Sarcomas of Soft Tissue and Bone

Sandra L. Wong

Key Points

1 Sarcomas are a rare and heterogeneous group of cancers that arise from mesoderm-derived elements

such as muscle, fat, nerve/nerve sheath, cartilage, blood vessels, bone, and other connective tissue.

They are histologically distinct from cancers of epithelial origin.

2 Clinical behavior and prognosis are largely defined by anatomic location, tumor grade, size, and

ability to achieve complete surgical resection.

3 For extremity sarcomas, radiotherapy is indicated for high-risk tumors to decrease disease relapse

and improve survival. Limb-sparing procedures are favored in order to maximize functional

outcomes.

4 Surgical resection is the cornerstone of treatment for intra-abdominal or retroperitoneal sarcomas.

Complete resection may require en bloc resection of adjacent or involved organs, most commonly of

the kidney and colon.

5 The use of imatinib, a selective tyrosine kinase inhibitor, in the management of gastrointestinal

stromal tumors (GISTs), is a paradigm for the successful use of targeted molecular therapies.

6 Increasing use of multimodality therapies including surgical resection, chemotherapy, and

radiotherapy has dramatically improved outcomes for sarcomas such as osteosarcoma and Ewing

sarcoma.

1 Sarcomas are a heterogeneous group of cancers that arise from mesenchymal cells, or mesodermderived elements, including muscle, fat, nerve/nerve sheath, cartilage, blood vessels, bone, and other

connective tissue. Sarcomas of soft tissue and bone are considered two distinct categories. Though

mesoderm-derived elements comprise nearly two-thirds of the body’s mass, sarcomas are relatively rare.

In 2016, just over an estimated 15,000 new cases of soft tissue and bone sarcoma were expected to be

diagnosed in the United States,1 which account for less than 1% of all new cancers. Sarcomas also

represent an extremely heterogeneous group of cancers, but taken together, 5-year overall survival is

about 50% to 60%.2,3 Anatomic location, tumor size, grade, and histopathology, are important

determinants of clinical presentation, treatment, and prognosis.

The Greek word “sarkoma,” meaning “fleshy excrescence” is the origin for the term “sarcoma.” As

early as AD 130 to 200, these fleshy tumors were regarded as cancerous by Galen.4 With the evolution

of light microscopy and cellular pathology, there was increasing recognition of soft tissue sarcomas.

Sarcomas, then called “soft cancers,” were differentiated from carcinomas by neuroanatomist Charles

Bell as early as 1816. Vichow refined the definition of sarcoma as “new formations of connective

tissue,” and developed classifications according to microscopic features which separated sarcomas from

carcinomas of epithelial origin. Modern foundations for the description and histogenic descriptions of

sarcoma are attributed to the work of James Ewing, who over the course of his pathology career refined

the classification of sarcomas, including the importance of grade in disease outcome.5

Multimodality therapies, including surgery, radiation, and chemotherapy, have been combined to

improve local and systemic tumor control. Over the past few decades, an evolution of multidisciplinary

approach has enabled successful treatment options to evolve from radical amputation to limb-sparing

procedures for extremity sarcoma. As refinements in pathologic classification continue, so does progress

in the use of treatment modalities. Modern molecular diagnostics are increasingly being translated to

clinical practice, and tailored treatment options are being developed as the histologic diversity of soft

tissue sarcomas is continually elucidated and better understood. As with many rare tumors, referral to

high-volume centers with clinical expertise is indicated when feasible.

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EPIDEMIOLOGY

Soft tissue sarcoma can occur in all age groups and are equally distributed between genders. While the

median age at diagnosis varies by histopathologic subtype, sarcomas are relatively rare in the adult

population. However, sarcomas are among the most common cancers seen in children and young adults,

representing approximately 15% of pediatric malignancies and often occurring in children under 5 years

of age.6 There are nearly 75 distinct histopathologic subtypes. Further, sarcomas can occur at any

anatomic site, though most arise in the extremities and trunk, and accordingly, anatomic site influences

treatment and outcomes (Fig. 108-1).

While the vast majority of sarcomas arise spontaneously, there are some predisposing conditions to

consider. Sarcomas are not thought to be the result of malignant degeneration of a long-standing benign

lesion such as a lipoma. An injury or other traumatic incident may lead to the initial recognition of a

mass, but there are no data to support the notion that antecedent trauma leads to the development of

either soft tissue or bony sarcomas. Clinical evaluation and subsequent workup, including biopsy if

indicated, should be able to distinguish malignant growths from a variety of benign posttraumatic

lesions, such as myositis ossificans, which must be differentiated from an extraosseous osteogenic

sarcoma.

Toxic exposures have been related to the development of sarcoma. Largely of historic interest, the

industrial use of thorium dioxide (Thorotrast), arsenic, and vinyl chloride led to accumulation of toxins

in the liver and were associated with the development of hepatic angiosarcomas. Several other

predisposing conditions are known to be associated with the development of sarcoma. The classic

Stewart–Treves syndrome was originally described in patients with lymphedema following radical

mastectomy and radiation for breast cancer who then developed lymphangiosarcoma of the affected

arm.7 Since then, long-standing extremity edema from other causes has also been linked to the

development of lymphangiosarcomas. Kaposi sarcoma was previously an uncommon cutaneous vascular

tumor thought limited to elderly men of Mediterranean origin. In the early 1980s it became one of the

first described opportunistic disease associated with HIV infection. Though the incidence of HIVassociated Kaposi sarcoma has markedly declined with effective antiretroviral therapy, it remains an

important cause of morbidity among HIV-infected patients and other immunosuppressed patients such as

renal allograft recipients.8–10

Figure 108-1. Distribution of sarcoma by anatomic location. (Adapted from Brennan MF, Antonescu CR, Moraco N, et al. Lessons

learned from the study of 10,000 patients with soft tissue sarcoma. Ann Surg 2014;260:416–422.)

Various types of radiation have been implicated in the delayed development of sarcomas. For

example, incidental ingestion of luminous paint containing 226radium by factory workers led to the

development of osteosarcomas. With the increasing use of external beam radiation in cancer treatment,

there has been a noted increase in the modern incidence of secondary sarcoma in patients previously

treated with radiation for a variety of malignancies. Following median latent periods of approximately

8 years (range 6 to 20 years), radiation-associated sarcomas are being increasingly diagnosed in

previously radiated areas. Common radiation-associated sarcoma subtypes are angiosarcomas,

undifferentiated pleomorphic sarcoma, fibrosarcoma, and leiomyosarcoma, and they are commonly, but

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not uniformly, high grade.11,12 Notably, with the advent of breast conservation therapy for breast

cancer (consisting of partial mastectomy/lumpectomy and adjuvant radiation therapy), there should be

an appropriate index of suspicion for breast angiosarcomas with findings of skin changes on the breast

(Fig. 108-2).

GENETIC CANCER SYNDROMES

While the vast majority of sarcomas are sporadic, numerous genetic alterations are associated with both

bone and soft tissue sarcomas.13 There are well-described genetic predispositions to sarcoma. Patients

with neurofibromatosis type 1 (NF-1, or von Recklinghausen disease) have mutations in the

neurofibromin 1 or 2 gene (NF1 or NF2, respectively) which are associated with the development of

malignant peripheral nerve sheath tumors (MPNSTs) in an estimated 5% of patients over a lifetime.14 A

genetic predisposition to desmoid tumors or desmoid fibromatosis is associated with familial

adenomatous polyposis (FAP), or Gardner syndrome which is the result of germline mutations in the

adenomatous polyposis coli (APC) gene.15,16 Intra-abdominal and extremity desmoids are a common

extracolonic manifestation of FAP and can be a source of increased morbidity in these patients following

proctocolectomy for the prevention or treatment of colon cancer.17

While somatic activation of c-KIT and overexpression of KIT protein are well described in the

pathogenesis of gastrointestinal stromal tumors (GISTs), there are described germline mutations as well.

Familial GIST syndrome has been ascribed to germline mutation in c-KIT as well as in the SDHB, SDHC,

and SDHD succinate dehydrogenase subunits, in association with Carney triad (GIST, pulmonary

chondromas, extra-adrenal paragangliomas) or Carney–Stratakis syndrome (GIST, paraganglioma).18,19

One well-documented mechanism of sarcoma development is the inactivation of tumor suppressor

genes. Retinoblastoma was known to be associated with a mutation in the retinoblastoma gene (RB1), a

13q chromosomal deletion. Investigation of the link between familial retinoblastoma and osteosarcoma

led to the discovery that a genetic defect in RB1 also plays a role in the pathogenesis of sarcomas.20,21

Another inherited defect of a tumor suppressor gene associated with soft tissue sarcomas is the Li–

Fraumeni syndrome, caused by an inherited mutation in the p53 gene, a key growth-regulatory gene.22

Germline mutations in affected patients are associated with high incidences of childhood

rhabdomyosarcomas, breast cancer, brain tumors, lung cancer, and leukemias).23 p53 abnormalities may

be seen in as many as 60% of osteosarcomas and malignant fibrous histiocytomas, as well as

approximately 33% of other sarcomas.24 Several oncogenes that can induce malignant transformation

and drive proliferation have also been associated with sarcoma development, including amplifications of

N-myc, c-erbB2, and members of the ras family.25

Figure 108-2. Radiation-associated angiosarcoma. This 79-year-old woman developed skin changes on her breast 7 years after

breast conservation therapy (lumpectomy and radiation therapy) for a 2-cm invasive ductal adenocarcinoma. Salvage mastectomy

was performed.

Cytogenetic aberrations have been recognized in a number of soft tissue sarcomas.13 Several

histologic subtypes of sarcomas have each been found to have specific genetic alterations – usually

simple karyotypes including fusion genes due to reciprocal translocations or specific point mutations

(Table 108-1). These chromosomal translocations serve as powerful diagnostic markers and may be

important in determining tumor biology and subsequent tumor behavior. For example, identification of

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the translocation of t(X;18)(p11;q11) can confirm the diagnosis of synovial sarcoma if there is any

doubt of its histopathology. There are data to suggest that the SYT-SSX1 fusion transcript carries a

worse prognosis than the SYT-SSX2 fusion transcript, with median survivals of 6.1 years and 13.7 years,

respectively.26,27

A better understanding of the molecular biology of sarcomas has revolutionized diagnosis of specific

histopathologic subtypes and has elucidated potential pathways for targeted molecular therapy.

SOFT TISSUE SARCOMAS

Clinical Presentation

The most common presentation of a soft tissue sarcoma is that of an asymptomatic mass. Sarcomas tend

to grow in a centrifugal fashion, usually pushing surrounding structures away rather than directly

invading them. Encasement of structures can occur, but again, this largely occurs in the absence of

direct invasion. Compression generally does not produce pain, swelling, or obstructive symptoms until

the tumors become quite large. Because of surrounding anatomic structures, some tumors of the

extremities tend to be detected at a relatively smaller size, whereas tumors of the retroperitoneum are

infrequently smaller than 10 cm at the time of presentation.5 Even very large abdominal or

retroperitoneal sarcomas present with nonspecific abdominal symptoms such as fullness, early satiety,

or minor abdominal discomfort (Fig. 108-3). The differential diagnosis for a soft tissue sarcoma includes

many types of benign lesions (e.g., lipomas, leiomyomas, and neuromas) but also other malignant

lesions (e.g., primary carcinoma, lymphoma, metastatic disease from melanoma, or testes cancer).

In general, the vast majority of soft tissue masses tend to be benign, but concerning features which

should prompt a higher index of suspicion for malignancy include large size (>5 cm), deep location

(subfascial, intramuscular, or intra-abdominal), variations in texture on examination, immobile nature

or noted fixation to underlying structures, or changes to an existing lesion (increasing size or worsening

compressive symptoms). No tumor markers for sarcomas exist, so serum bloodwork is generally not

useful in the evaluation of soft tissue masses.

Diagnosis

Diagnostic Imaging

Accurate radiologic imaging is critical in the diagnostic workup of sarcoma to provide information

about the precise location and extent of the primary tumor. Computed tomography (CT) scans and

magnetic resonance imaging (MRI) are the most important studies for evaluating the resectability of

soft tissue sarcomas, providing definition of the primary tumor in relation to bone, muscle,

neurovascular structures, and adjacent organs. Plain radiographs of bones and radionuclide bone scans

rarely provide useful information regarding invasion of bone by the tumor. Both CT and MRI can

provide critical information for treatment planning. While MRI may be preferred for extremity

sarcomas, CT is often the modality of choice for abdominal and retroperitoneal tumors. However, there

appears to be no difference between high-quality CT and MRI in terms of ability to determine

involvement of nearby structures, bone, or neurovascular structures.28–30

Table 108-1 Cytogenetic Abnormalities in Soft Tissue Sarcoma Subtypes

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Figure 108-3. Dedifferentiated liposarcoma of the retroperitoneum. This 51-year-old woman presented with only vague symptoms

of abdominal fullness from a very large retroperitoneal mass. The CT scan demonstrates a heterogeneous soft tissue mass in the

upper abdomen (A), which blends into a more fatty component (B) which encases the left kidney and displaces abdominal

contents. She underwent radical resection en bloc left nephrectomy, distal pancreatectomy, splenectomy, left colectomy, and

segmental resection of inferior vena cava.

Imaging is also important as part of the extent of disease workup. Because sarcomas are known to

predominantly metastasize to the lungs, directed chest imaging should be performed at time of

diagnosis. Chest radiography (CXR) may be used, but CT scans are increasingly being used as the

primary screening examination of choice for higher-risk patients, such as those with high-grade lesions

or tumors larger than 5 cm.31 Any abnormal CXR must be followed by a chest CT scan using appropriate

nodule protocol, usually involving thinner sections and often not requiring the use of IV contrast, for

more detailed evaluation of potential pulmonary metastases (Fig. 108-4). CT of the chest, abdomen, and

pelvis should be considered in any patient with a myxoid liposarcoma of an extremity because this

subtype often metastasizes to the abdomen or other “fat pads” such as the axilla.32

MRI is the most commonly used imaging modality for extremity sarcomas.28,33 Sequencing routinely

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involves axial T2-weighted and precontrast/postcontrast T1-weighted images. Contrast enhancement

with gadolinium is crucial for detecting and characterizing lesions with coronal, sagittal, and other

reconstructions. This imaging modality can accurately delineate between muscle groups and distinguish

among tumor and neurovascular structures (Fig. 108-5). Magnetic resonance angiography (MRA) can be

performed if more accurate delineation of vascular structures is required for surgical planning.

Positron emission tomography (PET) scanning using fluoro-13-deoxyglucose also offers the potential

for noninvasive analysis of tumor metabolism and has been shown to correlate with both tumor grade

and response to treatment for many types of cancers.34–37 PET maybe helpful in distinguishing between

benign and malignant lesions and may be useful for assessing response to treatment.38 However, its

accuracy and potential for false-negative results are still incompletely defined, so its use is not routine,

either for staging or for surveillance. Even with a PET scan, formal imaging with contrasted CT or MRI

is necessary so costs and extent of imaging should be considered.

Figure 108-4. Pulmonary metastasis. A noncontrasted CT scan of the thorax demonstrates a 1.1-cm noncalcified nodule consistent

with pulmonary metastasis in the upper lobe of the right lung.

Figure 108-5. Extremity sarcoma. MRI demonstrates a 20-cm low-grade myxoid liposarcoma. A: Coronal reconstruction

demonstrates location in the distal right thigh. B: Axial images show displacement of the popliteal vessels and vastus medialis

anteriorly; the common tibioperoneal nerve and biceps femoris laterally; and, the semimembranosus and semitendinosus muscles

medially.

Diagnostic Biopsy

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Properly performed biopsies are critical in directing a multimodality treatment approach. Image-guided

techniques are increasingly being applied so that open biopsy is not mandatory. Fine-needle aspiration

(FNA) is frequently used for the evaluation of enlarged lymph nodes, thyroid nodules, or breast masses.

However, FNA often does not provide sufficient materials for definitive histopathologic diagnosis,

especially for an index presentation. In select cases, FNA may be useful to demonstrate recurrent

disease. Core-needle biopsy (CNB) is considered the initial procedure of choice for diagnosis of soft

tissue sarcomas.39 CNB retrieves sufficient material for immunohistochemical staining, and when

necessary, for cytogenetic analysis or flow cytometry. Image-guided CNB, either using CT or

ultrasound, allows for the biopsy of deep masses that may not be easily palpable and can help target

suspicious areas in a heterogeneous field for better diagnostic value. An adequate sample from a viable

area of sarcoma is required for definitive diagnosis and accurate grading. CNB is associated with low

complication rates (<1%), with major concerns related to bleeding.40 Concerns about recurrence along

the tract are obviated with the use of a sheathed needle device and/or excision of the biopsy tract at the

time of definitive resection when possible.

Open surgical biopsy, or incisional biopsy, is uncommonly needed with increasing success of CNB.41

However, open biopsy should be considered when core-needle specimens yield nondiagnostic findings

and if preoperative diagnosis is definitely required for treatment planning. Several important technical

factors must be considered when performing an incisional biopsy. Incisions must be oriented along the

long axis of extremities to facilitate complete resection with definitive surgical management. Transverse

incisions in the extremity often commits the patient to more extensive procedures than would be

otherwise necessary, potentially compromising the ability to obtain clear margins with definitive limbsparing procedures. Attempts to enucleate the sarcoma within its pseudocapsule is discouraged, though

excisional biopsy can be considered as the primary approach for small, superficial lesions.5 Extensive

dissection during a biopsy, including undermining surrounding subcutaneous layers, should be

consciously avoided in order to contain the extent of disease and best manage subsequent procedures.

Attention to meticulous hemostasis also prevents extensive “seeding” of the area.

PATHOLOGIC CLASSIFICATION

Histopathologic designation of soft tissue sarcomas reflects an extremely heterogeneous group of

tumors. Sarcomas are generally classified according to the tissues they mimic rather than the type of

tissue from which the tumor arises. Some sarcomas have no recognizable normal tissue counterpart and

are characterized by other distinguishing histologic features.5,42 The various types of benign and

malignant soft tissue tumors are noted in Table 108-2. The development of specialized markers for

identifying individual types of sarcoma has led to greater precision in their classification. Helpful

immunohistochemical stains include the intermediate filaments (i.e., vimentin, keratin) and muscle

markers (i.e., desmin, actin). More specific markers can be instrumental in diagnosis, such as myoglobin

staining for rhabdomyosarcomas. In a small proportion of tumors (approximately 10% in most series),

the tumor cells are so poorly differentiated that no specific histogenesis can be determined, and these

may be designated as spindle cell sarcomas or undifferentiated pleomorphic sarcomas.

One of the most critical pieces of pathologic information for clinicians treating sarcoma patients is

histologic grade. Histologic grade is assessed based on the expert assessment of degree of cellular

atypia, the frequency of mitotic figures, and the presence or absence of spontaneous tumor necrosis.

While grading criteria have undergone numerous revisions over the years, in general, low-grade tumors

have relatively little cellular atypia, few mitoses, and no tumor necrosis. High-grade tumors show a

significant degree of necrosis in addition to atypia and frequent mitotic figures (Fig. 108-6). A

consistently applied grading system discriminates between tumors with good prognosis (low grade) and

those with relatively poorer prognosis (high grade). In the past, various grading systems have been used

(2-tiered systems (low vs. high); 3-tiered systems; and 5-tiered systems). The current American Joint

Commission on Cancer (AJCC) staging system recognizes a classification system ranging from grade 1

(G1, well differentiated) to grade 3 (G3, undifferentiated) tumors.43–45 Evaluation typically takes

histology, tumor differentiation, mitotic count, and tumor necrosis into account. There can be

disagreement about grading schemas and expert pathology opinion can vary from center to center.46,47

As such, it is important to take note of tumor classification when interpreting results from clinical trials

or retrospective reports.48 The metastatic potential for low-grade lesions is approximately 5% to 10%

compared to up to 50% to 60% for high-grade tumors.2 For lesions in which disparate areas exist, the

highest grade encountered is generally used to categorize the tumor.

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Table 108-2 Histologic Classification of Soft Tissue Tumors

STAGING

Because of the prognostic importance of staging, stage classification of the primary tumor is based on

both clinical and histologic information. The usual TNM classification used by the AJCC45 for other solid

tumors is modified to a GTNM system (Table 108-3) for soft tissue sarcomas.

Figure 108-6. Histologic grading of sarcomas. Photomicrographs demonstrate the appearance of different grades within the same

histologic subtype. A: Well-differentiated liposarcoma (lipoma-like) of the retroperitoneum with noted few atypical lipoblasts. B:

High-grade, dedifferentiated liposarcoma of the retroperitoneum with highly atypical lipoblasts. (Courtesy of David R. Lucas, MD,

University of Michigan, Ann Arbor, MI.)

Table 108-3 American Joint Commission on Cancer (AJCC): GTNM Classification

and Stage Grouping of Soft Tissue Sarcomas

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