Benign and Malignant Soft-Tissue Tumors Workup

Updated: Apr 28, 2022
  • Author: Vinod B Shidham, MD, FRCPath; Chief Editor: Omohodion (Odion) Binitie, MD  more...
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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 Angiography to evaluate any vascular involvement by soft tissue tumors has essentially been replaced by MRI.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. [22, 23] (See the image below.)

MRI is used to demonstrate involvement of critical MRI 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. [25] This 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. [28, 29] Proper 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. [30, 31, 32] A 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%). [34] However, 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.



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




Stage IB

GX, G1




Stage IIA

G2, G3




Stage IIB





Stage III


Any G


Any T





Stage IV

Any G Any T Any N M1

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.