Benign and Malignant Soft Tissue Tumors Workup

• 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.

• In the past 2 decades, imaging studies 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.^[7] See the images below. A computed-tomography (CT)–guided needle biopsy of a high-grade soft tissue sarcoma arising in the left hemipelvis. The CT artifact from the needle can be seen in the upper right corner of the image as the needle enters the lesion just anterior and medial to the dome of the left hip joint. Courtesy of Howard A. Chansky, MD Magnetic resonance imaging (MRI) is used to demonstrate involvement of critical structures by tumor. This recurrent, high-grade soft tissue sarcoma in the posterior calf abuts the tibial nerve and posterior tibial vessels. An extensive reactive zone surrounds the structures. This patient was treated with below-knee amputation. Courtesy of Howard A. Chansky, MD
• Imaging studies should be obtained before biopsy to ensure that a biopsy of a potentially malignant lesion is taken in a manner that will not preclude limb-salvage surgery. Imaging should also be performed before biopsy, to prevent the biopsy tract from adversely affecting the capture of anatomic detail by magnetic resonance imaging (MRI). The relationship 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 radiographs, computed tomography (CT) scanning, MRI, and bone scintigraphy (bone scan). Positron emission tomography (PET) scanning 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 scanning
    • Check for presence and number of pulmonary metastases.
    • Consider performing a CT scan of the liver in cases of intra-abdominal or retroperitoneal tumors.
  • MRI
    • In contrast to CT scanning, MRI is not limited to the transverse (axial) plane. Coronal, sagittal, and oblique planes may be imaged.
    • MRI best defines the relationship between a tumor and adjacent anatomic structures, such as compartment boundaries, nerves, vessels, and muscle.^{[8, 9]}
    • Although for most patients MRI alone suffices, the information obtained from CT scanning and MRI of the primary tumor occasionally may be complementary. Bony involvement may be better assessed with a CT scan, as may the boundary between normal muscle and fibrous lesions.

• 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 following 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 FNAB, core needle biopsy, incisional biopsy, and excisional biopsy. The choice of biopsy 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
    • This 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 Table 1 and Atlas of Genetics and Cytogenetics in Oncology and Haematology), or examination using electron microscopy or microbiology cultures.^[10]
    • Table 1. 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%

    • With the help of relevant ancillary techniques, diagnostic accuracy with FNAB is very high, and soft tissue tumors can be graded.^[11] This method is minimally invasive and relatively atraumatic.
    • Published literature highlights the rarity of needle-track seeding with FNAB. Core biopsy, on the other hand, has a higher rate of needle-track seeding.
  • Core needle biopsy
    • This technique retrieves a thin core of tissue (approximately 1×10 mm). The procedure may be performed using various needles (most commonly a Tru-Cut needle^[12] ). The core may not be representative of the entire tumor, so nonrepresentative grading is possible. FNAB samples a larger area of the tumor than does core needle biopsy.
    • 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. Similar to FNAB, a biopsy may be taken of deeper lesions under image guidance (eg, CT scanning, ultrasound scanning, MRI).
  • 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 while performing 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 this method, the entire lesion is removed surgically. Many sarcomas appear to be well demarcated grossly. 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 (< approximately 5 cm in diameter) or for those known to be benign.^[13]
  • Frozen section and intraoperative cytology
    • Frozen section and intraoperative cytology are extremely helpful tools for the management of soft tissue tumors.^{[14, 15]} Proper communication with a musculoskeletal oncopathologist preoperatively and intraoperatively is essential for evaluation. Frozen section can guide retrieval of adequate diagnostic material and, depending on the initial evaluation, can be an important triage mechanism to direct 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.

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.^{[16, 17, 18]} A 3-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.

WHO (2002) Classification of Soft Tissue Tumors

• Adipocytic tumors

  • Benign
    • Lipoma
    • Lipomatosis
    • Lipomatosis of nerve
    • Lipoblastoma/lipoblastomatosis
    • Angiolipoma
    • Myolipoma
    • Chondroid lipoma
    • Extrarenal angiomyolipoma
    • Extra-adrenal myelolipoma
    • Spindle cell/pleomorphic lipoma
    • Hibernoma
  • Intermediate (locally aggressive)
    • Atypical lipomatous tumor/well-differentiated liposarcoma
  • Malignant
    • Dedifferentiated liposarcoma
    • Myxoid liposarcoma
    • Round cell liposarcoma
    • Pleomorphic liposarcoma
    • Mixed-type liposarcoma
    • Liposarcoma, not otherwise specified
• Fibroblastic/myofibroblastic tumors

  • Benign
    • Nodular fasciitis
    • Proliferative fasciitis
    • Proliferative myositis
    • Myositis ossificans
      • Fibro-osseous pseudotumor of digits
    • Ischemic fasciitis
    • Elastofibroma
    • Fibrous hamartoma of infancy
    • Myofibroma/myofibromatosis
    • 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
    • Giant cell angiofibroma
  • Intermediate (locally aggressive)
    • Superficial fibromatoses - Palmar/plantar
    • Desmoid-type fibromatoses
    • Lipofibromatosis
  • Intermediate (rarely metastasizing)
    • Solitary fibrous tumor and hemangiopericytoma - Including lipomatous hemangiopericytoma
    • Inflammatory myofibroblastic tumor
    • Low-grade myofibroblastic sarcoma
    • Myxoinflammatory fibroblastic sarcoma
    • Infantile fibrosarcoma
  • Malignant
    • Adult fibrosarcoma
    • Myxofibrosarcoma
    • Low-grade fibromyxoid sarcoma
      • Hyalinizing spindle cell tumor
    • Sclerosing epithelioid fibrosarcoma
• So-called fibrohistiocytic tumors

  • Benign
    • Giant cell tumor of tendon sheath
    • Diffuse-type giant cell tumor
    • Deep benign fibrous histiocytoma
  • Intermediate (rarely metastasizing)
    • Plexiform fibrohistiocytic tumor
    • Giant cell tumor of soft tissues
  • Malignant
    • Pleomorphic 'MFH'/undifferentiated pleomorphic sarcoma
    • Giant cell 'MFH'/undifferentiated pleomorphic sarcoma with giant cells
    • Inflammatory 'MFH'/undifferentiated pleomorphic sarcoma with prominent inflammation
• Smooth muscle tumors

  • Angioleiomyoma
  • Deep leiomyoma
  • Genital leiomyoma
  • Leiomyosarcoma - Excluding skin
• Pericytic (perivascular) tumors

  • Glomus tumor (and variants)
    • Malignant glomus tumor
  • Myopericytoma
• Skeletal muscle tumors

  • Benign
    • Rhabdomyoma
      • Adult
      • Fetal
      • Genital type
  • Malignant
    • Embryonal rhabdomyosarcoma - Including spindle cell, botryoid, anaplastic
    • Alveolar rhabdomyosarcoma - Including solid and anaplastic
    • Pleomorphic rhabdomyosarcoma
• Vascular tumors

  • Benign
    • Hemangiomas of subcutaneous and deep soft tissue
      • Capillary
      • Cavernous
      • Arteriovenous
      • Venous
      • Intramuscular
      • Synovial
    • Epithelioid hemangioma
    • Angiomatosis
    • Lymphangioma
  • Intermediate (locally aggressive)
    • Kaposiform hemangioendothelioma
  • Intermediate (rarely metastasizing)
    • Retiform hemangioendothelioma
    • Papillary intralymphatic angioendothelioma
    • Composite hemangioendothelioma
    • Kaposi sarcoma
  • Malignant
    • Epithelioid hemangioendothelioma
    • Angiosarcoma of soft tissue
• Chondro-osseous tumors

  • Benign
    • Soft tissue chondroma
  • Malignant
    • Mesenchymal chondrosarcoma
    • Extraskeletal osteosarcoma
• Tumors of uncertain differentiation

  • Benign
    • Intramuscular myxoma - Including cellular variant
    • Juxta-articular myxoma
    • Deep ("aggressive") angiomyxoma
    • Pleomorphic hyalinizing angiectatic tumor
    • Ectopic hamartomatous thymoma
  • Intermediate (rarely metastasizing)
    • Angiomatoid fibrous histiocytoma
    • Ossifying fibromyxoid tumor - Including atypical/malignant
    • Mixed tumor
      • Myoepithelioma/parachordoma
  • Malignant
    • Synovial sarcoma
    • Epithelioid sarcoma
    • Alveolar soft-part sarcoma
    • Clear cell sarcoma of soft tissue
    • Extraskeletal myxoid chondrosarcoma - "Chordoid" type
    • Primitive neuroectodermal tumor (PNET)/extraskeletal Ewing tumor
      • Peripheral PNET
      • Extraskeletal Ewing tumor
    • Desmoplastic small round cell tumor
    • Extra-renal rhabdoid tumor
    • Malignant mesenchymoma
    • Neoplasms with perivascular epithelioid cell differentiation (PEComa)
      • Clear cell myomelanocytic tumor
    • Intimal sarcoma

As part of this 2002 WHO classification, soft tissue tumors are divided into the following 4 categories.

• Benign - These 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) - These 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) - These 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%).^[19] 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.

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

Histologic grading is an important prognostic factor in sarcomas. Therefore, the usual tumor, node, metastases (TNM) classification scheme is modified into a grading, tumor, node, metastases (GTNM) staging system for soft tissue tumors (see Table 2, below). This system, which is clinically very useful, stratifies patients into groups with distinct prognostic patterns.

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 of 5 cm or less in greatest dimension 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.^[20]

Site 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.

GTNM staging system definitions are as follows:

• G - Tumor grade

  • G1 - Well differentiated
  • G2 - Moderately differentiated
  • G3 - Poorly differentiated
• T - Primary tumor

  • T1 - Tumor less than 5 cm in greatest diameter
  • T2 - Tumor more than 5 cm in greatest diameter
• N - Regional lymph node involvement

  • N0 - No known metastasis to lymph nodes
  • N1 - Verified metastasis to lymph nodes
• M - Distant metastasis

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

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