Treatment statement for Health professionals

Adult Soft Tissue Sarcoma

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Holly L. Neville, MD
Resident, Department of Surgery, University of TexasHouston Medical School,
Houston, Texas
General Information
Cellular Classification
Stage Information
Treatment Option Overview
Stage I Adult Soft Tissue Sarcoma
Stage II and III Adult Soft Tissue Sarcoma
Stage IV Adult Soft Tissue Sarcoma
Recurrent Adult Soft Tissue Sarcoma
Changes to This Summary (05/05/2005)
More Information

General Information

Note: A separate PDQ summary on Childhood Soft Tissue Sarcoma Treatment is also available.

Note: Estimated new cases and deaths from soft tissue sarcoma in the United States in 2005: [1]

New cases: 9,420.

Deaths: 3,490.

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial
boards use a formal ranking system to help the reader judge the strength of evidence linked to the
reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more
information.)

Soft tissue sarcomas are malignant tumors that may arise in any of the mesodermal tissues of the
extremities (50%), trunk and retroperitoneum (40%), or head and neck (10%). Rarely, these tumors arise
in the gastrointestinal tract or gastrointestinal stroma, and a small percentage of these are called
gastrointestinal stromal tumors (GISTs). Malignant GISTs can occur from the esophagus to the rectum
but occur most commonly in the stomach and small intestine. Soft tissue sarcomas occur with greater
frequency in patients with: [2]

von Recklinghausens disease (neurofibromatosis).

 Gardners syndrome.
Werners syndrome.
Tuberous sclerosis.
Basal cell nevus syndrome.
Li-Fraumeni syndrome (p53 mutations).

Soft tissue sarcomas may be heterogeneous, so adequate tissue should be obtained via either core-needle
or incisional biopsy for microscopic examination to determine histologic type and tumor grade. Careful
planning of the initial biopsy is important to avoid compromising subsequent curative resection. Since
the selection of treatment is determined by the grade of the tumor, it is essential to have a careful review
of the biopsy tissue by a pathologist who is experienced in diagnosing sarcomas. Complete staging and
treatment planning by a multidisciplinary team of cancer specialists is required to determine the optimal
treatment for patients with this disease. In most cases, a combined modality approach of preoperative or
postoperative radiation therapy is used, rather than the radical surgical procedures that were used in the
past. The role of chemotherapy is less well defined. Because of the evolving nature of the state of the art
in the treatment of this disease, all patients with such lesions should be included in a clinical trial
whenever possible.

The prognosis for patients with adult soft tissue sarcomas depends on several factors, including the
patients age and the size, histologic grade, and stage of the tumor. [3] [4] [5] Factors associated with a
poorer prognosis include age older than 60 years, tumors >5 cm, or high-grade histology. [6]

While low-grade tumors are usually curable by surgery alone, higher-grade sarcomas (as determined by
the mitotic index and by the presence of hemorrhage and necrosis) are associated with higher local
treatment failure rates and increased metastatic potential. [7] When feasible, wide margin function-
sparing surgical excision is the cornerstone of effective treatment, with the goal of preservation of a
functional extremity. [8] [9] This may be facilitated by soft tissue reconstructive surgery. [10] Mohs
surgical technique may be considered as an alternative to wide surgical excision for small, well-
differentiated sarcomas when cosmetic results are considered to be very important, as margins can be
assured with minimal normal tissue removal. [2] [11] High-grade soft tissue sarcomas of the extremities
can often be effectively treated while preserving the limb with combined-modality treatment consisting
of preoperative or postoperative radiation therapy to reduce local recurrence. [8] [12] [13] [14] [15] [16]
[17] [18] [19] In adults, local control of high-grade soft tissue sarcomas of the trunk and the head and
neck can be achieved with surgery, often in combination with radiation therapy with or without
chemotherapy. [20]

Effective treatment of retroperitoneal sarcomas requires removal of all gross disease while sparing
adjacent viscera not invaded by tumor. The prognosis for patients with high-grade retroperitoneal
sarcomas is less favorable than for patients with tumors at other sites, partly because of the difficulty in
completely resecting these tumors and the limitations placed on high-dose radiation therapy. [2] [21]
Surgical resection is the most effective treatment modality for GISTs. [22] Evidence indicates that
imatinib mesylate, a tyrosine kinase inhibitor, induced sustained tumor response in patients with
unresectable or metastatic GIST tumors. [23] [24] [25][Level of evidence: 3iiiDiii] [26] [27]

Several prospective randomized trials have been unable to confirm conclusively whether doxorubicin-
based adjuvant chemotherapy benefits adults with resectable soft tissue sarcomas. The majority of these
studies accrued small numbers of patients and did not demonstrate a metastasis-free or an overall survival
benefit for adjuvant chemotherapy. [20] A small study of adjuvant chemotherapy showed a positive
impact in disease-free survival and overall survival in patients treated with postoperative chemotherapy.
[28] There was wide interstudy variability among the numerous trials, including differences in
therapeutic regimens, drug doses, sample size, tumor site, and histologic grade. A quantitative meta-
analysis of updated data from 1,568 individual patients from 14 trials of doxorubicin-based adjuvant
therapy showed an absolute benefit from adjuvant therapy of 6% for local relapse-free interval (95%
confidence interval [CI], 1-10), 10% for distant relapse-free interval (95% CI, 5-15), and 10% for
recurrence-free survival (95% CI, 5-15); however, there was no overall survival benefit at 10 years. [29]
[Level of evidence: 1iiDi] Patients with high-grade tumors (grades 3 or 4) >5 cm in diameter have the
greatest tendency for disease to metastasize and are eligible for prospective clinical trials of adjuvant
chemotherapy.

With distant metastases (stage IV), surgery with curative intent is possible for patients selected for
optimal underlying biologic behavior (i.e., patients with a limited number of metastases, with a long
disease-free interval, and with slow clinical growth) with pulmonary metastases who have undergone or
are undergoing complete resection of the primary tumor. [30] [31] [32] Doxorubicin alone or with
dacarbazine is considered the best chemotherapeutic regimen for advanced sarcoma. [33] [34] [35] A
randomized trial of 340 patients with advanced sarcoma showed a higher response rate (32% vs. 17%,
P<.002) and longer time-to-progression (6 vs. 4 months, P<.02) for doxorubicin, dacarbazine, ifosfamide,
and mesna (MAID) versus doxorubicin and dacarbazine alone. [36][Level of evidence: 1iiDii] The
increased response rate of the MAID regimen may be justified in preoperative management of younger
patients with borderline resectability, but the increased toxic effects argue against its use in older patients.
[36]

Complete surgical resection is often difficult for sarcomas of the retroperitoneum due to large size before
detection and anatomic location. [37] [38] Prospective randomized trials have not shown improved
survival with preoperative or postoperative adjuvant chemotherapy for this subgroup. [29]

Cellular Classification

Soft tissue sarcomas are classified histologically according to the soft tissue cell of origin, although the
cell type is not part of the prognostic staging system. Additional studies, including electron microscopy,
histochemistry, flow cytometry, cytogenetics, and tissue culture studies may allow identification of
particular subtypes within the major histologic categories. The histologic grade reflects the metastatic
potential of these tumors more accurately than the classic cellular classification listed below. [1] [2] [3]
Overall, malignant fibrous histiocytoma is the most common histologic type (40% of the total) followed
by liposarcoma (25%); however, frequency of histologic type is site-dependent. Pathologists assign grade
based on the number of mitoses per high-powered field, presence of necrosis, cellular and nuclear
morphology, and the degree of cellularity; discordance among expert pathologists can reach 40% on
prospective review. [3] [4]

Soft tissue sarcomas include the following tumors:

Alveolar soft-part sarcoma. [5]

Angiosarcoma.
Dermatofibrosarcoma protuberans. [6]
Epithelioid sarcoma.
Extraskeletal chondrosarcoma.
Extraskeletal osteosarcoma.
Fibrosarcoma.
Gastrointestinal stromal tumor (GIST).
Leiomyosarcoma.
Liposarcoma.
Malignant fibrous histiocytoma.
Malignant hemangiopericytoma.
Malignant mesenchymoma.
Malignant schwannoma.
Malignant peripheral nerve sheath tumor.
Peripheral neuroectodermal tumors.
 Rhabdomyosarcoma.
Synovial sarcoma.
Sarcoma, NOS (not otherwise specified).

GISTs are mesenchymal in origin and are immunohistochemically distinct from leiomyosarcomas,
schwannomas, and fibrosarcomas with which they are often classified. They can be distinguished by
being CD34 positive and CD117 positive. These tumors express a growth factor receptor with tyrosine
kinase activity called c-kit (CD117). GISTs of the stomach wall are considered malignant when they
exceed 5 to 10 cm, have a high mitotic index, or have metastasized. GISTs of the small bowel are
considered malignant if they have any mitoses or are >2 cm. Current evidence suggests that c-kit
mutations are more commonly identified in malignant GISTs than in benign GISTs. It should be noted
that malignant GISTs are also usually CD34 positive. [7] [8] [9] [10]

References:

Stage Information

Staging has an important role in determining the most effective treatment of soft tissue sarcomas. The
stage is determined by the size of the tumor, the histologic grade, and whether it has spread to lymph
nodes or distant sites. Intracompartmental or extracompartmental extension of extremity sarcomas is also
important for surgical decision making. For complete staging, a thorough physical examination, x-rays,
laboratory studies, and careful review of all biopsy specimens (including those from the primary tumor,
lymph nodes, or other suspicious lesions) are essential. Computed tomographic scan of the chest is
recommended for sarcomas >5 cm (T2) or with moderate to poor differentiation (grades 2-4). Nodal
involvement is rare, occurring in <3% of patients with sarcoma. [1]

The American Joint Committee on Cancer (AJCC) has designated staging by the 4 criteria of tumor size,
nodal status, grade, and metastasis (TNGM). [2]

Grade and TNM definitions

Tumor grade (G)
GX: Grade cannot be assessed
G1: Well differentiated
G2: Moderately differentiated
G3: Poorly differentiated
G4: Poorly differentiated or undifferentiated

Primary tumor (T)

TX: Primary tumor cannot be assessed
T0: No evidence of primary tumor
T1: Tumor 5 cm in greatest dimension
o T1a: Superficial tumor
o T1b: Deep tumor
T2: Tumor >5 cm in greatest dimension
o T2a: Superficial tumor
o T2b: Deep tumor

Superficial tumor is located exclusively above the superficial fascia without invasion of the fascia; deep
tumor is located either exclusively beneath the superficial fascia, or superficial to the fascia with
invasion of or through the fascia, or both superficial yet beneath the fascia. Retroperitoneal, mediastinal,
and pelvic sarcomas are classified as deep tumors.
 Regional lymph nodes (N)
NX: Regional lymph nodes cannot be assessed
N0: No regional lymph node metastasis
N1: Regional lymph node metastasis Presence of positive nodes (N1) is considered stage IV.

Distant metastasis (M)

MX: Distant metastasis cannot be assessed
M0: No distant metastasis
M1: Distant metastasis

AJCC stage groupings

Stage I

Stage I tumor is defined as low-grade, superficial, and deep.

G1, T1a, N0, M0

G1, T1b, N0, M0
G1, T2a, N0, M0
G1, T2b, N0, M0
G2, T1a, N0, M0
G2, T1b, N0, M0
G2, T2a, N0, M0
G2, T2b, N0, M0

Stage II

Stage II tumor is defined as high-grade, superficial, and deep.

G3, T1a, N0, M0

G3, T1b, N0, M0
G3, T2a, N0, M0
G4, T1a, N0, M0
G4, T1b, N0, M0
G4, T2a, N0, M0

Stage III

Stage III tumor is defined as high-grade, large, and deep.

G3, T2b, N0, M0

G4, T2b, N0, M0

Stage IV

Stage IV is defined as any metastasis to lymph nodes or distant sites.

Any G, any T, N1, M0

Any G, any T, N0, M1
Treatment Option Overview

The designations in PDQ that treatments are standard or under clinical evaluation are not to be used
as a basis for reimbursement determinations.

Stage I Adult Soft Tissue Sarcoma

Low-grade soft tissue sarcomas (grade 1 or 2) have little metastatic potential, but they may recur locally
if they are inadequately treated. Accordingly, surgical excision with negative tissue margins of 2 cm in
all directions is the treatment of choice for patients with these early-stage sarcomas. [1] Mohs surgical
technique may be considered as an alternative to wide surgical excision for small, well-differentiated
sarcomas when cosmetic results are considered to be very important, as margins can be assured with
minimal normal tissue removal. [2] [3]

Carefully executed high-dose radiation therapy using a shrinking field technique may be beneficial for
unresectable tumors or for resectable tumors in which a high likelihood of residual disease is thought to
be present, when margins are known to be <2 cm, and when wider resection would require either an
amputation or the removal of a vital organ. [4] Because of the low metastatic potential of these tumors,
chemotherapy is usually not given. [5]

Standard treatment options:

1. Surgical excision with negative tissue margins of several centimeters in all directions.
2. Conservative surgical excision with preoperative or postoperative radiation therapy. [6] [7]
3. If the tumor is unresectable, high-dose preoperative radiation therapy may be used, followed by
surgical resection and postoperative radiation therapy. [4] [8]
4. For tumors of the retroperitoneum, trunk, and head and neck:
o Surgical resection with the option of postoperative radiation therapy if negative
margins cannot be obtained. Wide margins are unusual in these sites, and radiation
therapy is usually advocated for trunk and head and neck primary sites. [3]
o Preoperative radiation therapy followed by maximal surgical resection. Radiation
therapy is usually used to maximize local control because of the inability to obtain
wide surgical margins.
o Fast neutron therapy. [9]

Stage II and III Adult Soft Tissue Sarcoma

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial
boards use a formal ranking system to help the reader judge the strength of evidence linked to the
reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more
information.)

High-grade localized soft tissue sarcomas have an increased potential for metastatic spread. For sarcomas
of the extremities, local control comparable to that obtained with amputation may be achieved with limb-
sparing surgery that involves wide local excision in combination with preoperative or postoperative
radiation therapy and in some instances, chemotherapy. [1] [2] [3] [4]

Several prospective randomized trials have been unable to confirm conclusively whether doxorubicin-
based adjuvant chemotherapy benefits adults with resectable soft tissue sarcomas. The majority of these
studies accrued small numbers of patients and did not demonstrate a metastasis-free or an overall survival
benefit for adjuvant chemotherapy. [5] Interstudy variability was wide among the numerous trials,
including differences in therapeutic regimens, drug doses, sample size, tumor site, and histologic grade. A
quantitative meta-analysis of updated data from 1,568 individual patients from 14 trials of doxorubicin-
based adjuvant therapy showed an absolute benefit from adjuvant therapy of 6% for local relapse-free
interval (95% confidence interval [CI], 1-10), 10% for distant relapse-free interval (95% CI, 5-15), and
10% for recurrence-free survival (95% CI, 5-15); however, there was no overall survival benefit at 10
years. [6][Level of evidence: 1iiDi] Patients with high-grade tumors (grades 3 or 4) >5 cm in diameter
have the greatest tendency for disease to metastasize and are eligible for prospective clinical trials of
adjuvant chemotherapy.

Complete surgical resection is often difficult for sarcomas of the retroperitoneum due to large size before
detection and anatomical location. [7] [8] As opposed to soft tissue sarcomas of the extremities, local
recurrence is the most common cause of death in patients with retroperitoneal soft tissue sarcomas.
Complete surgical resection (i.e., removal of all gross tumor) is the most important factor in preventing
local recurrence and, in many instances, requires resection of adjacent viscera. Prospective randomized
trials have not shown improved survival with preoperative or adjuvant chemotherapy for this subgroup.
[6] [9]

Standard treatment options:

1. Surgical excision with negative tissue margins of several centimeters in all directions.
2. If the tumor is >5 cm in diameter, surgical excision with negative tissue margins of several
centimeters in all directions followed by radiation therapy.
3. If the tumor is unresectable, high-dose radiation therapy may be used, but poor local control is
likely to result.

1. In some situations, radiation therapy or chemotherapy may be used prior to surgery to convert a
marginally resectable tumor to one that can be adequately resected with limb preservation; this
treatment may be followed by postoperative radiation therapy.

Stage IV Adult Soft Tissue Sarcoma

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial
boards use a formal ranking system to help the reader judge the strength of evidence linked to the
reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more
information.)

Nodal disease

Stage IV sarcomas are tumors that have metastatic involvement of regional lymph nodes or have spread
to distant organs. Soft tissue sarcomas that more commonly spread to lymph nodes include synovial cell
sarcomas, epithelioid sarcomas, and rhabdomyosarcomas. For stage IV sarcomas, local control of the
primary tumor is probably best obtained by resection with negative margins, lymphadenectomy when
appropriate, and postoperative external-beam radiation therapy. [1] For gastrointestinal stromal tumors
(GISTs), preliminary evidence indicates that imatinib mesylate, a tyrosine kinase inhibitor, induced
sustained tumor response in patients with unresectable or metastatic tumors. [2] [3] [4][Level of
evidence: 3iiiDiii]

Standard treatment options:

1. Surgical resection and lymphadenectomy for patients with clinically-positive lymph nodes, with
or without postoperative radiation to the primary site.
2. In some centers, radiation therapy may be used prior to and following surgical extirpation. [5]
 3. Adjuvant chemotherapy may be considered for patients eligible for clinical trials. [6] [7] [8] [9]

Visceral disease

With distant metastases, surgery with curative intent is possible for patients with limited pulmonary
metastases who are also undergoing or have undergone complete resection of the primary tumor. [10]
[11] [12] The role of adjuvant therapy for pulmonary nodules is under clinical evaluation. [13] The value
of resection of hepatic metastases is unclear. Doxorubicin alone or with dacarbazine is considered one of
the most frequently used chemotherapeutic regimens for advanced sarcoma. [14] [15] [16] When used as
single agents, only doxorubicin and ifosfamide show >20% response rates; less active drugs include
dacarbazine, cisplatin, methotrexate, and vinorelbine. [17] A randomized trial of 340 patients with
advanced sarcoma showed a higher response rate (32% vs. 17%, P<.002) and longer time-to-progression
(6 vs. 4 months, P<.02) for doxorubicin, dacarbazine, ifosfamide, and mesna versus doxorubicin and
dacarbazine alone. [18][Level of evidence: 1iiDii] For older patients, sequential use of single agents with
each recurrence is a better strategy for palliation. High-dose chemotherapy (with or without
transplantation) has not influenced disease-free or overall survival in published studies so far, but it
remains under clinical evaluation for patients with metastatic disease in first complete remission, after
resection of pulmonary nodules, or for inoperable large primaries. [19] For GISTs, preliminary evidence
indicates that imatinib mesylate, a tyrosine kinase inhibitor, induced sustained tumor response in patients
with unresectable or metastatic tumors. [2] [3] [4][Level of evidence: 3iiiDiii]

Standard treatment options:

1. Surgical resection of the primary tumor with radiation therapy. Resection of pulmonary lesions
may be performed following definitive therapy of the primary tumor. [10] [11] [12]
o Surgical excision with negative tissue margins.
o If the tumor is resectable but wide margins cannot be obtained, radiation therapy may
be added.
o If the tumor is unresectable, high-dose radiation therapy may be used, often with
chemotherapy.
o For tumors of the retroperitoneum, trunk, and head and neck, surgical resection with
preoperative and/or postoperative radiation therapy, and sometimes chemotherapy, may
be used.
2. For palliation of patients with unresectable visceral disease, chemotherapy with the following
agents:
o Doxorubicin. [14]
o Doxorubicin + dacarbazine. [14] [15]
o Doxorubicin + ifosfamide. [20]
o Doxorubicin + dacarbazine + ifosfamide + mesna. [18] [21]

1. High-dose ifosfamide regimens. [22] [23] [24]

Recurrent Adult Soft Tissue Sarcoma

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial
boards use a formal ranking system to help the reader judge the strength of evidence linked to the
reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more
information.)

Treatment of recurrent soft tissue sarcomas depends on the type of initial presentation and treatment.
Patients who develop a local recurrence often can only be salvaged by aggressive local therapy: local
excision plus radiation therapy after previous minimal therapy or amputation after previous aggressive
treatment. [1] [2] For selected patients who received radiation therapy, preoperative radiation therapy and
wide local excision may avoid the need for amputation. [3] [4] [5] Metastases to the lung as first
recurrence usually occur within 2 to 3 years of initial diagnosis and should be treated as described under
treatment for stage IV disease. [6] [7] [8] A 30% survival rate at 3 years is noted if limited pulmonary
metastases are resectable.

Doxorubicin alone or with dacarbazine is one of the most frequently used chemotherapeutic regimens for
advanced sarcoma. [9] [10] [11] When used as single agents, only doxorubicin and ifosfamide show
response rates >20%; less active drugs include dacarbazine, cisplatin, methotrexate, and vinorelbine.
[12] Pegylated liposomal doxorubicin has shown similar activity to doxorubicin, with fewer toxic effects,
in a small study. [13][Level of evidence: 3iiiDiii] A randomized trial of 340 patients with advanced
sarcoma showed a higher response rate (32% vs. 17%, P<.002) and longer time-to-progression (6 vs. 4
months, P<.02) for doxorubicin, dacarbazine, ifosfamide, and mesna versus doxorubicin and
dacarbazine alone. [14][Level of evidence: 1iiDii] Sequential use of doxorubicin followed by ifosfamide
or other drugs with each subsequent recurrence is frequently preferred. Clinical trials of phase I and II
agents should be considered for subsequent recurrences. High-dose chemotherapy (with or without
transplantation) has not influenced disease-free or overall survival in published studies, but it remains
under clinical evaluation for patients with metastatic disease in first complete remission, after resection
of pulmonary metastases, or for inoperable large primaries. [15] [16] [17] Information about ongoing
clinical trials is available from the NCI Web site.
Nonrhabdomyosarcoma Soft Tissue Sarcomas

Last Updated: March 21, 2003

Synonyms and related keywords: NRSTS, tumor, fibrosarcomas, malignant peripheral nerve sheath
tumors, malignant fibrous histiocytomas, synovial sarcomas, alveolar soft part sarcomas, leiomyosarcomas,
liposarcomas
AUTHOR INFORMATION Section 1 of 10

Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up

Miscellaneous Bibliography
Author: Gary D Crouch, MD, Program Director of Pediatric Hematology-Oncology Fellowship, Associate
Professor, Department of Pediatrics, Uniformed Services University of the Health Sciences
Gary D Crouch, MD, is a member of the following medical societies: American Academy of Pediatrics, and
American Society of Hematology
Editor(s): Samuel Gross, MD, Professor Emeritus, Department of Pediatrics, University of Florida,
Clinical Professor, Department of Pediatrics, UNC, Adjunct Professor, Department of Pediatrics, Duke
University; Robert Konop, PharmD, Director of Drug Programs and Utilization; Steven K Bergstrom,
MD, Clinical Instructor, Department of Pediatrics, Division of Hematology-Oncology, Deaconess Medical
Center; Paul D Petry, DO, FACOP, Assistant Professor, Department of Pediatrics, Division of Maternal
Child Health, Northeast Regional Medical Center; and Robert J Arceci, MD, PhD, King Fahd Professor of
Pediatric Oncology, Director, Department of Oncology, Division of Pediatric Oncology, Johns Hopkins
University School of Medicine

Disclosure
INTRODUCTION Section 2 of 10

Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up

Miscellaneous Bibliography

Background: Soft tissue sarcomas, the fifth most common solid tumor in children, are relatively rare,
comprising about 6-7% of childhood malignancies. Rhabdomyosarcomas account for about half of these
tumors; nonrhabdomyosarcoma soft tissue sarcomas (NRSTS) account for the remainder (ie, about 3% of
childhood malignancies).

NRSTS are a heterogenous set of tumors, sharing some biologic characteristics but differing in histology. The
most common types are the synovial cell sarcomas, malignant fibrous histiocytomas, fibrosarcomas, and
malignant peripheral nerve sheath tumors. Other histologies include the hemangiopericytomas, alveolar soft
part sarcomas, leiomyosarcomas, liposarcomas, and desmoplastic small cell tumors. Because soft tissue
sarcomas are more common in adults, many of the treatment modalities are extrapolated from the adult
experience. In many cases, the pediatric counterparts have a different clinical behavior and outcome. Infants
and young children with these tumors tend to have a better prognosis than adolescents and adults with similar
diagnoses.

Pathophysiology: Soft tissues comprise a variety of structural and supportive tissues in the body, including
muscle, connective tissues, endothelium, synovium, fat, lymphatics, and fascia. Soft tissue sarcomas may arise
in any part of the body. The most common sites are the trunk and the extremities. Approximately 15-30% of
patients have metastatic disease at presentation. The most common metastatic site is the lung. Other common
sites for metastatic disease are skin, bone, liver, and lymph nodes. Spread to omentum/peritoneum and brain
has been described as well. A brief discussion of the more common NRSTS follows.

Fibrosarcoma

The most common of the NRSTS in children, fibrosarcoma has 2 peaks in incidence in children, which occur
in children younger than 5 years and in individuals aged 10-15 years. Congenital fibrosarcoma is usually
observed in children younger than 2 years, it occurs in the extremity 70% of the time, it rarely is metastatic,
and it is associated with trisomy 11 chromosomal abnormality. The adult form of fibrosarcoma usually occurs
in individuals aged 10-15 years, occurs most often in the extremity, has high metastatic potential (usually to
the lung), and is genetically associated with clonal chromosomal translocations.

Histologically, fibrosarcoma is a spindle-shaped tumor with a characteristic herringbone pattern. Aggressive

fibromatosis, nodular fasciitis, myositis ossificans, and inflammatory pseudotumor are included as the most
important differentials. Congenital fibrosarcoma is usually treated with surgery alone, with survival rates of
more than 90% in some series. The adult form of fibrosarcoma is treated with aggressive surgical resection
with consideration for chemotherapy in some patients. Overall, the survival rate is approximately 60%.

Malignant peripheral nerve sheath tumor

Accounting for approximately 5-10% of NRSTS in children, malignant peripheral nerve sheath tumors are
associated with neurofibromatosis type I, and they have a common chromosome abnormality in region 17q11.
These tumors occur most frequently on the extremity. They have a similar pathologic appearance to the
fibrosarcoma but are a more aggressive malignancy. Surgery and radiation therapy are major modalities for
treatment. Malignant peripheral nerve sheath tumors are considered chemoresponsive; however, the role of
chemotherapy in ultimate outcome of these patients is still under study.

Malignant fibrous histiocytoma

Rarely observed in young children, malignant fibrous histiocytoma is usually observed in patients older than
10 years and occurs primarily in the extremity. Cytogenetic analysis demonstrates chromosome 19p + and
ringed chromosomes. Malignant fibrous histiocytoma has very similar histology to fibrosarcoma except for the
loss of a herringbone cellular pattern and more malignant phenotype. These tumors are commonly observed in
radiation-induced sarcomas. The most common metastatic site is the lung. Surgical excision with irradiation to
residual local disease is the therapy of choice. Chemotherapy may be useful in select cases. Chemotherapy
regimens, including the agents vincristine, dactinomycin, and cyclophosphamide, with and without radiation
have been somewhat successful in select pediatric and adult patients. Activity has also been observed with
ifosfamide and etoposide combinations. The optimal use of chemotherapy in this tumor is yet to be
determined.

Synovial sarcoma

One of the most common NRSTS, synovial sarcoma is rarely observed in children younger than 10 years. One
third of cases occur in individuals younger than 20 years. With synovial sarcoma, the most common
chromosomal abnormality is t(x;18)(p11.2,q11.2) and the genes involved are SYT-SSX. The tumors are usually
in the extremity, with lower extremity lesions more common than upper extremity lesions. Pathologically, the
2 forms of tumor are a spindle cell fibrous form and a glandular form with epithelial differentiation. The most
common site for metastasis is the lung. Surgical resection followed by radiation of residual disease is the best
therapy.

Chemotherapy may have a role in unresectable and metastatic disease. Series have demonstrated efficacy with
the use of cisplatin, doxorubicin, and high-dose ifosfamide in combination with surgery and radiation therapy.
Advanced-stage disease has been treated with regimens including cytoxan and doxorubicin, as well as the
combination of vincristine, dactinomycin, and cyclophosphamide. Low-stage disease has a 70% survival rate.
Higher-stage disease has a poor prognosis.

Alveolar soft part sarcoma

This NRSTS is rare, usually arising in individuals aged 15-35 years. The primary site of occurrence in children
is the head and neck; orbit and tongue tumors are most common. Patients with alveolar soft part sarcoma
usually present with an indolent slow-growing mass. Short-term prognosis is good, with 80% of patients alive
at 2 years from diagnosis. However, the long-term survival rate is poor regardless of initial stage of disease. In
several cases, a chromosomal abnormality at 17q25 has been demonstrated. Pathologic classification of this
tumor is uncertain, but some evidence of myogenic differentiation has been made. Alveolar soft part sarcoma
often arises in skeletal muscle tissue. The most common site of metastasis is the lung, followed by the brain,
bone, and lymph nodes. The primary treatment modality is surgical, with radiation and chemotherapy reserved
for disease recurrence. Surgical resection is also indicated for select metastatic sites as well.

Leiomyosarcoma

A rare tumor in children, leiomyosarcoma occurs only about 2% of the time in NRSTS. Pathologically, these
tumors are derived from smooth muscle tissue. Leiomyosarcomas are associated with human
immunodeficiency virus (HIV) disease, Epstein-Barr virus (EBV) infection, and immunosuppressive states.
The most common site for these tumors is the GI tract, particularly the stomach. An important clinical
presentation to recognize is the occurrence of leiomyosarcoma with extrarenal or adrenal paraganglioma and
pulmonary chondroma (ie, Carney triad), which is most commonly found in young women. Surgical resection
has been the most common approach to treatment of this NRSTS. Generally, tumors in the GI tract have a poor
prognosis. Prognosis is good with complete resections of tumors outside the GI tract. The role of radiation
therapy and chemotherapy in leiomyosarcoma is still unknown.

Liposarcoma

Primarily a disease of adults, liposarcoma may occur in older children. This NRSTS rarely occurs in young
children and infants and usually is benign in this setting if completely removed. A consistent cytogenetic
abnormality in myxoid liposarcoma tumors is a t(12;16)(q13;p11) translocation; genes involved are FUS-
CHOP. The lower extremity and the trunk are the 2 most common sites of presentation. Liposarcoma rarely
metastasizes, and for this reason, the treatment of choice is wide local excision. The role of radiation and
chemotherapy in the setting of gross residual disease is being investigated.

Frequency:

In the US: NRSTS accounts for approximately 3% of childhood malignancies. The most frequent
NRSTS is fibrosarcoma, which accounts for 23.9% of cases. In individuals younger than 20 years,
approximately 500-600 cases of NRSTS are diagnosed yearly.

Mortality/Morbidity: The two most important prognostic factors in children with NRSTS are tumor
invasiveness and histologic grade. Except for malignant fibrous histiocytoma and fibrosarcoma, most NRSTS
in children are immature and poorly differentiated with a highly malignant histologic grade. Patients with low-
grade localized disease have survival rates of 90%, while those with high-grade, invasive, or metastatic disease
have survival rates of less than 15%.

Race: Blacks have a slightly higher incidence than whites (14 cases versus 10 cases per 1 million population).
Sex: Males have a slightly higher incidence than females (12 cases versus 10 cases per 1 million population).

Age: Incidence rates for NRSTS among young children are highest in infancy, affecting approximately 15 per
1 million infants. Incidence drops in the second year of life to a fairly stable rate until about age 10 years when
approximately 8-10 per 1 million children are affected. For individuals older than 10 years, the incidence rate
increases to about 15 cases per 1 million population annually.

CLINICAL Section 3 of 10

Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up

Miscellaneous Bibliography

History: Usually, patients with NRSTS present with painless asymptomatic masses. These tumors may come
to attention secondary to an episode of trauma in the area. Mass effect from the tumor may cause specific signs
or symptoms depending on mass location. For instance, invasion of local neurovascular bundles in the
extremity may lead to pain, swelling, numbness, or loss of function. Large chest wall masses may cause
pulmonary dysfunction. If advanced metastatic disease is present, systemic symptoms with fever, sweats, and
weight loss may be observed. Hemangiopericytomas have been associated with hypoglycemia and
hypophosphatemic rickets. Hyperglycemia has been observed with fibrosarcoma of the lung.

Physical: Physical examination findings of patients with NRSTS depend on the location of the mass. A
palpable mass is noted in most cases. Specific tumors may be associated with specific findings. Malignant
peripheral nerve sheath tumors may be associated with neurofibromatosis type I, which is characterized by
caf au lait spots, axillary freckling, neurofibromas, skeletal dysplasias, learning disabilities, and a variety of
neoplasms. CNS tumors may cause an abnormal neurologic examination finding depending on the location of
the mass and what structures are affected.

Causes: Genetic conditions (eg, Li-Fraumeni syndrome associated with P53 mutations, neurofibromatosis
type I) are the only known risk factors for developing NRSTS. Factors with an implied, but not proven,
association with the development of sarcomas are low socioeconomic status, in utero exposure to ionizing
radiation, and parental use of recreational drugs.

Other Problems to be Considered:

Diagnosis can be confirmed only with biopsy of the mass. Other malignancies that cause masses in children
must be considered in the evaluation, such as lymphomas, osteosarcoma, Ewing sarcoma, rhabdomyosarcoma,
and neuroblastoma. Benign lesions, such as lipoma or rhabdomyoma should be considered as well.