Sarcoma, soft tissue, childhood: Treatment - Health Professional Information [NCI PDQ]

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Childhood Soft Tissue Sarcoma Treatment (PDQ®)

Purpose of This PDQ Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of childhood soft tissue sarcoma. This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board.

Information about the following is included in this summary:

  • Incidence and risk factors.
  • Cellular and histopathologic classification.
  • Stage information.
  • Treatment options.

This summary is intended as a resource to inform and assist clinicians and other health professionals who care for pediatric cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

In the summary, treatments are described as “standard” or “conventional” and “under clinical evaluation.” These designations should not be used as a basis for reimbursement determinations.

This summary is also available in a patient version, which is written in less-technical language, and in Spanish.

General Information

The National Cancer Institute provides the PDQ pediatric cancer treatment information summaries as a public service to increase the availability of evidence-based cancer information to health professionals, patients, and the public.

Cancer in children and adolescents is rare. Children and adolescents with cancer should be referred to medical centers that have a multidisciplinary team of cancer specialists with experience treating the cancers that occur during childhood and adolescence. This multidisciplinary team approach incorporates the skills of the primary care physician, pediatric surgical subspecialists, radiation oncologist, pediatric hematologist/oncologist, rehabilitation specialist, pediatric nurse specialists, social workers, and others to ensure that children receive treatment, supportive care, and rehabilitation that will achieve optimal survival and quality of life. Refer to the PDQ Supportive Care summaries for specific information about supportive care for children and adolescents with cancer.

Guidelines for pediatric cancer centers and their role in the treatment of pediatric patients with cancer have been outlined by the American Academy of Pediatrics.[1] At these pediatric cancer centers, clinical trials are available for most types of cancer that occur in children and adolescents, and the opportunity to participate in these trials is offered to most patients/families. Clinical trials for children and adolescents with cancer are generally designed to compare potentially better therapy with therapy that is currently accepted as standard. Most of the progress made in identifying curative therapies for childhood cancers has been achieved through clinical trials. Information about ongoing clinical trials is available from the NCI Web site.

In recent decades, dramatic improvements in survival have been achieved for children and adolescents with cancer. Childhood and adolescent cancer survivors require close follow-up because cancer therapy side effects may persist or develop months or years after treatment. Refer to the PDQ Late Effects of Treatment for Childhood Cancer for specific information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors.

Pediatric soft tissue sarcomas are a group of malignant tumors that originate from primitive mesenchymal tissue and account for 7% of all childhood tumors.[2] Rhabdomyosarcomas, tumors of striated muscle, and undifferentiated sarcomas account for more than one half of all cases of soft tissue sarcomas in children. (Refer to the PDQ summary on Childhood Rhabdomyosarcoma Treatment for more information.) The remaining nonrhabdomyosarcomatous soft tissue sarcomas (NRSTS) account for approximately 3% of all childhood tumors.[3] This heterogeneous group of tumors includes neoplasms of smooth muscle (leiomyosarcoma), connective tissue (fibrous and adipose), vascular tissue (blood and lymphatic vessels), and the peripheral nervous system.[4] Synovial sarcomas, fibrosarcomas, and malignant peripheral nerve sheath tumors predominate in pediatric patients.[5,6,7,8,9]

NRSTS are more common in adults [4] than in children; therefore, much of the information regarding the treatment and natural history of children with these lesions has been on the basis of findings from adult studies. Pediatric NRSTSs, however, are often associated with a better outcome. This difference is most pronounced for infants and children younger than 4 years with fibrosarcoma, whose tumors are locally aggressive but not metastatic. These patients have an excellent prognosis when chemosensitive and treated with surgery only.[3,4,10,11] Soft tissue sarcomas in older children and adolescents often behave similarly to those in adult patients.[3,4]

Although they can develop in any part of the body, NRSTSs arise most commonly in the trunk and extremities.[5,6,12] These neoplasms can present initially as an asymptomatic solid mass, or they may be symptomatic because of local invasion of adjacent anatomical structures. Systemic symptoms (e.g., fever, weight loss, and night sweats) are rare. Hypoglycemia and hypophosphatemic rickets have been reported in cases of hemangiopericytoma, whereas hyperglycemia has been noted in patients with fibrosarcoma of the lung.[4]

Genetic and environmental factors influence the development of NRSTS. Heritable cancer-associated changes of the p53 tumor suppressor gene can occur in families with Li-Fraumeni syndrome.[13] Members of these families have an increased risk of developing soft tissue tumors, bone sarcomas, breast cancer, brain tumors, and acute leukemia.[3] Approximately 4% of patients with neurofibromatosis type 1 develop malignant peripheral nerve sheath tumors, which usually develop after a long latency; some patients develop multiple lesions.[4,14,15] Some NRSTSs (particularly malignant fibrous histiocytoma) can develop within a previously irradiated site; others (e.g., leiomyosarcoma) have been linked to Epstein-Barr virus infection in patients with AIDS.[3,4,16]

Synovial sarcomas are the most common NRSTS reported in children. The most common location is the lower extremity followed by upper extremity, trunk, abdomen, and head and neck. Approximately 30% of patients with synovial sarcoma are younger than 20 years. The most common site of metastasis is the lung.[17] Factors such as International Union Against Cancer/American Joint Committee on Cancer stage III/stage IVA, tumor necrosis, truncal locations, elevated mitotic rate, age, and histologic grade have been associated with a worse prognosis in adults.[18,19,20]

(Refer to the PDQ summary on Childhood Rhabdomyosarcoma Treatment for more information. Refer to the PDQ summary on Ewings Family of Tumors Treatment for more information on extraosseous Ewing, peripheral neuroepithelioma, and Askin tumor.)

The prognosis and biology of NRSTS tumors vary greatly depending on the age of the patient, the primary site, tumor size, tumor invasiveness, histologic grade, depth of invasion, and extent of disease at diagnosis. Because long-term related morbidity must be minimized while disease-free survival is maximized, the ideal therapy for each patient must be carefully and individually determined utilizing these prognostic factors before initiating therapy for these patients.[6,10,17,21,22,23]

References:

  1. Guidelines for the pediatric cancer center and role of such centers in diagnosis and treatment. American Academy of Pediatrics Section Statement Section on Hematology/Oncology. Pediatrics 99 (1): 139-41, 1997.
  2. Pappo AS, Pratt CB: Soft tissue sarcomas in children. Cancer Treat Res 91: 205-22, 1997.
  3. Miser JS, Triche TJ, Kinsella TJ, et al.: Other soft tissue sarcomas of childhood. In: Pizzo PA, Poplack DG, eds.: Principles and Practice of Pediatric Oncology. 3rd ed. Philadelphia, Pa: Lippincott-Raven, 1997, pp 865-888.
  4. Weiss SW, Goldblum JR: Enzinger and Weiss's Soft Tissue Tumors. 4th ed. St. Louis, Mo: Mosby, 2001.
  5. Dillon P, Maurer H, Jenkins J, et al.: A prospective study of nonrhabdomyosarcoma soft tissue sarcomas in the pediatric age group. J Pediatr Surg 27 (2): 241-4; discussion 244-5, 1992.
  6. Rao BN: Nonrhabdomyosarcoma in children: prognostic factors influencing survival. Semin Surg Oncol 9 (6): 524-31, 1993 Nov-Dec.
  7. Fletcher CD, Dal Cin P, de Wever I, et al.: Correlation between clinicopathological features and karyotype in spindle cell sarcomas. A report of 130 cases from the CHAMP study group. Am J Pathol 154 (6): 1841-7, 1999.
  8. Skytting BT, Bauer HC, Perfekt R, et al.: Clinical course in synovial sarcoma: a Scandinavian sarcoma group study of 104 patients. Acta Orthop Scand 70 (6): 536-42, 1999.
  9. Herzog CE: Overview of sarcomas in the adolescent and young adult population. J Pediatr Hematol Oncol 27 (4): 215-8, 2005.
  10. Dillon PW, Whalen TV, Azizkhan RG, et al.: Neonatal soft tissue sarcomas: the influence of pathology on treatment and survival. Children's Cancer Group Surgical Committee. J Pediatr Surg 30 (7): 1038-41, 1995.
  11. Neville H, Corpron C, Blakely ML, et al.: Pediatric neurofibrosarcoma. J Pediatr Surg 38 (3): 343-6; discussion 343-6, 2003.
  12. Zeytoonjian T, Mankin HJ, Gebhardt MC, et al.: Distal lower extremity sarcomas: frequency of occurrence and patient survival rate. Foot Ankle Int 25 (5): 325-30, 2004.
  13. Chang F, Syrjänen S, Syrjänen K: Implications of the p53 tumor-suppressor gene in clinical oncology. J Clin Oncol 13 (4): 1009-22, 1995.
  14. deCou JM, Rao BN, Parham DM, et al.: Malignant peripheral nerve sheath tumors: the St. Jude Children's Research Hospital experience. Ann Surg Oncol 2 (6): 524-9, 1995.
  15. Stark AM, Buhl R, Hugo HH, et al.: Malignant peripheral nerve sheath tumours--report of 8 cases and review of the literature. Acta Neurochir (Wien) 143 (4): 357-63; discussion 363-4, 2001.
  16. McClain KL, Leach CT, Jenson HB, et al.: Association of Epstein-Barr virus with leiomyosarcomas in children with AIDS. N Engl J Med 332 (1): 12-8, 1995.
  17. Pappo AS, Fontanesi J, Luo X, et al.: Synovial sarcoma in children and adolescents: the St Jude Children's Research Hospital experience. J Clin Oncol 12 (11): 2360-6, 1994.
  18. Trassard M, Le Doussal V, Hacène K, et al.: Prognostic factors in localized primary synovial sarcoma: a multicenter study of 128 adult patients. J Clin Oncol 19 (2): 525-34, 2001.
  19. Guillou L, Benhattar J, Bonichon F, et al.: Histologic grade, but not SYT-SSX fusion type, is an important prognostic factor in patients with synovial sarcoma: a multicenter, retrospective analysis. J Clin Oncol 22 (20): 4040-50, 2004.
  20. Ferrari A, Gronchi A, Casanova M, et al.: Synovial sarcoma: a retrospective analysis of 271 patients of all ages treated at a single institution. Cancer 101 (3): 627-34, 2004.
  21. Marcus KC, Grier HE, Shamberger RC, et al.: Childhood soft tissue sarcoma: a 20-year experience. J Pediatr 131 (4): 603-7, 1997.
  22. Pratt CB, Pappo AS, Gieser P, et al.: Role of adjuvant chemotherapy in the treatment of surgically resected pediatric nonrhabdomyosarcomatous soft tissue sarcomas: A Pediatric Oncology Group Study. J Clin Oncol 17 (4): 1219, 1999.
  23. Pratt CB, Maurer HM, Gieser P, et al.: Treatment of unresectable or metastatic pediatric soft tissue sarcomas with surgery, irradiation, and chemotherapy: a Pediatric Oncology Group study. Med Pediatr Oncol 30 (4): 201-9, 1998.

Cellular and Histopathologic Classification

Nonrhabdomyosarcomatous soft tissue tumors are fairly readily distinguished from rhabdomyosarcoma or Ewing family of tumors; however, classification of childhood nonrhabdomyosarcomatous soft tissue sarcoma (NRSTS) type is often difficult. Obtaining adequate tumor tissue is crucial to allow for conventional histology, immunocytochemical analysis, and other studies such as light and electron microscopy, cytogenetics, fluorescence in situ hybridization, and molecular pathology.[1,2] For this reason, open biopsy (or multiple core-needle biopsies) is strongly encouraged so that adequate tumor tissue can be obtained to allow for all of these crucial studies to be performed.

Chromosomal Abnormalities

Many NRSTSs are characterized by chromosomal abnormalities. Some of these chromosomal translocations lead to a fusion of two disparate genes. The resulting fusion transcript can be readily detected by using polymerase chain reaction-based techniques, thus facilitating the diagnosis of those neoplasms that have translocations. Some of the most frequent aberrations seen in nonrhabdomyosarcomatous soft tissue tumors are listed in Table 1.

Table 1. Frequent Aberrations Seen In Nonrhabdomyosarcomatous Soft Tissue Tumors*

* Adapted from Sandberg[3]

HistologyChromosomal Aberrations Genes Involved
Alveolar soft part sarcomat(x;17)(p11.2;q25)ASPL/TFE3 [4,5]
Clear cell sarcoma (malignant melanoma of soft parts)t(12;22)(q13;q12)ATF1/EWS
Dermatofibrosarcoma t(17;22)(q22;q13)COL1A1/PDGFB
Desmoplastic small round cell tumorst(11;22)(p13;q12)WT1/EWS [6]
Extraskeletal myxoid chondrosarcomat(9;22)(q22;q12)EWS-CHN
Hemangiopericytomat(12;19)(q13;q13.3) and t(13;22)(q22;q13.3)
Infantile fibrosarcomat(12;15);+11; also +8,+17,+20ETVG(TEL)/NTRK3
Leiomyosarcomat(12;14)
Low-grade fibromyxoid sarcomat(7;16)(q33;p11)FUS/BBF2H7
Malignant fibrous histiocytoma 19p+, ring chromosome
Myxoid liposarcoma t(12;16)(q13;p11)FUS/CHOP
Neurofibrosarcoma Deletion 17q11.2
Synovial sarcomat(x;18)(p11.2;q11.2) SYT/SSX

Histologic Classification

Pediatric soft tissue sarcomas are classified histologically according to the soft tissue cell they resemble and include the following:[1]

Tumors of fibrous tissue

  • Fibromatoses (desmoid tumors).
  • Adult and infantile fibrosarcoma.
  • Dermatofibrosarcoma.

Fibrohistiocytic tumors

  • Malignant fibrous histiocytoma (MFH) (also called undifferentiated pleomorphic sarcoma, or spindle cell sarcoma).

Tumors of adipose tissue

  • Liposarcoma.

Tumors of smooth muscle

  • Leiomyosarcoma.

Tumors of blood and lymph vessels

  • Angiosarcoma.
  • Lymphangiosarcoma.
  • Hemangiopericytoma.
  • Hemangioendothelioma.

Tumors of peripheral nervous system

  • Malignant schwannoma (malignant peripheral nerve sheath tumor [MPNST]).

Tumors of bone and cartilage

  • Extraosseous osteosarcoma.
  • Extraosseous myxoid chondrosarcoma.
  • Extraosseous mesenchymal chondrosarcoma.

Tumors of more than one tissue type

  • Malignant mesenchymoma.
  • Malignant Triton tumor.
  • Malignant ectomesenchymoma.[7]

Tumors of unknown histogenesis

  • Alveolar soft part sarcoma (ASPS).
  • Epithelioid sarcoma.
  • Clear cell sarcoma (malignant melanoma of soft parts [MMSP]).
  • Synovial sarcoma.
  • Desmoplastic small round cell tumor.[6]

Selected Soft Tissue Sarcomas in Children

Alveolar soft part sarcoma

This is a tumor of uncertain histogenesis. A consistent chromosomal translocation t(X;17)(p11.2;q25) juxtaposes the ASP gene with the TFE3 gene.[4] ASPS almost never has an objective response to chemotherapy.[8] In children, ASPS often presents with metastases,[9] and sometimes has a very indolent course. There are single case reports of objective responses to interferon-alpha and to bevacizumab.[10,11].

Angiosarcoma

A review of 20 years of experience in the Italian and German Soft Tissue Sarcoma Cooperative Group identified 12 children with angiosarcoma.[12] Only one objective response to chemotherapy was observed, and the overall behavior of this tumor was identical to angiosarcoma in adults.

Dermatofibrosarcoma

Dermatofibrosarcoma is a rare tumor, but many of the reported cases arise in children.[13] The tumor has a consistent chromosomal translocation t(17;22)(q22;q13) that juxtaposes the COL1A1 gene with the PDGF-beta gene. Most tumors are cured by surgical resection. When surgical resection cannot be accomplished or the tumor is recurrent, treatment with imatinib has been effective.[14]

Desmoid tumors

Desmoid tumors are low-grade malignancies with very low potential to metastasize. The tumors are locally infiltrating, and surgical control can be difficult because of the need to preserve normal structures. These tumors also have a high potential for local recurrence. Desmoid tumors have a highly variable natural history, including well documented examples of spontaneous regression.[15] Repeated surgical resection can sometimes bring recurrent lesions under control.[16]

Leiomyosarcoma

A retrospective analysis of the Italian cooperative group identified one child with leiomyosarcoma over a 24-year period.[17] A retrospective analysis of the St. Jude Children’s Research Hospital experience from 1962 to 1996 identified 40 children with NRSTS; none had leiomyosarcoma.[18] Among 43 children with HIV/AIDS who developed tumors, eight developed Epstein-Barr virus–associated leiomyosarcoma.[19]

Liposarcoma

A retrospective analysis of the Italian cooperative group identified two children with liposarcoma over a 24-year period.[17] The tumors did not respond to chemotherapy. Outcomes were the same as those observed in adults with liposarcoma.[20]

Malignant fibrous histiocytoma

At one time, MFH was the single most common histiotype among adults with soft tissue sarcomas. Since it was first recognized in the early 1960s, however, MFH has been plagued by controversy in terms of both its histogenesis and its validity as a clinicopathologic entity. The latest World Health Organization classification includes MFH no longer as a distinct diagnostic category but rather as a subtype of an undifferentiated pleomorphic sarcoma.[21]

Malignant peripheral nerve sheath tumor

MPNST arises in children with type 1 neurofibromatosis (NF1), and it arises sporadically.[22] Features with favorable prognosis have been reported to include absence of NF1, less invasiveness, lower stage, and an extremity as the primary site.[22,23] Chemotherapy has achieved objective responses in childhood MPNST. The role of adjuvant chemotherapy following resection of MPNST has not been prospectively evaluated. A retrospective survey of cancer centers in Japan identified 56 patients with MPNST, mostly adults, but including children and adolescents.[24] This survey identified large tumor size, metastasis at presentation, and high histologic grade as unfavorable prognostic features. In this report, documentation of NF1 did not confer an inferior prognosis.

Synovial sarcoma

Synovial sarcoma is considered to be more chemotherapy responsive than many other soft tissue sarcomas. There is ample documentation of objective responses of synovial sarcoma to systemic chemotherapy.[17,25,26,27] The value of adjuvant chemotherapy following resection of localized disease has not been conclusively supported in prospective trials, but most pediatric oncologists favor adjuvant chemotherapy for all but the smallest, completely resected tumors.[26,28,29,30]

Diagnosis of synovial sarcoma is made by immunohistochemical analysis, ultrastructural findings, and demonstration of the specific chromosomal translocation t(x;18)(p11.2;q11.2). This abnormality is specific for synovial sarcoma and is found in all morphologic subtypes. Synovial sarcoma results in rearrangement of the SYT gene on chromosome 18 with one of the subtypes (1, 2, or 4) of the SSX gene on chromosome X.[31] Synovial sarcoma can be subclassified as monophasic fibrous type, biphasic type with distinct epithelial and spindle cell components, or poorly differentiated. Poorly differentiated synovial sarcoma has features of monophasic or biphasic synovial sarcoma but also a variable proportion of poorly differentiated areas characterized by high cellularity, pleomorphism, and polygonal or small round-cell morphology, numerous mitoses, and often necrosis.[32]

Undifferentiated soft tissue sarcoma

Patients with undifferentiated sarcoma have been eligible for participation in rhabdomyosarcoma trials coordinated by the Intergroup Rhabdomyosarcoma Study Group and the Children’s Oncology Group. The rationale for this inclusion was the observation that patients with undifferentiated sarcoma have similar sites of disease and outcome to those with alveolar rhabdomyosarcoma. In therapeutic trials for adults with soft tissue sarcoma, patients with undifferentiated sarcoma are included with all other histologies and treated in a similar manner. Contemporary treatment for adult soft tissue sarcoma utilizes ifosfamide and doxorubicin, sometimes with the addition of other chemotherapy agents, surgery, and radiation therapy. No data are available to compare these two approaches. (Refer to the PDQ summary on Childhood Rhabdomyosarcoma Treatment for more information.)

Soft Tissue Sarcoma Tumor Grading System

In most cases, accurate histopathologic classification of soft tissue sarcomas alone does not yield optimal information about their clinical behavior. Therefore, several histologic parameters including degree of cellularity, cellular pleomorphism, mitotic activity, degree of necrosis, and invasive growth are evaluated in the grading process. This process is used to improve the correlation between histologic findings and clinical outcome.[33] In children, grading of soft tissue sarcomas is compromised by the good prognosis of certain tumors such as infantile fibrosarcoma. In addition, testing of a grading system within the pediatric population is difficult because of the rarity of these neoplasms. In March 1986, the Pediatric Oncology Group conducted a prospective study on pediatric soft tissue sarcomas other than rhabdomyosarcoma and devised the grading system that is shown below. Analysis of outcome for patients with localized soft tissue sarcomas other than rhabdomyosarcoma demonstrated that patients with grade 3 tumors fared significantly worse than did those with grade 1 or grade 2 lesions. This finding suggests that this system can accurately predict the clinical behavior of nonrhabdomyosarcomatous soft tissue tumors in children.[2,33,34]

Grade 1 lesions

  • Myxoid and well-differentiated liposarcoma.
  • Deep-seated dermatofibrosarcoma protuberans.
  • Well-differentiated or infantile (patient 4 years or younger) fibrosarcoma.
  • Well-differentiated or infantile (patient 4 years or younger) hemangiopericytoma.
  • Well-differentiated malignant peripheral nerve sheath tumor.
  • Extraosseus myxoid chondrosarcoma.
  • Angiomatoid malignant fibrous histiocytoma.

Grade 2 lesions

In grade 2 lesions, which are soft tissue sarcomas not included in grade 1 and grade 3 lesions, less than 15% of the surface area shows necrosis, and there are fewer than five mitotic figures per ten high-power fields (40X objective). As secondary criteria of grade 2 tumors, the incidence of nuclear atypia is not marked, and the tumor is not markedly cellular.

Grade 3 lesions

  • Pleomorphic or round cell liposarcoma.
  • Mesenchymal chondrosarcoma.
  • Extraosseous osteosarcoma.
  • Triton tumor (MPNST with rhabdomyosarcomatous elements).
  • Alveolar soft part sarcoma.
  • Synovial sarcoma.
  • Epithelioid sarcoma.
  • Clear cell sarcoma (MMSP).

Any other sarcoma not included in grade 1 in which more than 15% of the surface area is necrotic or in which there are more than five mitotic figures per ten high-power fields (40X objective) is considered a grade 3 lesion. Marked atypia and cellularity are less predictive but may assist in placing tumors in this category.

References:

  1. Weiss SW, Goldblum JR: Enzinger and Weiss's Soft Tissue Tumors. 4th ed. St. Louis, Mo: Mosby, 2001.
  2. Recommendations for the reporting of soft tissue sarcomas. Association of Directors of Anatomic and Surgical Pathology. Mod Pathol 11 (12): 1257-61, 1998.
  3. Sandberg AA: Translocations in malignant tumors. Am J Pathol 159 (6): 1979-80, 2001.
  4. Ladanyi M, Lui MY, Antonescu CR, et al.: The der(17)t(X;17)(p11;q25) of human alveolar soft part sarcoma fuses the TFE3 transcription factor gene to ASPL, a novel gene at 17q25. Oncogene 20 (1): 48-57, 2001.
  5. Ladanyi M: The emerging molecular genetics of sarcoma translocations. Diagn Mol Pathol 4 (3): 162-73, 1995.
  6. Barnoud R, Sabourin JC, Pasquier D, et al.: Immunohistochemical expression of WT1 by desmoplastic small round cell tumor: a comparative study with other small round cell tumors. Am J Surg Pathol 24 (6): 830-6, 2000.
  7. Oppenheimer O, Athanasian E, Meyers P, et al.: Malignant ectomesenchymoma in the wrist of a child: case report and review of the literature. Int J Surg Pathol 13 (1): 113-6, 2005.
  8. Reichardt P, Lindner T, Pink D, et al.: Chemotherapy in alveolar soft part sarcomas. What do we know? Eur J Cancer 39 (11): 1511-6, 2003.
  9. Kayton ML, Meyers P, Wexler LH, et al.: Clinical presentation, treatment, and outcome of alveolar soft part sarcoma in children, adolescents, and young adults. J Pediatr Surg 41 (1): 187-93, 2006.
  10. Roozendaal KJ, de Valk B, ten Velden JJ, et al.: Alveolar soft-part sarcoma responding to interferon alpha-2b. Br J Cancer 89 (2): 243-5, 2003.
  11. Azizi AA, Haberler C, Czech T, et al.: Vascular-endothelial-growth-factor (VEGF) expression and possible response to angiogenesis inhibitor bevacizumab in metastatic alveolar soft part sarcoma. Lancet Oncol 7 (6): 521-3, 2006.
  12. Ferrari A, Casanova M, Bisogno G, et al.: Malignant vascular tumors in children and adolescents: a report from the Italian and German Soft Tissue Sarcoma Cooperative Group. Med Pediatr Oncol 39 (2): 109-14, 2002.
  13. Buckley PG, Mantripragada KK, Benetkiewicz M, et al.: A full-coverage, high-resolution human chromosome 22 genomic microarray for clinical and research applications. Hum Mol Genet 11 (25): 3221-9, 2002.
  14. Price VE, Fletcher JA, Zielenska M, et al.: Imatinib mesylate: an attractive alternative in young children with large, surgically challenging dermatofibrosarcoma protuberans. Pediatr Blood Cancer 44 (5): 511-5, 2005.
  15. Lewis JJ, Boland PJ, Leung DH, et al.: The enigma of desmoid tumors. Ann Surg 229 (6): 866-72; discussion 872-3, 1999.
  16. Faulkner LB, Hajdu SI, Kher U, et al.: Pediatric desmoid tumor: retrospective analysis of 63 cases. J Clin Oncol 13 (11): 2813-8, 1995.
  17. Cecchetto G, Alaggio R, Dall'Igna P, et al.: Localized unresectable non-rhabdo soft tissue sarcomas of the extremities in pediatric age: results from the Italian studies. Cancer 104 (9): 2006-12, 2005.
  18. Spunt SL, Hill DA, Motosue AM, et al.: Clinical features and outcome of initially unresected nonmetastatic pediatric nonrhabdomyosarcoma soft tissue sarcoma. J Clin Oncol 20 (15): 3225-35, 2002.
  19. Pollock BH, Jenson HB, Leach CT, et al.: Risk factors for pediatric human immunodeficiency virus-related malignancy. JAMA 289 (18): 2393-9, 2003.
  20. Lietman SA, Barsoum WK, Goldblum JR, et al.: A 20-year retrospective review of surgically treated liposarcoma at the Cleveland Clinic. Orthopedics 30 (3): 227-34, 2007.
  21. Randall RL, Albritton KH, Ferney BJ, et al.: Malignant fibrous histiocytoma of soft tissue: an abandoned diagnosis. Am J Orthop 33 (12): 602-8, 2004.
  22. Carli M, Ferrari A, Mattke A, et al.: Pediatric malignant peripheral nerve sheath tumor: the Italian and German soft tissue sarcoma cooperative group. J Clin Oncol 23 (33): 8422-30, 2005.
  23. Hagel C, Zils U, Peiper M, et al.: Histopathology and clinical outcome of NF1-associated vs. sporadic malignant peripheral nerve sheath tumors. J Neurooncol 82 (2): 187-92, 2007.
  24. Okada K, Hasegawa T, Tajino T, et al.: Clinical relevance of pathological grades of malignant peripheral nerve sheath tumor: a multi-institution TMTS study of 56 cases in Northern Japan. Ann Surg Oncol 14 (2): 597-604, 2007.
  25. Pappo AS, Devidas M, Jenkins J, et al.: Phase II trial of neoadjuvant vincristine, ifosfamide, and doxorubicin with granulocyte colony-stimulating factor support in children and adolescents with advanced-stage nonrhabdomyosarcomatous soft tissue sarcomas: a Pediatric Oncology Group Study. J Clin Oncol 23 (18): 4031-8, 2005.
  26. Okcu MF, Despa S, Choroszy M, et al.: Synovial sarcoma in children and adolescents: thirty three years of experience with multimodal therapy. Med Pediatr Oncol 37 (2): 90-6, 2001.
  27. Pappo AS, Rao BN, Jenkins JJ, et al.: Metastatic nonrhabdomyosarcomatous soft-tissue sarcomas in children and adolescents: the St. Jude Children's Research Hospital experience. Med Pediatr Oncol 33 (2): 76-82, 1999.
  28. Brecht IB, Ferrari A, Int-Veen C, et al.: Grossly-resected synovial sarcoma treated by the German and Italian Pediatric Soft Tissue Sarcoma Cooperative Groups: discussion on the role of adjuvant therapies. Pediatr Blood Cancer 46 (1): 11-7, 2006.
  29. Raney RB: Synovial sarcoma in young people: background, prognostic factors, and therapeutic questions. J Pediatr Hematol Oncol 27 (4): 207-11, 2005.
  30. Okcu MF, Munsell M, Treuner J, et al.: Synovial sarcoma of childhood and adolescence: a multicenter, multivariate analysis of outcome. J Clin Oncol 21 (8): 1602-11, 2003.
  31. van de Rijn M, Barr FG, Collins MH, et al.: Absence of SYT-SSX fusion products in soft tissue tumors other than synovial sarcoma. Am J Clin Pathol 112 (1): 43-9, 1999.
  32. van de Rijn M, Barr FG, Xiong QB, et al.: Poorly differentiated synovial sarcoma: an analysis of clinical, pathologic, and molecular genetic features. Am J Surg Pathol 23 (1): 106-12, 1999.
  33. Parham DM, Webber BL, Jenkins JJ 3rd, et al.: Nonrhabdomyosarcomatous soft tissue sarcomas of childhood: formulation of a simplified system for grading. Mod Pathol 8 (7): 705-10, 1995.
  34. Skytting B, Meis-Kindblom JM, Larsson O, et al.: Synovial sarcoma--identification of favorable and unfavorable histologic types: a Scandinavian sarcoma group study of 104 cases. Acta Orthop Scand 70 (6): 543-54, 1999.

Stage Information

Clinical staging has an important role in predicting the clinical outcome and determining the most effective therapy for pediatric soft tissue sarcomas. As yet, there is no well-accepted staging system that is applicable to all childhood sarcomas; the system from the American Joint Commission for Cancer that is used for adults has not been validated in pediatric studies.[1] Two systems are currently in use for staging pediatric nonrhabdomyosarcomatous soft tissue tumors. The surgicopathologic staging system used by the Intergroup Rhabdomyosarcoma Study (see below) is based on the amount of tumor that remains after initial surgery and whether the disease has metastasized.[2]

Nonmetastatic Disease

  • GROUP I: Tumor completely resected with histologically negative margins.
  • GROUP II: Grossly resected tumor with microscopic residual tumor.
  • GROUP III: Incomplete resection or biopsy with gross residual tumor.

Metastatic Disease

  • GROUP IV: Any localized or regional tumor with distant metastases present at the time of diagnosis.

Recurrent/Progressive Disease

  • Any soft tissue sarcoma that recurs after initial treatment or progresses after radiation therapy, chemotherapy, or initial surgery.

The other schema typically used to stage pediatric soft tissue tumors is the TNM system of the International Union Against Cancer.[3] In this staging system, T1 lesions are those that are confined to the organ of origin, and T2 lesions invade adjacent organs. These categories can be subclassified to reflect the maximum tumor diameter (a: =5 cm; b: >5 cm). Nodal involvement is indicated by N1 (N0: no nodal involvement), and the presence of distant metastases at the time of diagnosis is indicated by the M1 (vs. M0) designation. Several adult and pediatric series have shown that patients with large or invasive tumors have a significantly worse prognosis than do those with small, noninvasive tumors.

These two staging systems have proven to be of prognostic significance in pediatric and adult nonrhabdomyosarcomatous soft tissue sarcomas.[4,5,6,7,8] In a review of a large adult series of nonrhabdomyosarcomas, superficial extremity sarcomas have a better prognosis than deep tumors. Thus, in addition to grade and size, the depth of invasion of the tumor should be considered.[9]

References:

  1. Weiss SW, Goldblum JR: Enzinger and Weiss's Soft Tissue Tumors. 4th ed. St. Louis, Mo: Mosby, 2001.
  2. Maurer HM, Beltangady M, Gehan EA, et al.: The Intergroup Rhabdomyosarcoma Study-I. A final report. Cancer 61 (2): 209-20, 1988.
  3. Harmer MH, ed.: TNM Classification of Pediatric Tumors. Geneva: UICC, 1982.
  4. Rao BN: Nonrhabdomyosarcoma in children: prognostic factors influencing survival. Semin Surg Oncol 9 (6): 524-31, 1993 Nov-Dec.
  5. Pisters PW, Leung DH, Woodruff J, et al.: Analysis of prognostic factors in 1,041 patients with localized soft tissue sarcomas of the extremities. J Clin Oncol 14 (5): 1679-89, 1996.
  6. Coindre JM, Terrier P, Bui NB, et al.: Prognostic factors in adult patients with locally controlled soft tissue sarcoma. A study of 546 patients from the French Federation of Cancer Centers Sarcoma Group. J Clin Oncol 14 (3): 869-77, 1996.
  7. Pappo AS, Fontanesi J, Luo X, et al.: Synovial sarcoma in children and adolescents: the St Jude Children's Research Hospital experience. J Clin Oncol 12 (11): 2360-6, 1994.
  8. Pratt CB, Maurer HM, Gieser P, et al.: Treatment of unresectable or metastatic pediatric soft tissue sarcomas with surgery, irradiation, and chemotherapy: a Pediatric Oncology Group study. Med Pediatr Oncol 30 (4): 201-9, 1998.
  9. Brooks AD, Heslin MJ, Leung DH, et al.: Superficial extremity soft tissue sarcoma: an analysis of prognostic factors. Ann Surg Oncol 5 (1): 41-7, 1998 Jan-Feb.

Treatment Option Overview

Because of the rarity of pediatric nonrhabdomyosarcomatous soft tissue sarcomas (NRSTS), all children, adolescents, and young adults with these tumors should have their treatment planned by a multidisciplinary team composed of pediatric oncologists, surgeons, and radiotherapists. To better define the natural history and response to therapy of the tumors, children with rare neoplasms should be considered for entry into national or institutional treatment protocols.

Every attempt should be made to resect the primary tumor with negative margins before or after chemotherapy. The timing of surgery depends on an assessment of the feasibility and morbidity of surgery. Involvement of a surgeon with special expertise in the resection of soft tissue sarcomas in the decision is highly desirable. Sentinel lymph node mapping is employed at some centers to identify the regional nodes that are the most likely to be involved, though its contribution has not been clearly defined.[1,2] If the original operation failed to achieve pathologically negative tissue margins, a second procedure should be performed to obtain clear, but not necessarily wide margins.[3,4,5,6,7] When the initial operation was done without the knowledge that cancer was present, a re-excision of the affected region should always be considered, even in the absence of a mass on magnetic resonance imaging.[8] When there is concern about the adequacy of the surgical margin, radiation therapy is indicated.[9] This is particularly important in high-grade tumors with tumor margins less than 1 cm.[10,11] Thus, by using these two treatment modalities, local control of the primary tumor can be achieved in more than 80% of patients.[12,13] Although combined surgery and radiation therapy have dramatically improved outcome in adults and children with soft tissue sarcomas over the past 20 years,[9] the morbidity of high-dose radiation therapy is of concern in infants and young children with these tumors.[14] Brachytherapy and intraoperative radiation may be applicable in select situations.[13,15,16] Preoperative radiation therapy has been associated with excellent local control rates [17,18,19] but has been associated with an increased rate of wound complications in adults.[20] Patients in the pediatric age group with unresected NRSTS have a poor outcome. Only about one-third of patients treated with multimodality therapy remain disease free.[20,21]

Therapeutic strategies for children and adolescents with soft tissue tumors are similar to those for adult patients, though there are important differences. For example, the biology of the pediatric form of the neoplasm may differ dramatically from that of the adult lesion. Limb-sparing procedures are more difficult to perform in pediatric patients. In addition, the morbidity of radiation therapy in young children may be much greater than that observed in adults. Lastly, the concern regarding potential long-term side effects of combined modality therapy (radiation, surgery, and chemotherapy) is greater for children, whose survival may be much longer than that of adults. Therefore, to maximize tumor control and minimize long-term morbidity, treatment must be individualized for children and adolescents with nonrhabdomyosarcomatous soft tissue tumors. These patients should be enrolled in prospective studies that accurately assess any potential complications.[22]

The role of adjuvant (postoperative) chemotherapy remains controversial. A meta-analysis of updated data from adult soft tissue sarcoma patients from all available randomized trials concluded that recurrence-free survival was better with adjuvant chemotherapy.[23] The largest prospective pediatric trial failed to demonstrate any benefit with adjuvant vincristine, dactinomycin, cyclophosphamide, and doxorubicin.[12] Synovial sarcoma appears to be more sensitive to chemotherapy than many other soft tissue sarcomas, and children with synovial sarcoma seem to have a better prognosis.[24,25,26,27,28] A German trial suggested a benefit for adjuvant chemotherapy in children with synovial sarcoma.[29] A meta-analysis also suggested that chemotherapy may provide benefit.[30] Many treatment centers advocate adjuvant chemotherapy following resection of synovial sarcoma in children and young adults; unequivocal proof of the value of this strategy from prospective, randomized clinical trials is lacking.

References:

  1. Neville HL, Andrassy RJ, Lally KP, et al.: Lymphatic mapping with sentinel node biopsy in pediatric patients. J Pediatr Surg 35 (6): 961-4, 2000.
  2. Neville HL, Raney RB, Andrassy RJ, et al.: Multidisciplinary management of pediatric soft-tissue sarcoma. Oncology (Huntingt) 14 (10): 1471-81; discussion 1482-6, 1489-90, 2000.
  3. Okcu MF, Despa S, Choroszy M, et al.: Synovial sarcoma in children and adolescents: thirty three years of experience with multimodal therapy. Med Pediatr Oncol 37 (2): 90-6, 2001.
  4. Sugiura H, Takahashi M, Katagiri H, et al.: Additional wide resection of malignant soft tissue tumors. Clin Orthop (394): 201-10, 2002.
  5. Cecchetto G, Guglielmi M, Inserra A, et al.: Primary re-excision: the Italian experience in patients with localized soft-tissue sarcomas. Pediatr Surg Int 17 (7): 532-4, 2001.
  6. Chui CH, Spunt SL, Liu T, et al.: Is reexcision in pediatric nonrhabdomyosarcoma soft tissue sarcoma necessary after an initial unplanned resection? J Pediatr Surg 37 (10): 1424-9, 2002.
  7. Paulino AC, Ritchie J, Wen BC: The value of postoperative radiotherapy in childhood nonrhabdomyosarcoma soft tissue sarcoma. Pediatr Blood Cancer 43 (5): 587-93, 2004.
  8. Kaste SC, Hill A, Conley L, et al.: Magnetic resonance imaging after incomplete resection of soft tissue sarcoma. Clin Orthop (397): 204-11, 2002.
  9. Marcus KC, Grier HE, Shamberger RC, et al.: Childhood soft tissue sarcoma: a 20-year experience. J Pediatr 131 (4): 603-7, 1997.
  10. Blakely ML, Spurbeck WW, Pappo AS, et al.: The impact of margin of resection on outcome in pediatric nonrhabdomyosarcoma soft tissue sarcoma. J Pediatr Surg 34 (5): 672-5, 1999.
  11. Skytting B: Synovial sarcoma. A Scandinavian Sarcoma Group project. Acta Orthop Scand Suppl 291: 1-28, 2000.
  12. Pratt CB, Pappo AS, Gieser P, et al.: Role of adjuvant chemotherapy in the treatment of surgically resected pediatric nonrhabdomyosarcomatous soft tissue sarcomas: A Pediatric Oncology Group Study. J Clin Oncol 17 (4): 1219, 1999.
  13. Merchant TE, Parsh N, del Valle PL, et al.: Brachytherapy for pediatric soft-tissue sarcoma. Int J Radiat Oncol Biol Phys 46 (2): 427-32, 2000.
  14. Suit H, Spiro I: Radiation as a therapeutic modality in sarcomas of the soft tissue. Hematol Oncol Clin North Am 9 (4): 733-46, 1995.
  15. Schomberg PJ, Gunderson LL, Moir CR, et al.: Intraoperative electron irradiation in the management of pediatric malignancies. Cancer 79 (11): 2251-6, 1997.
  16. Nag S, Shasha D, Janjan N, et al.: The American Brachytherapy Society recommendations for brachytherapy of soft tissue sarcomas. Int J Radiat Oncol Biol Phys 49 (4): 1033-43, 2001.
  17. Sadoski C, Suit HD, Rosenberg A, et al.: Preoperative radiation, surgical margins, and local control of extremity sarcomas of soft tissues. J Surg Oncol 52 (4): 223-30, 1993.
  18. Virkus WW, Mollabashy A, Reith JD, et al.: Preoperative radiotherapy in the treatment of soft tissue sarcomas. Clin Orthop (397): 177-89, 2002.
  19. Zagars GK, Ballo MT, Pisters PW, et al.: Preoperative vs. postoperative radiation therapy for soft tissue sarcoma: a retrospective comparative evaluation of disease outcome. Int J Radiat Oncol Biol Phys 56 (2): 482-8, 2003.
  20. O'Sullivan B, Davis AM, Turcotte R, et al.: Preoperative versus postoperative radiotherapy in soft-tissue sarcoma of the limbs: a randomised trial. Lancet 359 (9325): 2235-41, 2002.
  21. Spunt SL, Hill DA, Motosue AM, et al.: Clinical features and outcome of initially unresected nonmetastatic pediatric nonrhabdomyosarcoma soft tissue sarcoma. J Clin Oncol 20 (15): 3225-35, 2002.
  22. Miser JS, Triche TJ, Kinsella TJ, et al.: Other soft tissue sarcomas of childhood. In: Pizzo PA, Poplack DG, eds.: Principles and Practice of Pediatric Oncology. 3rd ed. Philadelphia, Pa: Lippincott-Raven, 1997, pp 865-888.
  23. Adjuvant chemotherapy for localised resectable soft-tissue sarcoma of adults: meta-analysis of individual data. Sarcoma Meta-analysis Collaboration. Lancet 350 (9092): 1647-54, 1997.
  24. McGrory JE, Pritchard DJ, Arndt CA, et al.: Nonrhabdomyosarcoma soft tissue sarcomas in children. The Mayo Clinic experience. Clin Orthop (374): 247-58, 2000.
  25. Ferrari A, Gronchi A, Casanova M, et al.: Synovial sarcoma: a retrospective analysis of 271 patients of all ages treated at a single institution. Cancer 101 (3): 627-34, 2004.
  26. Van Glabbeke M, van Oosterom AT, Oosterhuis JW, et al.: Prognostic factors for the outcome of chemotherapy in advanced soft tissue sarcoma: an analysis of 2,185 patients treated with anthracycline-containing first-line regimens--a European Organization for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group Study. J Clin Oncol 17 (1): 150-7, 1999.
  27. Koscielniak E, Harms D, Henze G, et al.: Results of treatment for soft tissue sarcoma in childhood and adolescence: a final report of the German Cooperative Soft Tissue Sarcoma Study CWS-86. J Clin Oncol 17 (12): 3706-19, 1999.
  28. Pappo AS, Devidas M, Jenkins J, et al.: Phase II trial of neoadjuvant vincristine, ifosfamide, and doxorubicin with granulocyte colony-stimulating factor support in children and adolescents with advanced-stage nonrhabdomyosarcomatous soft tissue sarcomas: a Pediatric Oncology Group Study. J Clin Oncol 23 (18): 4031-8, 2005.