Benign and Malignant Soft-Tissue Tumors


Practice Essentials

Soft tissue is defined as the supportive tissue of various organs and the nonepithelial, extraskeletal structures exclusive of lymphohematopoietic tissues. It includes fibrous connective tissue, adipose tissue, skeletal muscle, blood/lymph vessels, and the peripheral nervous system. Embryologically, most of it is derived from mesoderm, with a neuroectodermal contribution in the case of peripheral nerves.

Soft-tissue tumors constitute a large and heterogeneous group of neoplasms. Traditionally, tumors have been classified according to histogenetic features. (Fibrosarcoma, for example, is categorized as a tumor arising from fibroblasts.) However, histomorphologic, immunohistochemical, and experimental data suggest that most, if not all, sarcomas arise from primitive, multipotential mesenchymal cells, which in the course of neoplastic transformation differentiate along one or more lines.

Thus, a liposarcoma appears to arise from a lipoblast but may actually develop through lipoblastic differentiation of a precursor multipotent mesenchymal cell. At the clinical level, soft tissue tumors are classified according to various parameters, including location, growth pattern, likelihood of recurrence, presence and distribution of metastases, patient age, and prognosis.

Although most soft tissue tumors of various histogenetic types are classified as either benign or malignant, many are of an intermediate nature, which typically implies aggressive local behavior with a low-to-moderate propensity for metastasis.

Current achievements in the field of soft-tissue tumors are the result of advances in molecular biology, oncogenetics, imaging techniques, immunochemistry, diagnosis by fine-needle aspiration (FNA), surgical reconstruction, radiation therapy, and tissue banking.

Benign soft-tissue tumors are fairly common and are treated with surgery alone. Prior to the 1970s, surgery was the primary therapy for malignant soft tissue tumors, and most patients with high-grade tumors had a poor prognosis and a significant mortality. Since the mid-1970s, radiation therapy, chemotherapy, and advanced surgical techniques have helped increase long-term survival and decrease the need for ablative surgery. [1]

Future advances in molecular oncology may further improve diagnostic, prognostic, and treatment protocols for patients with soft-tissue sarcomas. [23 See Soft-Tissue Sarcomas: What You Need to Know, a Critical Images slideshow, to help identify and treat some of these malignant tumors of mesenchymal origin.

Pathophysiology

Generally, soft-tissue tumors grow centripetally, though some benign tumors (eg, fibrous lesions) may grow longitudinally along tissue planes. Most soft-tissue tumors respect fascial boundaries, remaining confined to the compartment of origin until the later stages of development.

Once the tumor reaches the anatomic limits of the compartment, the tumor is more likely to breach compartmental boundaries. Major neurovascular structures usually are displaced as opposed to being enveloped or invaded by tumor. Tumors arising in extracompartmental locations, such as the popliteal fossa, may expand more quickly because of a lack of fascial boundaries; they are also more likely to involve neurovascular structures.

The peripheral portion of the tumor compresses surrounding, normal soft tissue because of centripetal expansile growth. This results in the formation of a relatively well-defined zone of compressed fibrous tissue that may contain scattered tumor cells. This zone may also consist of inflammatory cells and demonstrate neovascularity.

A thin layer of tissue called the reactive zone surrounds the compression zone, especially in higher-grade tumors. Together, the compression and reactive zones form a pseudocapsule that encloses the tumor and is useful in defining the extent of surgical resection.

Some extremely aggressive lesions with infiltrative growth patterns, such as childhood rhabdomyosarcoma, may not respect anatomic compartmental boundaries and frequently will invade fascial planes.

Local recurrence

Soft-tissue sarcomas have a propensity for local recurrence. Because recurrences are more difficult to treat than the primary lesion is, complete resection and appropriate use of radiation therapy are critical during the initial treatment. The pseudocapsule provides surgeons with a more or less obvious plane of dissection; however, such an excision can leave behind microscopic or occasionally gross tumor. This may lead to local recurrences in as many as 80% of patients. [4The addition of postoperative radiation therapy decreases the risk of recurrence associated with a marginal resection.

Technical ease of resectability (and, thus, the likelihood of local control) may be affected by the location of a soft-tissue sarcoma. For example, lesions of the head and neck are more likely to involve or abut vital structures; consequently, they often are more difficult to resect than are lesions of the extremities. Even in an extremity, the tumor site may have prognostic implications. For proximal tumors, local control is more difficult to achieve than in tumors located more distally. Retroperitoneal sarcomas, which typically have a poor prognosis, have a higher proclivity for local recurrence and for intra-abdominal dissemination.

The pattern of recurrence generally is predictable, and most tumors destined to recur do so within the first 2-3 years. Adjuvant radiation therapy clearly minimizes local recurrence, but its ability to increase overall chances of survival, though likely, is not certain. Adjuvant chemotherapy may decrease the risk of local recurrence of high-grade tumors, presumably because of a reduction in the size of the tumor and an increase in the reactive zone, but this notion is very controversial.

Distant metastasis

Regional lymph node involvement is rare in soft-tissue sarcomas; fewer than 4% of cases have nodal metastases at presentation. Lymph node involvement is more frequent in epithelioid sarcoma, rhabdomyosarcoma, synovial sarcoma, and clear cell sarcoma. Carcinoma and melanoma should be included in the differential diagnosis for any mass presenting with lymph node metastases.

Many patients with high-grade soft-tissue sarcomas, as well as a few with the low-grade type, progress to metastatic disease, even after adequate local control of the primary tumor has been achieved. The lung is by far the most common site of metastasis, which occurs in up to 52% of patients with high-grade lesions. [5]

Although most patients do not have clinically evident metastases at the time of presentation, they may have occult micrometastases that eventually manifest clinically. This would appear to be an impetus for the development of chemotherapeutic methods of systemic disease control. At present, however, this is a controversial area of investigation, and it is uncertain whether systemic chemotherapy can improve long-term survival rates for patients with high-grade sarcomas.

Etiology

Genetic conditions

Good evidence exists suggesting that certain genetic disorders and gene mutations are predisposing factors for some benign and malignant soft-tissue tumors. The NF1 gene in neurofibromatosis is a classic example, predisposing patients to multiple neurofibromas with a proclivity for malignant transformation. Many tumor suppressor genes, oncogenes, and cytogenetic defects are now associated with various soft-tissue sarcomas. Other clinical risk factors account for a small proportion of soft tissue malignancies.

Various cytogenetic abnormalities (see Table 1 below) have been reported to play a significant role in diagnosis, and in the future, some of these abnormalities may become therapeutically significant.

Table 1. Selected Characteristic Cytogenetic Aberrations in Soft-Tissue Tumors (Open Table in a new window)

Benign Soft-Tissue Tumors

Characteristic

Cytogenetic Events

Frequency

Benign schwannoma

Monosomy 22

50%

Desmoid tumor

Trisomy 8

25%

 

Deletion of 5q

10%

Lipoblastoma

Rearrangement of 8q

>25%

Lipoma, solitary

Rearrangement of bands 12q14-15

75%

 

Rearrangement of 6p

10%

 

Deletion of 13q

10%

Uterine leiomyoma

t(12;14)(q15;q24)

20%

 

Deletion of 7q

15%

 

Trisomy 12

10%

Malignant Soft-Tissue Tumors

Characteristic

Cytogenetic Events

Frequency

Clear cell sarcoma

t(12;22)(q13;q12)

>75%

Dermatofibrosarcoma protuberans

Ring chromosome 17

>75%

Ewing sarcoma

t(11;22)(q24;q12)

95%

Extraskeletal myxoid chondrosarcoma

t(9;22)(q31;q12)

50%

Liposarcoma, myxoid

t(12;16)(q13;p11)

75%

Liposarcoma, well differentiated

Ring chromosome 12

80%

Alveolar rhabdomyosarcoma

t(2;13)(q35;q14)

80%

Synovial sarcoma

t(X;18)

95%

Specific translocations involving selected genes have been observed. One of these, the t(X;18) translocation in synovial sarcoma, results in fusion of the SYT gene from chromosome 18 to either of two highly homologous genes at Xp11, SSX1 or SSX2.SYT-SSX fusion transcript may be detected by reverse transcriptase-polymerase chain reaction (RT-PCR) assay, using a cytologic specimen from FNA biopsy (FNAB), histologic material from paraffin block, or frozen material.

Radiation

Similar to postirradiation bone tumors, postirradiation fibrosarcomas have been described. The pathogenetic mechanism is the emergence of radiation-induced genetic mutations that encourage neoplastic transformation.

Chronic lymphedema

As observed in patients with late-stage breast carcinoma, chronic lymphedema may predispose individuals to the development of lymphangiosarcoma.

Environmental carcinogens

An association between exposure to various carcinogens and an increased incidence of soft-tissue tumors has been reported. The occurrence of hepatic angiosarcoma, for example, has been linked to arsenic, thorium dioxide, and vinyl chloride exposure.

Infection

A classic example of an infection-induced soft-tissue tumor is Kaposi sarcoma resulting from human herpesvirus type 8 in patients with human immunodeficiency virus (HIV). Infection with Epstein-Barr virus in an immunocompromised host also increases the likelihood of soft-tissue tumor development.

Trauma

The relation between trauma and soft-tissue tumors appears to be coincidental. Trauma probably draws medical attention to a preexisting lesion.

Epidemiology

In general, benign soft-tissue tumors occur at least 10 times more frequently than malignant ones, though the true incidence of soft-tissue tumors is not well documented. However, some insight regarding the incidence of soft-tissue sarcomas can be derived from the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) Program, which, between 1973 and 1983, accumulated data on 6883 such tumors.

Overall, the age-adjusted annual incidence of soft-tissue sarcomas ranges from 15 to 35 per 1 million population. The incidence increases steadily with age and is slightly higher in men than in women. Malignant soft-tissue tumors occur twice as often as primary bone sarcomas.

Approximately 45% of sarcomas occur in the lower extremities, 15% in the upper extremities, 10% in the head-and-neck region, 15% in the retroperitoneum, and the remaining 15% in the abdominal and chest wall. Visceral sarcomas, arising from the connective tissue stroma in parenchymal organs, are not common.

The different types of soft-tissue tumors have distinct age distributions. Rhabdomyosarcoma is seen more frequently in children and young adults. Synovial sarcoma arises in young adults. Malignant fibrous histiocytoma and liposarcoma generally occur in older adults. Benign deep masses in adults usually are due to intramuscular lipoma.

In general, the prognosis in older patients with a diagnosis of high-grade sarcoma is poor.

Prognosis

Outcome and prognosis depend on several, often interrelated factors, including the following:

  • Tumor size
  • Depth of tumor
  • Histologic type
  • Adequacy of surgical margins
  • Histologic grade
  • Clinical stage
  • DNA ploidy
  • Cell proliferation
  • Oncogene mutations

As with tumors of other tissues, a direct relation exists between the size of soft-tissue sarcomas and outcome. The larger tumors confer a worse prognosis. [6]

Superficially located tumors (dermis and subcutaneous tissue) have a relatively better prognosis than do deep-seated lesions (intermuscular/intramuscular, retroperitoneal) of similar histologic type. [78 This difference probably results from the fact that superficial lesions are considerably smaller at the time of excision.

With few exceptions, most sarcomas of the same stage and grade behave the same regardless of histologic subtype. Some soft-tissue tumors (eg, atypical lipomatous tumors) are low-grade, without any ability to metastasize. Others, such as pleomorphic liposarcoma, are highly aggressive, with a tendency for distant metastases.

Adequacy of surgical margins is directly related to local relapse. [9108116 However, development of distant metastases may not be related to the development of local recurrence. [12]

A relation exists between various microscopic histologic grading systems and outcome. [76]

Clinical stage is the most important predictor of clinical outcome. Clinical staging is done in accordance with the grade-tumor-node-metastasis (GTNM) system, which incorporates microscopic grading (see Histologic Findings).

DNA ploidy can be evaluated by flow-cytometric studies performed on formalin-fixed, paraffin-embedded tissue sections or by image analysis using cytology smears. Aneuploidy is observed in tumors that have a higher microscopic grade and a greater rate of cell proliferation. However, its role as an independent prognostic factor has not been established. [13]

The number of mitotic figures stratifies the tumors into benign, intermediate, and malignant categories and is incorporated into most grading systems. Cell proliferation markers, including Ki-67 and p105, are useful for evaluation of proliferative activity and its relation to prognosis. [141516 Like DNA ploidy, however, proliferation markers remain to be established as independent prognostic factors.

Oncogene mutations (eg, mutations of TP53, overexpression of MDM2, and altered expression of the retinoblastoma gene) have reportedly been associated with a worse prognosis.



History

A mass is the most common sign of a soft-tissue tumor. It usually is painless and does not cause limb dysfunction. However, depending on the anatomic location of the tumor, it may cause pain or neurologic symptoms by compressing or stretching nerves, by irritating overlying bursae, or by expanding sensitive structures. A rapid rate of increase in the size of a mass should arouse suspicion that the lesion is malignant.

Physical Examination

Physical examination can be used to determine the location and size of a mass and to exclude other, more common causes of pain. Whether the mass is deep or subcutaneous, transilluminates (cysts), and adheres to underlying structures also can be gleaned from physical examination. Regional lymph nodes should be examined as well. Neurovascular examination is useful for the detection of either primary or secondary tumor involvement.

Extremity masses larger than 5-7 cm and deeper than subcutaneous tissue favor a diagnosis of a malignant soft-tissue tumor. However, as many as 30% of soft-tissue sarcomas occur in subcutaneous tissue and exhibit relatively less aggressive behavior.


Laboratory Studies

Other than histologic and cytogenetic analysis, no specific laboratory tests exist for diagnosing soft-tissue tumors. However, ancillary studies may be indicated as part of the general workup in patients with other systemic conditions.

The National Comprehensive Cancer network has issued guidelines on genetic testing for soft-tissue sarcoma (see Soft-Tissue Sarcoma Guidelines).

Imaging Studies

Over the past two decades, imaging studies (eg, plain radiography, computed tomography [CT], magnetic resonance imaging [MRI], bone scintigraphy, and positron emission tomography [PET]) have contributed greatly to the management of soft-tissue tumors. Although these studies cannot themselves yield a specific diagnosis (except for a few conditions, such as lipoma or liposarcoma), they are extremely useful for defining anatomic location, tumor extent, and involvement of vital structures. [21]

Imaging studies should be obtained before biopsy, for the following reasons:

  • To ensure that a biopsy of a potentially malignant lesion is taken in a manner that will not preclude limb-salvage surgery
  • To prevent the biopsy tract from adversely affecting the capture of anatomic detail by MRI

The relation of the tumor and surrounding normal structures to the planned biopsy site should be evaluated, as should the functional status of the involved limb, signs of lymph node involvement, and any other factors that could compromise optimal surgical or radiation therapy.

Because prognosis is primarily dependent on the disease stage rather than the histologic tumor type, evaluation of local and distant extent is pivotal in the ultimate management of soft-tissue sarcoma. Imaging methods commonly used for such evaluation include plain radiography, CT, MRI, and bone scintigraphy. PET is being used more frequently to assess the metabolic activity and, presumably, the biologic aggressiveness of a lesion. Angiography to evaluate any vascular involvement by soft tissue tumors has essentially been replaced by MRI.

CT is useful in checking for the presence and number of pulmonary metastases. Consider performing a CT scan of the liver in cases of intra-abdominal or retroperitoneal tumors.

Unlike CT, MRI is not limited to the transverse (axial) plane. Coronal, sagittal, and oblique planes may be imaged. MRI best defines the relation between a tumor and adjacent anatomic structures, such as compartment boundaries, nerves, vessels, and muscle. [2223(See the image below.)

MRI is used to demonstrate involvement of criticalMRI is used to demonstrate involvement of critical structures by tumor. This recurrent, high-grade soft tissue sarcoma in posterior calf abuts tibial nerve and posterior tibial vessels. Extensive reactive zone surrounds structures. Patient was treated with below-knee amputation. Image courtesy of Howard A Chansky, MD.

Although MRI alone suffices for most patients, the information obtained from CT and MRI of the primary tumor occasionally may be complementary. Bony involvement may be better assessed with CT, as may the boundary between normal muscle and fibrous lesions.

Tissue Diagnosis

Biopsy usually is indicated for a soft-tissue mass arising in a patient without a history of trauma or for a mass that persists for more than 6 weeks after local trauma. All soft-tissue masses larger than 5 cm, as well as any enlarging or symptomatic lesions, also should be biopsied. Small, subcutaneous lesions that persist unchanged for years may be considered for observation rather than biopsy. A high level of suspicion is necessary to ensure early treatment.

Early tissue diagnosis is the most important component of multimodality treatment for soft-tissue tumor. Proper and timely biopsy is critical. An inadequately performed biopsy may complicate patient care and result in loss of limb or life.

Several biopsy techniques are available, including the following:

  • Fine-needle aspiration biopsy (FNAB)
  • Core needle biopsy
  • Incisional biopsy
  • Excisional biopsy

The choice of biopsy technique is based on the size and location of the mass and the experience of the surgeon. Excisional biopsy is indicated only for small, superficial masses (< 3-5 cm in greatest dimension), in which the probability of malignancy is low. Effective reexcision is more likely for smaller malignant lesions that initially are unintentionally treated as benign.

Fine-needle aspiration biopsy

FNAB is a cytologic technique involving the use of a fine-gauge (usually 21- to 25-gauge) needle to aspirate individual tumor cells and microfragments from the mass. The aspirated material can be examined as a cytology smear, with immediate evaluation of specimen adequacy.

Depending on the initial cytomorphologic features observed during the onsite adequacy evaluation, additional passes may be performed at the same time to obtain more material for cell-block preparation (for histomorphology and immunocytochemical evaluation), cytogenetic analysis (see Etiology and Atlas of Genetics and Cytogenetics in Oncology and Haematology), or examination using electron microscopy or microbiology cultures. [24]

With the help of relevant ancillary techniques, diagnostic accuracy with FNAB is very high, and soft tissue tumors can be graded. [25This method is minimally invasive and relatively atraumatic.

Published literature highlights the rarity of needle-track seeding with FNAB. Core needle biopsy, on the other hand, has a higher rate of needle-track seeding.

Core needle biopsy

Core needle biopsy retrieves a thin core of tissue (approximately 1 × 10 mm). The procedure may be performed using various needles (most commonly a Tru-Cut needle [26). The core may not be representative of the entire tumor; thus, nonrepresentative grading is possible. FNAB samples a larger area of the tumor than core needle biopsy does.

Concern has been expressed about possible dissemination of tumor cells beyond the confines of the primary site; however, this appears to be uncommon. Both core needle and open biopsies can result in histologic diagnosis and grading of a sarcoma in more than 90% of cases. As with FNAB, a biopsy may be taken of deeper lesions under the guidance of imaging modalities (eg, CT, ultrasonography, or MRI). (See the image below.)

CT-guided needle biopsy of high-grade soft tissue CT-guided needle biopsy of high-grade soft tissue sarcoma arising in left hemipelvis. CT artifact from needle can be seen in upper right corner of image as needle enters lesion just anterior and medial to dome of left hip joint. Image courtesy of Howard A Chansky, MD.

Incisional biopsy

Open incisional biopsy is used for most soft-tissue masses. A generous wedge of tissue is removed, with minimal manipulation of tissue. Several important technical factors must be considered in the performance of an incisional biopsy. In the case of extremity lesions, the incision should be oriented along the long axis. Any biopsy incision and tract should be oriented so that they can be resected during definitive surgery for the soft tissue mass.

The sample obtained may be evaluated for adequacy by using intraoperative cytology or a frozen section at the time of biopsy. Meticulous hemostasis minimizes local dissemination of tumor cells.

Excisional biopsy

With an excisional biopsy, the entire lesion is removed surgically. Grossly, many sarcomas appear to be well demarcated. Microscopically, however, the demarcation usually is seen to exist along a pseudocapsule with foci of infiltrating tumor. Removal of the tumor along this apparent plane may leave gross or microscopic sarcoma behind. Excisional biopsy may be safely performed for small, superficial tumors (less than about 5 cm in diameter) or for those known to be benign. [27]

Frozen sectioning and intraoperative cytology

Frozen sectioning and intraoperative cytology are extremely helpful tools for the management of soft-tissue tumors. [2829Proper communication with a musculoskeletal oncopathologist preoperatively and intraoperatively is essential for evaluation. Frozen sectioning can guide retrieval of adequate diagnostic material and, depending on the initial evaluation, can be an important triage mechanism for directing further pathologic workup.

If support is available, FNAB offers most of the advantages for diagnostic biopsy that frozen sectioning does. However, open biopsy—with the help of frozen-sectioning support—may be indicated when the FNAB result is equivocal or for other clinical reasons.

Fatty lesions are not suitable for frozen-section evaluation, because of a loss of diagnostic material during frozen sectioning and other technical difficulties. In addition, freezing compromises the final interpretation on permanent sections.

Histologic Findings

The outline below comprises the histologic classification of soft-tissue tumors. The histopathologic evaluation of these lesions, with categorization into one of the groups listed below, is performed on permanent sections. Such classification may require data from various sources, including immunochemical, cytogenetic, electron microscopic, and molecular studies.

Sarcomas usually are assigned a histologic grade. Low-grade lesions rarely metastasize but can be locally aggressive; high-grade sarcomas pose a significant threat of metastasis and carry a greater risk of local recurrence. Although assigning a pathologic grade to an individual tumor is a subjective and difficult task, the grade's clinical importance in determining a treatment strategy cannot be overemphasized. An ideal biopsy, with proper sampling of the lesion, should allow a confident grade assignment.

Many grading systems exist; they generally are based on evaluation of histomorphologic features, including cellularity, cellular pleomorphism, mitotic activity, and necrosis, as well as histologic category. [303132A three-grade system (grades 1, 2, 3) may be simplified further by lumping the sarcomas into low-grade (grade 1) and high-grade (grade 2) categories.

Other markers have been investigated as potential indicators of proliferation activity of soft tissue tumors. They include Ki-67, argyrophilic stain for nucleolar organizer regions (AgNOR), mast cell counts, and DNA flow cytometry.

World Health Organization 2013 classification of soft-tissue tumors

In 2013, the World Health Organization (WHO) issued an updated classification of soft-tissue tumors that divided them into the following categories [33:

  • Adipocytic tumors
  • Fibroblastic/myofibroblastic tumors
  • So-called fibrohistiocytic tumors
  • Smooth-muscle tumors
  • Pericytic (perivascular) tumors
  • Skeletal-muscle tumors
  • Vascular tumors
  • Chondro-osseous tumors
  • Gastrointestinal stromal tumors
  • Nerve-sheath tumors
  • Tumors of uncertain differentiation
  • Undifferentiated/unclassified sarcomas

In addition, as part of this classification, soft tissue tumors were divided into the following four categories as appropriate:

  • Benign
  • Intermediate (locally aggressive)
  • Intermediate (rarely metastasizing)
  • Malignant

This terminology should not be confused with the grading system mentioned above, in which grade 2 may be regarded as intermediate.

Adipocytic tumors

Benign adipocytic tumors include the following:

  • Lipoma
  • Lipomatosis
  • Lipomatosis of nerve
  • Lipoblastoma/lipoblastomatosis
  • Angiolipoma
  • Myolipoma
  • Chondroid lipoma
  • Extrarenal angiomyolipoma
  • Extra-adrenal myelolipoma
  • Spindle cell/pleomorphic lipoma
  • Hibernoma

Intermediate (locally aggressive) adipocytic tumors include the following:

  • Atypical lipomatous tumor/well-differentiated liposarcoma

Malignant adipocytic tumors include the following:

  • Dedifferentiated liposarcoma
  • Myxoid liposarcoma
  • Pleomorphic liposarcoma
  • Liposarcoma, not otherwise specified

Fibroblastic/myofibroblastic tumors

Benign fibroblastic/myofibroblastic tumors include the following:

  • Nodular fasciitis
  • Proliferative fasciitis
  • Proliferative myositis
  • Myositis ossificans
  • Fibro-osseous pseudotumor of digits
  • Ischemic fasciitis
  • Elastofibroma
  • Fibrous hamartoma of infancy
  • Fibromatosis colli
  • Juvenile hyaline fibromatosis
  • Inclusion body fibromatosis
  • Fibroma of tendon sheath
  • Desmoplastic fibroblastoma
  • Mammary-type myofibroblastoma
  • Calcifying aponeurotic fibroma
  • Angiomyofibroblastoma
  • Cellular angiofibroma
  • Nuchal-type fibroma
  • Gardner fibroma
  • Calcifying fibrous tumor

Intermediate (locally aggressive) fibroblastic/myofibroblastic tumors include the following:

  • Superficial fibromatoses - Palmar/plantar
  • Desmoid-type fibromatoses
  • Lipofibromatosis
  • Giant cell fibroblastoma

Intermediate (rarely metastasizing) fibroblastic/myofibroblastic tumors include the following:

  • Dermatofibrosarcoma protuberans - Fibrosarcomatous, pigmented
  • Solitary fibrous tumor - Solitary fibrous tumor, malignant
  • Inflammatory myofibroblastic tumor
  • Low-grade myofibroblastic sarcoma
  • Myxoinflammatory fibroblastic sarcoma/atypical myxoinflammatory fibroblastic tumor
  • Infantile fibrosarcoma

Malignant fibroblastic/myofibroblastic tumors include the following:

  • Adult fibrosarcoma
  • Myxofibrosarcoma
  • Low-grade fibromyxoid sarcoma
  • Sclerosing epithelioid fibrosarcoma

So-called fibrohistiocytic tumors

Benign tumors of this type include the following:

  • Tenosynovial giant cell tumor - Localized, diffuse, malignant
  • Deep benign fibrous histiocytoma

Intermediate (rarely metastasizing) tumors of this type include the following:

  • Plexiform fibrohistiocytic tumor
  • Giant cell tumor of soft tissues

Smooth-muscle tumors

These tumors include the following:

  • Benign - Leiomyoma of deep soft tissue
  • Malignant - Leiomyosarcoma (excluding skin)

Pericytic (perivascular) tumors

These tumors include the following:

  • Glomus tumor (and variants) - Glomangiomatosis, malignant glomus tumor
  • Myopericytoma - Myofibroma, myofibromatosis
  • Angioleiomyoma

Skeletal-muscle tumors

These tumors include the following:

  • Rhabdomyoma
  • Embryonal rhabdomyosarcoma
  • Alveolar rhabdomyosarcoma 
  • Pleomorphic rhabdomyosarcoma
  • Spindle cell/sclerosing rhabdomyosarcoma

Vascular tumors

Benign vascular tumors include the following:

  • Hemangioma - Synovial, venous, arteriovenous hemagnioma/malformation
  • Epithelioid hemangioma
  • Angiomatosis
  • Lymphangioma

Intermediate (locally aggressive) vascular tumors include the following:

  • Kaposiform hemangioendothelioma

Intermediate (rarely metastasizing) vascular tumors include the following:

  • Retiform hemangioendothelioma
  • Papillary intralymphatic angioendothelioma
  • Composite hemangioendothelioma
  • Pseudomyogenic (epithelioid sarcoma-like) hemangioendothelioma
  • Kaposi sarcoma

Malignant vascular tumors include the following:

  • Epithelioid hemangioendothelioma
  • Angiosarcoma of soft tissue

Chondro-osseous tumors

These tumors include the following:

  • Soft-tissue chondroma
  • Mesenchymal chondrosarcoma
  • Extraskeletal osteosarcoma

Gastrointestinal stromal tumors

Gastrointestinal stromal tumors (GISTs) include the following:

  • Benign GIST
  • GIST of uncertain malignant potential
  • Malignant GIST

Nerve-sheath tumors

Benign nerve-sheath tumors include the following:

  • Schwannoma (including variants)
  • Melanotic schwannoma
  • Neurofibroma (including variants) - Plexiform neurofibroma
  • Perineurioma - Malignant perineurioma
  • Granular cell tumor
  • Dermal nerve sheath myxoma
  • Solitary circumscribed neuroma
  • Ectopic meningioma
  • Nasal glial heterotopia
  • Benign Triton tumor
  • Hybrid nerve-sheath tumors

Malignant nerve-sheath tumors include the following:

  • Malignant peripheral nerve sheath tumor
  • Epithelioid malignant nerve sheath tumor
  • Malignant Triton tumor
  • Malignant granular cell tumor
  • Ectomesenchymoma

Tumors of uncertain differentiation

Benign tumors of uncertain differentiation include the following:

  • Acral fibromyxoma
  • Intramuscular myxoma (including cellular variant)
  • Juxta-articular myxoma
  • Deep ("aggressive") angiomyxoma
  • Pleomorphic hyalinizing angiectatic tumor
  • Ectopic hamartomatous thymoma

Intermediate (locally aggressive) tumors of uncertain differentiation include the following:

  • Hemosiderotic fibrolipomatous tumor

Intermediate (rarely metastasizing) tumors of uncertain differentiation include the following:

  • Atypical fibroxanthoma
  • Angiomatoid fibrous histiocytoma
  • Ossifying fibromyxoid tumor - Including malignant
  • Mixed tumor NOS - Including malignant
  • Myoepithelioma
  • Myoepithelial carcinoma
  • Phosphaturic mesenchymal tumor - Benign, malignant

Malignant tumors of uncertain differentiation include the following:

  • Synovial sarcoma NOS - Spindle cell, biphasic
  • Epithelioid sarcoma
  • Alveolar soft-part sarcoma
  • Clear cell sarcoma of soft tissue
  • Extraskeletal myxoid chondrosarcoma
  • Extraskeletal Ewing sarcoma
  • Desmoplastic small round cell tumor
  • Extrarenal rhabdoid tumor
  • Neoplasms with perivascular epithelioid cell differentiation (PEComa)
  • Intimal sarcoma

Undifferentiated/unclassified sarcomas

These tumorsinclude the following:

  • Undifferentiated spindle cell sarcoma
  • Undifferentiated pleomorphic sarcoma
  • Undifferentiated round cell sarcoma
  • Undifferentiated epithelioid sarcoma
  • Undifferentiated sarcoma NOS

Benign vs intermediate vs malignant tumors

Benign soft-tissue tumors usually do not recur locally, and if they do, the recurrence is nondestructive and almost always readily curable by complete local excision. Morphologically benign lesions, which are extremely rare, may give rise to distant metastases, which cannot be predicted on the basis of routine, contemporary histologic evaluation. This is best documented in rare, cutaneous benign fibrous histiocytoma.

Intermediate (locally aggressive) soft-tissue tumors show an infiltrative and locally destructive growth pattern. However, although they may recur locally, they do not metastasize. They usually require excision with a wide margin of normal tissue for better local control. The example in this category is desmoid (fibromatosis).

Intermediate (rarely metastasizing) soft-tissue tumors are often locally aggressive, but in some cases, they also have a tendency to produce distant metastases (usually in a lymph node or lung). This risk is low (< 2%), but histomorphologically, it is not reproducibly predictable. The classic examples in this group are plexiform fibrohistiocytic tumor and angiomatoid fibrous histiocytoma.

Malignant soft-tissue sarcomas are locally destructive with the potential to recur. The risk of distant metastasis is significant. (Depending on histologic type and grade, the potential ranges from 20% to almost 100%). Histologically low-grade sarcomas have a lower chance of metastasis (only 2-10%). [34However, the recurrences of such tumors may advance in grade and attain a higher risk of metastatic potential similar to that associated with myxofibrosarcoma and leiomyosarcoma.

Staging

Histologic grading is an important prognostic factor in sarcomas. Therefore, the usual tumor-node-metastases (TNM) scheme is modified into a grade-tumor-node-metastases (GTNM) scheme for classifying soft-tissue tumors.

Tumor grade (G) currently is commonly based on cellular differentiation (scored as 1-3), mitotic rate (scored as 1-3), and extent of necrosis (scored as 0-2). The scores for these variables are combined the following G values:

  • GX - Grade cannot be assessed
  • G1 - Total score of 2 or 3
  • G2 - Total score of 4 or 5
  • G3 - Total score of 6 or higher

Possible values for primary tumor (T) are defined as follows:

  • TX - Tumor cannot be assessed
  • T0 - No evidence of primary tumor
  • T1 - Tumor ≤5 cm in greatest dimension: T1a, superficial; T1b, deep
  • T2 - Tumor >5 cm in greatest dimension: T2a, superficial; T2b, deep

Possible values for regional lymph node involvement (N) are defined as follows:

  • NX - Regional lymphnodes cannot be assessed
  • N0 - No known metastasis to lymph nodes
  • N1 - Verified metastasis to lymph nodes

Possible values for distant metastasis are defined as follows:

  • M0 - No known distant metastasis
  • M1 - Known distant metastasis

The G, T, N, and M values are combined to derive the stage grouping (see Table 2 below).

Table 2. AJCC GTNM Classification and Stage Grouping of Soft Tissue Sarcomas (Open Table in a new window)

Stage Groupings

Tumor Grade

Primary Tumor

Regional Lymph Node Involvement

Distant Metastasis

Stage IA

GX, G1

T1

N0

M0

Stage IB

GX, G1

T2

N0

M0

Stage IIA

G2, G3

T1

N0

M0

Stage IIB

G2

T2

N0

M0

Stage III

G3

Any G

T2

Any T

N0

N1

M0

M0

Stage IV

Any GAny TAny NM1

The GTNM system, which is clinically very useful, stratifies patients into groups with distinct prognostic patterns.

The size of the tumor also is of prognostic significance. The risk of metastasis and death is higher with larger primary sarcomas. According to the current American Joint Commission on Cancer (AJCC) system, tumors with a greatest dimension of 5 cm or less are designated as T1, and those exceeding 5 cm are categorized as T2. Although they are not a part of the AJCC system, tumors larger than 10 cm have a worse prognosis than do those larger than 5 cm. [35]

The site of the tumor is another important prognostic factor. Superficially located tumors (those situated entirely superficial to the deep or muscular fascia) have a relatively better prognosis than that characterizing deeper sarcomas. Alternative staging systems incorporate site into their classification strategy.



Approach Considerations

Management of soft-tissue tumors may evolve as a result of the advent of molecular diagnostics and antitumor therapies. It is problematic, however, that despite the existence of many histologic subtypes of soft-tissue tumors, only a small number of them are seen at any one institution. More multi-institutional studies are necessary.

Soft-tissue sarcomas are challenging lesions that demand a multidisciplinary and multimodality approach for proper clinical evaluation and treatment. Although in the past, high-grade extremity sarcomas were treated with amputation, limb-sparing therapies for these tumors are well established today. Successful management of such lesions requires a multidisciplinary team of surgeons, radiologists, pathologists, medical oncologists, radiation oncologists, oncology nurses, rehabilitation therapists, and social workers.

Because of the comparative rarity of soft-tissue sarcomas and a general lack of related medical expertise, patients with these tumors should be considered for referral, preferably during the initial evaluation phase, to medical centers experienced in sarcoma management. [36]

For more information on treatment of these sarcomas, see Soft-Tissue Sarcoma Guidelines and Soft-Tissue Sarcoma Treatment Protocols.

Medical Therapy

High-grade soft-tissue sarcomas often are treated with ifosfamide- and doxorubicin-based chemotherapy. This is controversial, in that no definitive studies exist proving that adjuvant chemotherapy contributes to prolonged overall survival. [37383940]

Surgical Therapy

Localized tumors

Complete local excision is adequate treatment for benign soft-tissue tumors. However, a variety of treatment options, including surgery alone or combined with radiation therapy or chemotherapy, may be considered for treatment of localized primary and recurrent sarcomas.

Extremity sarcoma

Extremity sarcomas may be treated surgically, with or without radiation therapy and adjuvant chemotherapy.

Surgical therapy

Surgery is the most important component of any treatment plan for a clinically localized primary or recurrent soft-tissue sarcoma. On the basis of the achievable margin, one of the following four types of excisions may be performed:

  • Intracapsular excision and amputation
  • Marginal excision and amputation
  • Wide excisions and amputation
  • Radical excision and amputation

An intracapsular excision or amputation passes within the tumor itself. The tumor inside the pseudocapsule is removed (often piecemeal). Incidence of local recurrence with these types of excisions is virtually 100%; these procedures are performed only in unusual circumstances.

In marginal excisions and amputation, the excision is performed through the pseudocapsule surrounding the tumor. Shelling-out procedures and most excisional biopsies belong to this category. The chance of local recurrence is 20-75%, depending on the nature of the tumor and whether or not radiotherapy is used.

In a wide excision, the tumor is excised with a wide margin of surrounding normal tissue but within the muscular compartment. Without adjuvant therapy, the incidence of local recurrence after wide excision varies but may reach 30%; the rate depends on the selection criteria used and the adequacy of the histologically assessed surgical margin. A wide amputation is performed through the normal tissue proximal to the reactive zone around the tumor but remains within the involved compartment. Limb-sparing procedures belong to this category.

Radical excisions are en-bloc excisions of the tumor along with the entire muscle compartment. Amputation with disarticulation of the joint proximal to the involved compartment is called radical amputation. The risk of local recurrence is lowest with this procedure.

Radiation therapy

Small, superficial, or low-grade tumors treated with only a wide local excision have a very low risk of local recurrence. [27For better local control, many patients undergoing surgical excision receive radiation therapy. In patients who refuse or cannot tolerate surgery, radiation alone can be an effective treatment for certain extremity sarcomas.

After wide surgical excision, radiation therapy enhances local control for primary extremity sarcomas. The concept of limb-sparing surgery with postoperative irradiation has been validated by randomized trials of amputation versus wide local excision. [41Usually, a total dose of about 60 Gy is adequate. A large, single-institution series reported long-term disease control with postoperative radiation therapy for soft-tissue sarcoma of the extremities with acceptable toxicity. Older age and recurrence were poor prognostic factors. [42]

Postoperative radiation can also be delivered to the tumor bed by means of brachytherapy, in which radioactive sources are implanted in the patient. The advantage of this approach is that it requires a much shorter time for initiation and completion of therapy than external radiation does. External beam radiation is used for 6 weeks, beginning 1 month or more after surgery; brachytherapy usually is started within a week of surgery and completed in 4 or 5 days.

Because of its technical complexity, brachytherapy requires an experienced radiation oncologist during the operating procedure. Brachytherapy and external beam radiation appear to be equally effective when properly administered.

The employment of preoperative radiation therapy may allow less radical forms of surgery to be used, specifically on large tumors that otherwise may compromise limb-sparing procedures. Radiation-induced tumor shrinkage decreases the magnitude of resection needed and reduces the risk of seeding by viable tumor cells. Local fibrosis may make the resection more challenging.

Findings from one study showed that intensity-modulated radiotherapy (IMRT) achieved better local control of high-grade soft-tissue sarcoma at 5 years than brachytherapy did, though higher rates of adverse features occurred in the group receiving IMRT. [43]

Chemotherapy

Even after local control is achieved in patients with intermediate- and high-grade soft-tissue sarcomas, the risk of metastatic disease following multimodality treatments without amputation is as high as 50%. The risk is even greater if stage IIIB tumors are included.

Thus, effective systemic, adjuvant chemotherapy is desirable after definitive treatment of local disease. However, conclusive evidence that adjuvant chemotherapy for extremity sarcomas increases overall survival rates is lacking. Randomized trials have not demonstrated that higher overall survival rates occur with surgery and adjuvant doxorubicin therapy than with surgery alone.

In randomized clinical trials, multiagent chemotherapy with doxorubicin, cyclophosphamide, and methotrexate following surgery improved disease-free survival rates for patients with high-grade extremity sarcomas (except when the lesions were associated with the trunk or retroperitoneum). [44However, the toxicity associated with this regimen was substantial. [45]

Preoperative chemotherapy, also called neoadjuvant chemotherapy, is an option for most patients with osteosarcomas of the extremity. However, it has not been established that this treatment is superior to conventional chemotherapy for soft-tissue tumors. Preoperative chemotherapy may be used alone or with preoperative or postoperative radiation therapy.

A significant hypothetical advantage of neoadjuvant chemotherapy is that it allows treatment effectiveness to be monitored through evaluation of the degree of necrosis in the resected primary tumor. However, no evidence exists that this results in improved clinical prognosis.

Nonextremity sarcoma

As with sarcomas of extremities, options for therapeutic management of nonextremity sarcomas include surgery, radiation, and chemotherapy.

Sarcomas arising in the head and neck, thoracic or abdominal wall, mediastinum, or retroperitoneum are difficult to treat. Most of these tumors develop in areas where surrounding normal tissue limits the maximum dosage of radiation that can safely be delivered to the tumor bed. In general, the risk of local recurrence is high. For retroperitoneal tumors, the patient usually succumbs as a result of local complications, before metastases are evident.

In a subgroup analysis of the prospectively randomized EORTC 62961 phase III trial, Angele et al determined that the addition of regional hyperthermia (RHT) to systemic chemotherapy yielded significant improvements in local progression-free survival (LPFS) and disease-free survival (DFS) after resection of high-risk retroperitoneal and abdominal soft tissue sarcomas, as compared with chemotherapy alone. [46However, no significant improvements were noted in overall survival or perioperative morbidity and mortality.

Recurrent and metastatic disease

As many as 35% of patients develop local recurrence or distant metastases following a combination of surgical resection and adjuvant therapy. [47Eighty percent of local recurrences and disseminated metastases were observed within 5 years. [5]

Although removal of normal lymph nodes generally has no role in the treatment of soft-tissue sarcomas, dissection of biopsy-proven tumor-positive lymph nodes is recommended in the absence of metastatic disease elsewhere. Radical lymphadenectomy in patients who have nodal involvement without pulmonary metastases may yield better 5-year survival rates. [48]

Whenever it is technically amenable, surgical removal of pulmonary metastases is recommended following thorough evaluation for extrapulmonary tumor. In one study, resection of isolated pulmonary metastases achieved an actuarial 3-year survival rate of 38%. [5The presence of fewer than three or four metastatic nodules, as observed with preoperative computed tomography (CT), is a favorable prognostic factor.

Because some clinical response has been achieved with neoadjuvant chemotherapy in soft-tissue sarcomas, studies to evaluate the use of high-dose therapy with autologous stem cell transplantation have been conducted. These studies have been pursued for patients with a high risk of metastatic disease at the time of diagnosis and as salvage therapy at the time of disease relapse. Most of this research has been conducted in children with small blue cell tumors (Ewing sarcomas, primitive neuroectodermal tumors). [49]

The results of these studies have been mixed. Randomized trials have not been reported. Some studies showed better survival rates for patients treated with the newer technique than for control patients treated with conventional therapy. Other research has failed to show any improvement in outcomes. Thus, the use of high-dose therapy in sarcomas remains controversial. This approach should be investigated further in well-designed, randomized clinical trials.

Postoperative Care

Compressive bandages and suction drains should be used to minimize seroma formation that can delay administration of chemotherapy or radiation therapy. Physical therapy and rehabilitation support may be required.

Complications

Complications can be divided into those that occur before therapy is completed and those that develop after its completion.

Complications that may occur before completion of therapy include the following:

  • Related to the tumor - Skin ulceration, thrombocytopenia, hemorrhage, fracture (depending on histopathologic category and anatomic site)
  • Related to operative procedures - Infection, wound dehiscence

Complications that may occur after completion of therapy include the following:

  • Related to the tumor - Local recurrence, distant metastasis
  • Related to chemotherapy and radiation therapy - Infection (from immunosuppression), postirradiation sarcoma (usually ≥10 years after radiation therapy)

Long-Term Monitoring

General follow-up care includes surveillance studies to evaluate local recurrence and distant metastasis of malignant and intermediate tumors. The precise interval between and the duration of various follow-up studies are not well defined. In general, vigorous surveillance continues for 3-5 years after treatment. Benign tumors generally do not require such surveillance.


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