction with a skin graft or soft tissue flap.

Because core biopsy is a less invasive procedure, most sarcoma specialists have transitioned from routine use of incisional biopsy for preoperative diagnosis of a soft tissue lesion. Analysis of core biopsies that are evaluated by an experienced pathologist demonstrated that samples obtained in this manner can be used to accurately determine both tumor histology and grade (75 and 88%, respectively) [19]. When this method of biopsy is chosen, multiple cores should be obtained from each quadrant of the tumor and the biopsy needle, as in the case of incisional biopsy, should be inserted through the skin at the site of the planned incision. When image guidance is necessary to safely perform the biopsy, direct communication between the surgeon and interventional radiologist regarding planned surgical incision can greatly facilitate proper placement of the biopsy site.

Biopsy is not always required prior to resection of retroperitoneal sarcomas; the lesions are almost universally either wellor dedifferentiated liposarcomas or leiomyosarcomas. When primary management of these tumors would be surgery, biopsy can be deferred in the context of characteristic imaging findings interpreted by an experienced radiologist. As in the extremity, well-differentiated and dedifferentiated liposarcomas are associated with regions of abnormal-appearing fat, often with enhancing septa and, in the case of dedifferentiated lesions, a solid component. If abnormal fat is not visualized on imaging, a heterogeneous, solid mass in the retroperitoneum most likely represents leiomyosarcoma, particularly when associated with the inferior vena cava or if localized to the region of the gonadal vein (generally just below the kidney). Rarely, large retroperitoneal tumors may represent lymphoma, carcinoma (renal cell, adrenal), metastatic disease, or neurogenic tumor (schwannoma or malignant peripheral nerve sheath tumor), and if the differential diagnosis includes these entities, image-guided biopsy should be performed.

Патология

There are over 50 different histological subtypes of STS. Due to the considerable histopathological heterogeneity and rarity of STS, consultation by an expert pathologist familiar with these rare tumors is a critical first step in treatment planning. Prognosis, clinical course, and sensitivity to systemic therapy may be dependent on identifying the specific histological subtype of STS. The process of classification of sarcomas into various subtypes is based on identification of specific architectural, cytoplasmic, and nuclear characteristics that give clues to the type of connective tissue that the tumor most closely resembles. The resemblance to a normal connective tissue counterpart does not imply that the cell of origin is a mature connective tissue cell; in fact, current research suggests that sarcomas develop from primitive multipotential mesenchymal stem cells and may or may not differentiate towards a particular lineage that enables classification. Tumors that lack specific features of any particular connective tissue are often classified as unclassified sarcoma. Tumors that bear features of a particular connective tissue are classified as such: for example, tumors with features of smooth muscle are classified as leiomyosarcoma, those with features of adipose tissue are classified as liposarcoma, while those with features of cartilage are classified as chondrosarcoma, and so on. Light microscopy, immunohistochemistry, and cytogenetics are widely used to establish the pathological diagnosis. Identification of the lineage of differentiation is often a difficult task and results in differences in opinion regarding the pathological diagnosis in as high as 40% of patients, even among expert pathologists. The presence of specific clonal abnormalities of chromosome number or arrangement for certain sarcoma subtypes is often immensely useful for arriving at a specific pathological diagnosis. Characteristic translocations such as t(11;22)(q24;q12) in Ewing sarcomas, t(12;16) (q13–14;p11) in myxoid liposarcomas, t(X;18)(p11.2;q11.2) in synovial sarcoma, and so on are exceptionally useful in establishing a diagnosis of translocation-related sarcomas which account for about-one third of all sarcomas. Molecular pathology is therefore expected to play an increasing role in establishing the pathological diagnosis, predicting response to therapy, and aiding prognostication [20,21].

In addition to histologic typing, grading is extremely helpful in evaluating the degree of malignancy and is derived from multiple histologic parameters. When the diagnosis is being established from a core needle biopsy, bias introduced by preferential sampling of a heterogeneous tumor should always be considered. Grade has considerable value in predicting metastases and overall survival. Grading should not be used separate from histologic type as different histologic subtypes with the same grade can have very different risks of metastasis.

Стадийность

Стадийность саркомы предосталяет информацию о распространенности заболевания и влияет на планирование лечения и определение прогноза. Наиболее часто используемой моделью является система стадирования Американского объединенного комитета по раку (American Joint Committee on Cancer, AJCC), которая включает объем опухоли (T), узлокачественность (G), статус лимфоузлов (N) и наличие метастатического заболевания (M). Восьмое издание этой системы было опубликовано и может использоваться клиницистами для поддержки решений по менеджменту пациентов с января 2017 года. Определения восьмого издания для различных категорий T, N и M для STS туловища и конечностей представлены в таблице 43.1, а стадии, определяемые комбинацией вышеупомянутых факторов, приведены в таблице 43.2. [22]. Восьмое издание также включает различные Т категории для STS головы и шеи, а также для органов брюшной полости и внутренних органов, но для этих областей не было разработана группировка прогностических стадий.

Таблица 43.1. Определения категорий первичной опухоли (T), региональных лимфоузлов (N), и отдаленных метастазов (M) для сарком мягких тканей туловища и конечностей [22].

Определение первичной опухоли (T)
T категория T критерий
TX Первичная опухоль не может быть оценена
T0 Нет свидетельства первичной опухоли
T1 Опухоль ≤5 см в наибольшем размере
T2 Опухоль >5 см и ≤10 см в наибольшем размере
T3 Опухоль >10 см и ≤15 см в наибольшем размере
T4 Опухоль >15 см в наибольшем размере
Определение региональных лимфатических узлов (N)
N категория N критерий
N0 Нет метастазов в региональные лимфоузлы или неизвестный статус лимфатических узлов
N1 Метастаз в региональные лимфоузлы
Определение отдаленного метастазирования (M)
M категория M критерий
M0 Нет отдаленных метастазов
M1 Отдаленный метастаз

Nodal metastases are unusual among STS and occur in 3–5% of cases. However, these patients have better survival compared to patients with hematogenous metastases and are thus classified as stage III. Notable exceptions for nodal involvement are rhabdomyosarcoma, synovial, clear cell, vascular, and epithelioid sarcomas. Grade (based on mitotic count, necrosis, and  differentiation) is a strong predictor of metastatic potential patients with low(G1), intermediate(G2), and high(G3) grade sarcoma have 5-year metastasis-free survival of 91–98%, 71–85%, and 44–64%, respectively. Size is an independent predictor of metastasis.

Table 43.2. AJCC Prognostic Stage Groups for trunk and extremity soft tissue sarcomas [22].

Когда T есть… И N есть… И M есть… И степень злокачественности есть … Тогда стадийная группа есть…
T1 N0 M0 G1, GX IA
T2, T3, T4 N0 M0 G1, GX IB
T1 N0 M0 G2, G3 II
T2 N0 M0 G2, G3 IIIA
T3, T4 N0 M0 G2, G3 IIIB
Любой T N1 M0 Любой G IV
Любой T Любой N M1 Любой G IV

The heterogeneity of sarcomas makes it challenging to develop a system that accurately prognosticates survival. While stage is correlated with survival, several additional variables are incorporated in a nomogram derived from a prospectively maintained database at Memorial Sloan Kettering Cancer Center (MSKCC) that predicts the 12-year risk of sarcomaspecific death in the postoperative setting. This nomogram captures the different variables that predict local and distant recurrence risks and disease-specific mortality. For example, local recurrence is predicted by margin status, age (>50), local recurrence at presentation, and histology (fibrosarcoma or malignant peripheral nerve sheath) while the distant recurrence is predicted by high grade, size >5 cm, depth, local recurrence at presentation, and histology (leiomyosarcoma and nonliposarcoma) [23].

Первичное мультимодальное лечение неметастатической болезни

Хирургия

Historically, surgical resection of an STS in the extremity meant amputation of the affected limb. Randomized controlled trials have demonstrated that while this approach may minimize local recurrences, overall survival is not compromised if these tumors are managed by wide excision and selective use of radiation therapy [24]. For this reason, limb-salvage procedures are routinely employed in the management of extremity sarcomas. Fewer than 10% of patients will ultimately require amputation and in most cases this is associated with local recurrence.

Wide local excision forms the basis of the limb-sparing procedure. Unlike melanoma, STS rarely metastasizes to the lymph nodes, and surgery to evaluate the nodal basin is not required [17]. Surgery is performed with the intention of removing the sarcoma en bloc with the biopsy site and at least 1 cm margin of normal tissue (or fascial plane) circumferentially. The margin of normal tissue is necessary because despite the fact that many lesions appear to be well-encapsulated, microscopic disease can extend beyond this visible “pseudocapsule.” It is essential to know the histologic subtype of the STS prior to planning surgical resection as in cases of dermatofibrosarcoma protuberans and myxofibrosarcoma microscopic disease can actually extend farther than 1 cm from the center of gross disease. These tumors have infiltrative borders and should be removed, when possible, with 2 cm of normal tissue circumferentially to minimize the need for re-excision [25–27]. In planning surgery for myxofibrosarcoma, it is also important to remember that this lesion can infiltrate across fascial boundaries, and in superficial lesions, unlike in surgery for other histologic subtypes, underlying muscle not just fascia should be taken with the specimen.

The surgeon may be limited in his or her ability to obtain wide margins if an STS is located directly adjacent to bone or neurovascular bundles. In this instance, the morbidity of resecting the nerve, artery, vein, or bone is not justified. Instead, the tumor should be resected by carefully skeletonizing these structures off the lesion, and radiation used as an adjunct to minimize local recurrence. Skeletonization should include removal of the neurovascular sheath, perineurium, or periosteum to optimize the margin. Encasement of neurovascular structures by a soft tissue tumor may make skeletonization difficult or impossible. When major nerves, arteries, and veins pass through a lowgrade lesion, the sarcoma should be bivalved to preserve these structures (e.g., femoral or sciatic nerve, superficial femoral artery or vein). This is not feasible when the nerve, artery, and/ or vein are encased by a high-grade sarcoma, however, and in these instances involved components of the neurovascular bundle should be resected with the tumor. In these situations, postoperative physical therapy can assist patients in learning to compensate for loss of femoral or ulnar nerves. Bracing can be used to assist with foot drop or radial nerve palsy [28]. Arterial bypass is performed if a major artery is resected (e.g., superficial femoral artery) while compression is used to minimize edema associated with venous resection.

Resection of these structures is more common in the context of locally recurrent tumors than in primary STS. Similar principles of management apply to locally recurrent disease as to primary lesions. The entire surgical bed should be resected in continuity with the recurrent lesion, and a margin of normal tissue should be removed with the tumor when possible. When possible, neurovascular structures should be skeletonized but encasement by a high-grade recurrence necessitates resection of major arteries, veins, or nerves. In addition, adjuvant radiation delivered during management of the patient’s primary disease often increases the risk of wound healing complications; local advancement and free flaps may be used to repair the soft tissue defect created by resection, particularly if primary repair would be under significant tension or if the incision overlies major vascular structures. Rarely, limb-salvage surgery is not possible (e.g., in the context of multiple recurrences, poor reconstructive options, or certain instances of bony involvement) and amputation is required. It is important to note that local recurrence of a high-grade STS is associated with significant risk of metastasis; complete extent of disease workup should be performed prior to any morbid surgical resection or amputation and systemic therapy considered as an alternative if distal disease is detected.

As in the extremity, surgical resection is the mainstay of treatment for primary retroperitoneal tumors; however, anatomic constraints often preclude removal of retroperitoneal tumors with wide margins. In treating retroperitoneal tumors, complete R0. (no residual microscopic disease) or R1. (only microscopic residual disease) resection is the goal of operative intervention. To accomplish complete resection, adjacent organs are removed in the context of tumor invasion. Segments of colon, the spleen, and distal pancreas may be resected in continuity with the tumor if necessary. In instances where the tumor is directly adjacent to the kidney, the renal capsule can be removed to provide a margin while preserving renal function. Encasement of the renal vessels or ureter may preclude such a maneuver, however, and nephrectomy may be required to perform complete gross resection.

Controversy exists regarding whether adjacent organs should be removed in the absence of tumor invasion. Theoretically, their removal would provide an additional margin of normal tissue that might prevent local recurrence [29]. However, the limiting margin of retroperitoneal resection is often the central vessels where recurrence is often observed, and removal of adjacent organs significantly increases surgical morbidity. For these reasons, it is not clear that removal of adjacent but uninvolved organs is of clinical benefit. Generally, removal of the tumor will be performed with posterior psoas muscle, involved organs, and renal capsule as noted previously [30,31].

Recurrence is common after resection of retroperitoneal tumors. Surgery plays a limited role in the context of this clinical scenario as it is rarely curative and can carry a high rate of morbidity. In many cases, recurrence at the level of the central or mesenteric vessels makes gross resection impossible. Good clinical outcomes are observed when recurrence is detected after prolonged disease-free interval and a limited number of tumors are identified. Rapid recurrence is a contraindication to surgical resection. If tumors recur at a rate of greater than 1 cm per month after a patient’s last surgery, resection is not associated with improved survival as compared to management of recurrent disease with systemic therapies [32]. As in primary disease, the goal of surgery should be complete gross resection; residual disease is associated with poor outcomes and patients undergoing R2. resection (with macroscopic residual disease) fare no better than those treated with nonoperative interventions [33].

Лучевая терапия

The standard practice for the treatment of STS is radiotherapy in combination with limb-sparing surgical resection, although radiation therapy is often administered alone in cases where surgery is not feasible for technical or medical reasons [34]. Several randomized studies support the use of radiotherapy in contemporary management of STS of the extremities and trunk. These studies demonstrated a significant improvement in local disease-free survival (DFS) when radiotherapy is combined with limb-sparing surgical excision of the tumor. Improved local control is most significant for patients with high-grade sarcomas. Radiotherapy may be administered preoperatively, postoperatively, or in both periods. Most often, radiotherapy is given via external beam; however, interstitial implants (brachytherapy) also may be used to deliver irradiation locally. Considerable debate has sought to determine which method results in the best local control rate, but no randomized trials have offered a definitive conclusion. Overall, local control rates are similar for these approaches and are approximately 80–90%. Advocates of preoperative radiotherapy argue that smaller fields and lower doses are necessary (typically, 50. Gy in 25. fractions over 5 weeks), reducing acute morbidity and cost. However, preoperative externalbeam radiotherapy is associated also with a fourto fivefold increase in delayed wound healing and in complications requiring intervention (e.g., infection, debridement, grafting) as compared to surgery in a nonirradiated field [35]. Preoperative radiotherapy is contraindicated when vascular reconstruction within the irradiated field is anticipated. Typically, postoperative external-beam radiotherapy is administered at doses of 60–70. Gy, with the higher doses used for positive or uncertain margins. Postoperatively, the radiotherapy field is larger because the entire surgical field with a margin of undisturbed tissue must be irradiated. Long-term complications of radiotherapy may include bone necrosis, pathologic fracture (30%), growth plate arrest with limb shortening in skeletally immature patients, soft tissue fibrosis, joint contracture, and secondary malignancies. Hence, the late complication risk, particularly fibrosis, which is associated with larger radiation fields, may be higher in the patients who receive radiation postoperatively [36].

Modern high conformal radiotherapy, such as intensity modulated radiotherapy (IMRT), may help to further reduce the risk of radiation-related complications [37]. Although a nonrandomized comparison, a recent update from MSKCC reported a significant benefit for local control in favor of IMRT over brachytherapy (95% vs 81% at 5 years, P = 0.04), suggesting that IMRT may be preferable to brachytherapy in the postoperative setting [38]. Radiotherapy is frequently used to palliate metastases in many body sites. Both conventional and imageguided focal radiation can benefit patients who suffer from complications of metastases. High-dose focal radiotherapy in particular is emerging as an effective palliative modality for radioresistant tumors in the spine and offers benefit for patients with metastatic disease who have limited options for systemic treatment [39].

Адъювантная химиотерапия

The decision to initiate systemic cytotoxic chemotherapy in either the adjuvant or metastatic setting is a complex one that requires a nuanced understanding of the different sarcoma histology. Adjuvant chemotherapy for sarcoma is controversial and the decision to recommend adjuvant therapy is highly variable even between sarcoma experts [40,41]. When possible, patients should be referred to a tertiary care sarcoma center for a multidisciplinary evaluation and consideration of clinical trials. The decision to initiate adjuvant chemotherapy should be based on histology, tumor size, grade, location, age, and patient expectations. Table 43.3. provides a rough guide to chemotherapy sensitivity in the metastatic setting. Abdominal and visceral disease do not benefit from adjuvant chemotherapy. To further aid in this decision-making process, an online (https://www.mskcc. org/nomograms/sarcoma) nomogram from MSKCC is available to estimate risk of death from disease for select histology. It is important to note that small cell sarcoma, osteosarcoma, and rhabdomyosarcoma are excluded from this discussion where adjuvant therapy is standard of care.

Гистология и химиотерапия

It is clear that adjuvant chemotherapy delays local recurrence, however its benefit on overall survival (OS) is not clear. A metaanalysis of 14. randomized trials involving 1,568 patients treated with adjuvant doxorubicin-containing regimens showed a significant benefit in local and distant recurrence-free rates in extremity sarcoma with only a nonsignificant trend towards improved OS [42] (Table 43.4). At 10 years, the OS improved from 50% to 54% in the treatment arm, which represents a 4% absolute benefit; however, in extremity tumors, a 7% benefit was seen in the treatment arm. In 2008, two updates to the meta-analysis were published. The first showed a statistically significant survival benefit with an odds ratio of 0.56 and an absolute OS risk reduction of 10% for anthracycline/ifosfamide combination therapy; however this did not include a large negative trial from the European Organisation for Research and Treatment of Cancer (EORTC) [43]. The second meta-analysis involving 2,170 patients showed significant improvement in relapse-free survival at 5 years (hazard ratio (HR) 0.71, P = 0.0001) but no improvement in OS at 10 years (HR 0.87). A retrospective analysis of a prospectively maintained database by the French Sarcoma Group showed a significantly improved 5-year metastasis-free survival (58% vs 49%, P = 0.1) and 5-year OS (58% vs-. 45% P = 0.0002) in patients with high-grade sarcoma but no benefit in patients with low-grade sarcoma [44]. This analysis is limited due to non-randomized and nonstandardized treatments during 1980–1999. A retrospective analysis from MSKCC and UCLA showed an improved OS in patients with large (>5 cm), high-grade extremity lesions with an adjuvant ifosfamide-based regimen but no survival benefit with doxorubicin [45]. In a randomized trial by the Italian Sarcoma Group, patients with high-grade or recurrent extremity sarcoma received adjuvant epirubicin and ifosfamide versus observation [46]. At a median follow-up of 59 months, there was a significant improvement in DFS (48 vs 16 months) and OS (75 vs 46 months). The absolute benefit with chemotherapy at 2 and 4 years was 13% and 19%, respectively. At longer followup, the estimated 5-year OS was higher in the treatment arm (66% vs 46%, P = 0.04) but the difference was not statistically significant in the intent-to-treat analysis.

Таблица 43.3. Вариабельный ответ на химиотерапию согласно гистологии саркомы.

Ответ на цитотоксическую химиотерапию [3]
Резистентные Высокодифференцированная липосаркома, светлоклеточная саркома, альвеолярная саркома мягких тканей, обычная хордома, миксофибросаркома, GIST, дерматофибросаркома protuberans, солитарная фиброзная опухоль и/или гемангиоперицитома, экстраскелетная миксоидная хондросаркома, эпителиоидная саркома
Сенситивные (низко-средне) MFH/UPS, дедифференцированная и плеоморфная липосаркома, радиация-ассоциированная саркома, MPNST, фибросаркома, саркома матки (высоко злокачественная), дедифференцированная хордома, десмоидные опухоли
Сенситивные (высоко) Саркома Юинга, миксоидная/круглоклеточная липосаркома, лейомиосаркома, ангиосаркома, синовиальная саркома, рабдомиосаркома

GIST, гастроинтестинальная стромальная опухоль; MFH/UPS, злокачественная фиброзная гистиоцитома или недифференцированная плеоморфная саркома; MPNST, злокачественная опухоль оболочки периферического нерва.

Таблица 43.4. Изучения адъювантной химиотерапии саркомы.

CYVADIC, cyclophosphamide, vincristine, Adriamycin, dacarbazine; EI, epirubicin, ifosfamide; EORTC, European Organisation for Research and Treatment of Cancer; HR, hazard ratio; IFADIC, ifosfamide, Adriamycin, dacarbazine; ITT, intention~to~treat; LLR, late local recurrence; MSKCC, Memorial Sloan Kettering Cancer Center; OR, odds ratio; OS, overall survival; RFS, recurrence~free survival.

In a trial by the EORTC, patients were randomized to cyclophosphamide, vincristine, Adriamycin, and dacarbazine (CYVADIC) versus observation [47]. The treatment arm had lower local recurrence (56% vs 43%) and improved RFS rates (17% vs 31%), however there was no benefit in distant metastases or OS. A similar trial of grade 2 and 3. STS with ifosfamide, Adriamycin, dacarbazine (IFADIC) versus observation also failed to show any benefit in RFS or OS [48]. A large phase 3 study by the EORTC randomized 351 patients to observation or adjuvant doxorubicin, ifosfamide, and lenograstim [49]. No difference was seen in the 5-year RFS or OS (64% vs 69%) between the two groups. These studies were criticized for using lower doses of ifosfamide. A phase 2 study comparing doxorubicin with either 6 mg/m2. or 12 mg/m2. of ifosfamide showed higher toxicities in the 12 mg/m2. cohort with no difference in DFS or OS [50]. In conclusion, there is no benefit for adjuvant chemotherapy in small, low-grade tumors while it is controversial in stage IIB and III tumors. Certain histologies and locations do not have any benefit. Any potential benefit should be discussed in the context of acute and long-term toxicities of chemotherapy. The response rates of chemotherapy in the metastatic setting are 30–40% and therefore a neoadjuvant approach would provide an opportunity to determine response while enabling limb-sparing surgery.

In summary, adjuvant chemotherapy to improve OS can only be recommended in carefully selected patients with high-risk disease that is chemotherapy sensitive after a transparent discussion with the patient regarding toxicity and small absolute benefit.

Локальный рецидив или распространенная болезнь

In contrast to extremity lesions (50%), retroperitoneal (40%) and head and neck sarcomas (5%) have a much higher risk of local recurrence due to anatomic constraints that limit wide surgical resections and high doses of radiation. Local recurrence has a higher risk of tumor-related mortality as recurrence is associated with distant metastases. Management of local recurrence takes into consideration numerous aspects such as anatomy, prior radiation or chemotherapy, and time from initial diagnosis to recurrence, and thus requires a multidisciplinary approach. In select cases, oligo-metastatic lesions to the lung or other organs can be surgically cured (5-year OS 10–35%) depending on number of lesions, histology, and disease-free interval [53,54]. In extremity lesions that are unresectable, isolated limb perfusion or limb infusion with melphalan or doxorubicin (or dactinomycin) with the option of adding TNF-a may be an effective modality in high-grade sarcomas [55,56]. This procedure is only approved in Europe and Canada.

Метастатическая болезнь

In the metastatic setting, systemic chemotherapy is not curative and is thus used for palliation. Exceptions to this rule include small round blue cell tumors (Ewing), osteosarcoma, rhabdomyosarcoma, etc. The decision to initiate chemotherapy in the metastatic setting should involve a frank discussion regarding goals of care where the benefit of palliative therapy should be balanced against potential toxicities of treatment [16]. Doxorubicin as a single agent or in combination with ifosfamide is a well-established first-line therapy [57]. The single-agent response rate is approximately 15–20% for each drug and combinations of cytotoxic therapies have an improved response rate without any benefit in PFS or OS. Cardiac toxicity can be potentially minimized by split-dose or continuous administration of doxorubicin. Pegylated doxorubicin is increasingly used when the cumulative dose of doxorubicin is exceeded or when cardiac comorbidities preclude doxorubicin. There is no standard of care for duration of treatment and thus some centers administer a fixed number of cycles followed by observation while other centers treat until the response plateaus and switch to observation [16]. The randomized phase 1/2 study of doxorubicin plus or minus olaratumab, a PDGFRA monoclonal antibody, was the first study to demonstrate a doubling of OS (26.5 vs 14.7 months, stratified HR 0.46, P = 0.0003) [58]. This led to the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) approval of doxorubicin and olaratumab in combination followed by olaratumab maintenance therapy in the first-line setting in STS. A confirmatory phase 3 study is currently underway. Other combinations include the addition of dacarbazine and cyclophosphamide with similar response rates. Gemcitabine and docetaxel are increasingly used in the first-line setting, especially in leiomyosarcoma, and the combination has improved PFS and OS when compared to single-agent gemcitabine [59]. Splitting the dose of gemcitabine and docetaxel has significantly lower toxicities and obviates the need for growth factor support. Paclitaxel has little to no activity in most STS except in angiosarcoma and Kaposi sarcoma [16]. Trabectedin, a natural compound from a marine squirt and an inhibitor of the minor groove of DNA, has potent activity in translocationassociated sarcoma and leiomyosarcoma. In a pivotal phase 3. randomized study of advanced metastatic liposarcoma and leiomyosarcoma, trabectedin resulted in a 45% risk reduction in PFS compared to dacarbazine (4.2 vs 1.5 months, HR 0.55, P<0.001), however there was no improvement in OS [60]. The benefit was notable in leiomyosarcoma and myxoid liposarcoma, but disappointing in welland dedifferentiated liposarcoma. This led to the approval of trabectedin in the US in the secondline setting for leiomyosarcoma and liposarcoma. Eribulin, a microtubule inhibitor, was evaluated against dacarbazine in a phase 3. pivotal study in patients with advanced liposarcoma and leiomyosarcoma. The study showed no improvement in PFS but an improvement in OS in favor of eribulin (13.5. vs 11.5 months, HR 0.77, P = 0.0169) [61]. This led to the FDA and EMA approval of eribulin in leiomyosarcoma and liposarcoma. The benefit of eribulin is particularly striking in pleomorphic liposarcoma.

Several other chemotherapeutic agents, including dacarbazine (DTIC), cisplatin, irinotecan, and methotrexate, have minimal activity in the majority of STS. Dactinomycin, vincristine, and etoposide are active only in small cell sarcomas, including extraskeletal Ewing sarcoma/primitive neuroectodermal tumor and rhabdomyosarcoma.

Pazopanib, an oral tyrosine kinase inhibitor (TKI) against VEGF and PDGF, was recently approved as a second-line agent in all STS except liposarcomas, embryonal rhabdomyosarcoma, chondrosarcoma, osteosarcoma, small cell sarcomas, GIST, and a few other rare histologies. A large randomized phase 3 trial showed a 4.6. versus 1.6 months and 12.5. versus 10.7 months for PFS and OS in the pazopanib and placebo arms, respectively [62]. The discovery of near universal gene amplification of CDK4 and MDM2. in welland dedifferentiated liposarcoma led to evaluation of palbociclib (a CDK4. inhibitor) in dedifferentiated liposarcoma. In a single-arm phase 2 study, palbociclib demonstrated a median PFS of 18 weeks and exceeded the primary endpoint of the study [63]. An identical study design evaluating a different dosing schedule showed a median PFS of 17.9 weeks with one complete response [64]. These studies led to National Comprehensive Cancer Network (NCCN) expert panel designation of palbociclib as a therapeutic option for dedifferentiated liposarcoma.

Специфическая гистология

Гастроинтестинальные стромальные опухоли (GIST)

GIST arise from the interstitial cells of Cajal and are the most common type of sarcoma with an annual incidence of about 3,000. cases in the US [3]. The most common location is stomach (65%) followed by small intestine (25%), rectum, esophagus, and abdomen. Greater than 95% of GIST express c-KIT along with DOG1. [65]. However, activating mutations in tyrosine kinase receptors occur less frequently – KIT (80%), PDGFR (8%), and BRAF (2%) – and most of the remaining “wild-type” GIST have recently been shown to carry mutations in SDHB [12,66]. Histology, immunohistochemical stains (KIT/CD117, DOG1), and mutational status are diagnostic and can guide therapy. When GIST are resectable, open or laparoscopic surgery is the primary treatment of choice so long as the pseudocapsule can be carefully preserved and tumor spillage is avoided. Prognosis of GIST is dependent on size (<2, 2–5 and >5 cm), location (gastric vs small intestine), and mitotic index (>5. per 50. high-power fields (HPF)). Small gastric lesions with low mitotic index are benign [16,65]. In large gastric GIST or those located in rectum or esophagus, a neoadjuvant approach may help achieve less morbid surgeries and negative margins and prevent rupture of the pseudocapsule and seeding. Cytotoxic chemotherapy and radiation are ineffective in GIST. In phase 3. studies, patients with metastatic GIST were randomized to a low (400 mg) or high dose (800 mg) of imatinib, an oral TKI of KIT and PDGFR, and demonstrated equivalent response, PFS, and OS rates in both arms [67–70]. The current recommendation is 400 mg daily but data suggest that GIST with KIT exon 9. mutations may respond to higher doses of the drug, nevertheless mutational analysis is not routinely done as it is not sufficiently discriminatory for clinical decision-making [16,71,72] patients typically develop resistance after 9–18 months depending on the type of KIT or PDGF mutation, and increasing the dose of imatinib to 600. or 800 mg daily may be beneficial in a subset of patients patients with primary or acquired resistance to imatinib may go to second-line therapy with sunitinib, also a TKI, which demonstrated improved PFS when compared to a placebo in a randomized phase 3 study with crossover at progression [73]. Regorafenib is a third-line agent which was recently approved based on significant PFS improvement over placebo (4.8 vs 0.9 months) [74]. However, when available, enrollment to clinical trials is always recommended. Other TKIs include dasatinib and sorafenib. In the adjuvant setting, intermediateand high-risk GIST is treated with up to 3 years of imatinib [75]. High-risk patients have gastric GIST, >5 cm, and mitoses of >5/50. HPF, while those with non-gastric locations have either >5 cm or >5/50. HPF of mitoses. For more information on GIST, please refer to Chapter 11.

Десмоидные опухоли

Desmoid tumors or aggressive fibromatosis (DT) are rare fibroblastic sarcomas that are locally aggressive but lack metastatic potential [76,77]. They occur at a median age of 30. with a slightly female preponderance and most often arise in the extremities, abdominal wall and cavity, thorax, and head and neck. The majority of DT are sporadic and harbor mutations in CTNNB1, and a minority with familial adenomatous polyposis (FAP) syndrome demonstrate APC mutations, both converging in the Wnt signaling pathway [78]. Evaluating estrogen receptors has no therapeutic or diagnostic benefit. In patients with FAP the risk of DT is 1000-fold higher than the general population. There are anecdotal reports of DT associated with antecedent surgery/trauma and pregnancy. The natural history of desmoids is highly variable. If asymptomatic, DT can be observed and may spontaneously regress in <2% of cases. Mortality from DT is low and is due to compromise of vital structures resulting in hydronephrosis or bowel and bladder obstruction. Adjuvant chemotherapy has no benefit in this disease. In symptomatic patients, surgery is the mainstay of therapy though recurrence rates are as high as 40% even with negative margins. Observation may be appropriate in a subgroup of patients [79]. Therefore the risks and benefits of surgery must be carefully evaluated, especially in patients with high risk of recurrence – young patients with large, extremity lesions. A nomogram is available to determine risk of recurrence [80]. Prior to any surgery, patients should be evaluated by a multidisciplinary team for radiation and/or systemic therapies in an attempt to avert mutilating surgeries where large intestinal resections are likely or limb function will be affected. Long-term consequences of radiation-induced sarcomas must be considered in young patients. Systemic therapies include tamoxifen, sorafenib, imatinib, doxorubicin, pegylated doxorubicin, dacarbazine, methotrexate, vinblastine, and cyclophosphamide [16].

Мелкоклеточная саркома (Юинга, PNET, рабдомиосаркома)

A clearly defined role for systemic therapy in patients with STS is limited to the subset of patients with small cell sarcomas (e.g., Ewing sarcoma, primitive neuroectodermal tumor, rhabdomyosarcoma) and to patients with recurrence or overt metastatic disease. When possible, patients should be enrolled in a clinical trial. Ewing sarcoma and PNET are described in Chapter 47. Rhabdomyosarcoma is a tumor with skeletal muscle differentiation and is primarily a pediatric cancer, described in Chapter 47. The three histologies include embryonal, alveolar, and pleomorphic. All three are represented in adults but the pleomorphic variant is over-represented in adults. Multimodal therapy with surgery, chemotherapy, and radiation is required to eradicate primary and micrometastatic disease. The outcome of adults with rhabdomyosarcoma is worse and likely due to an over-representation of the pleomorphic histology [81] patients who are enrolled in clinical trials appeared to benefit more than non-trial patients [82]. Chemotherapy typically used includes cyclophosphamide, dactinomycin or doxorubicin, and vincristine, with or without ifosfamide and etoposide. ALK translocations have been described and a phase 2 study is currently ongoing with crizotinib, an ALK inhibitor.

Наблюдение

Surveillance includes follow-up physical examination and imaging of the primary site and, if necessary, distant sites. Lungs are the most common organ for distant metastases. Radiographic surveillance of STS in the postoperative setting should be based on biological behavior, risk of recurrence (grade, size, site, margins), and duration of time after treatment [16]. For example, desmoid tumors and well-differentiated liposarcoma typically have local recurrence and thus extensive imaging of distant sites may not be useful. Meanwhile, STS such as undifferentiated pleomorphic sarcoma and pleomorphic liposarcoma have a higher propensity for distant metastases and will require more extensive evaluation. There are no studies to prove that CT scans are superior to chest X-ray, however clinical judgment should be personalized. Imaging is performed every 2–4 months during the first 2 years and less frequently after that. While the risk of recurrence decreases beyond 3 years, continued surveillance is recommended for an additional 5 years. Late recurrence beyond 10 years has also been reported. There are no surveillance tumor markers in STS.

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