Cellular and Histopathologic Classification

Chromosomal Abnormalities
Histologic Classification
        Tumors of fibrous tissue
        Fibrohistiocytic tumors
        Tumors of adipose tissue
        Tumors of smooth muscle
        Tumors of peripheral nervous system
        Tumors of bone and cartilage
        Tumors of more than one tissue type
        Tumors of unknown histogenesis
        Tumors of vascular structures
Selected Soft Tissue Sarcomas in Children
        Alveolar soft part sarcoma
        Clear cell sarcoma
        Dermatofibrosarcoma
        Desmoid tumors
        Desmoplastic small round cell tumor
        Epithelioid sarcoma
        Inflammatory myofibroblastic tumor
        Leiomyosarcoma
        Liposarcoma
        Malignant fibrous histiocytoma
        Malignant peripheral nerve sheath tumor
        Mesenchymal chondrosarcoma
        Perivascular epithelioid cell neoplasms (PEComas)
        Plexiform histiocytic tumor
        Synovial sarcoma
        Undifferentiated soft tissue sarcoma
        Vascular tumors
Biopsy Technique for Soft Tissue Sarcoma

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 NRSTS^a

Histology	Chromosomal Aberrations	Genes Involved
Alveolar soft part sarcoma	t(x;17)(p11.2;q25)	ASPL/TFE3 [4-6]
Angiomatoid fibrous histiocytoma	t(12;16)(q13;p11), t(2;22)(q33;q12)	FUS/ATF1, EWSR1/CREB1 [7]
Clear cell sarcoma	t(12;22)(q13;q12)	ATF1/EWS
Congenital (infantile) fibrosarcoma/mesoblastic nephroma	t(12;15)(p13,q25) [4]	ETV-NTRK3 [4]
Dermatofibrosarcoma	t(17;22)(q22;q13)	COL1A1/PDGFB
Desmoplastic small round cell tumors	t(11;22)(p13;q12)	WT1/EWS [8]
Extraskeletal myxoid chondrosarcoma	t(9;22)(q22;q12)	EWS-CHN
Hemangiopericytoma	t(12;19)(q13;q13.3) and t(13;22)(q22;q13.3)
Inflammatory myofibroblastic tumor	t(1;2)(q23;q23), t(2;19)(q23;q13), t(2;17)(q23;q23), t(2;2)(p23;q13)[9]	TPM3/ALK, TPM4/ALK, CLTC/ALK, RANBP2/ALK
Leiomyosarcoma	t(12;14)
Low-grade fibromyxoid sarcoma	t(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
Rhabdoid tumor	t(1;22)(p36:q11.2) [4]	SNFS/INI1 [4]
Synovial sarcoma	t(x;18)(p11.2;q11.2)	SYT/SSX

NRSTS = nonrhabdomyosarcomatous soft tissue sarcoma.

aAdapted from Sandberg [3] and Slater et al.[4]

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 ²).
• Adult and infantile fibrosarcoma.
• Dermatofibrosarcoma ³.

Fibrohistiocytic tumors

• Malignant fibrous histiocytoma (MFH) ⁴ (also called undifferentiated pleomorphic sarcoma, or spindle cell sarcoma).

Tumors of adipose tissue

• Liposarcoma ⁵.

Tumors of smooth muscle

• Leiomyosarcoma ⁶.

Tumors of peripheral nervous system

• Malignant schwannoma (malignant peripheral nerve sheath tumor [MPNST]) ⁷.

Tumors of bone and cartilage

• Extraosseous osteosarcoma.
• Extraosseous myxoid chondrosarcoma.
• Mesenchymal chondrosarcoma ⁸.[10]

Tumors of more than one tissue type

• Malignant mesenchymoma.
• Malignant Triton tumor.[11]
• Malignant ectomesenchymoma.[12]

Tumors of unknown histogenesis

• Alveolar soft part sarcoma (ASPS) ⁹.
• Clear cell sarcoma ¹⁰ (malignant melanoma of soft parts [MMSP]).
• Desmoplastic small round cell tumor ¹¹.[8]
• Epithelioid sarcoma.
• Synovial sarcoma ¹².
• Undifferentiated soft tissue sarcoma ¹³.[13]

Tumors of vascular structures

• Angiosarcoma ¹⁴.
• Hemangioendothelioma ¹⁵.
• Hemangiopericytoma.
• Lymphangiosarcoma.

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 ASPSCR1 gene with the TFE3 gene.[5,14] ASPS is considered a chemoresistant tumor.[15] In children, ASPS often presents with metastases,[16] and sometimes has a very indolent course. Pediatric ASPS seems to have a better outcome than its adult counterpart.[17] In a series of 19 treated patients, one group reported a 5-year overall survival (OS) rate of 80%, a 91% OS rate for patients with localized disease, a 100% OS rate for patients with tumors 5 cm or smaller, and a 31% OS rate for patients with tumors larger than 5 cm.[18] In another series of 33 patients, OS was 68% at 5 years and 53% at 10 years from diagnosis. Survival was better for smaller tumors (≤5 cm) and completely resected tumors.[19][Level of evidence: 3iiA] A subset of renal tumors found in young people was previously considered to be renal cell carcinoma, but the subset now appears to be genetically related to ASPS.[20] There are sporadic reports of objective responses to interferon-alpha, bevacizumab, and sunitinib.[21-23]

Clear cell sarcoma

Clear cell sarcoma (malignant melanoma of soft parts), also called clear cell sarcoma of tendons and aponeuroses, is somewhat similar to cutaneous malignant melanoma, but is cytogenetically distinct; most cases have a t(12;22)(q13;q12) translocation that has not been reported in melanoma.[24] Patients who have small, localized tumors with low mitotic rate, and intermediate histologic grade fare best.[25]

Dermatofibrosarcoma

Dermatofibrosarcoma is a rare tumor, but many of the reported cases arise in children.[26] 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.[27]

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.[28] Mutations in exon 3 of the beta-catenin gene are seen in over 80% of desmoid tumors and the mutation 45F has been associated with an increased risk of disease recurrence.[29] Repeated surgical resection can sometimes bring recurrent lesions under control.[30]

Desmoplastic small round cell tumor

Desmoplastic small round cell tumor is a primitive sarcoma that most frequently involves the abdomen, pelvis, or tissues around the testes.[31-33] The tumor occurs mainly in males and invades locally but may spread to the lungs and elsewhere. Cytogenetic studies of these tumors have demonstrated the recurrent translocation t(11;22)(p13;q12), which has been characterized as a fusion of the WT1 and EWS genes.[34]

Epithelioid sarcoma

Epithelioid sarcoma is a rare mesenchymal tumor of uncertain histogenesis which displays multilineage differentiation.[35] It is characterized by inactivation of the SMARC/INI1 gene which is present in both conventional and proximal types of epithelioid sarcoma.[36] There are also alterations in rhabdoid tumors, but the mechanisms of inactivation seem to be distinctive. This tumor commonly presents as a slow growing firm nodule based in the deep soft tissue; the proximal type predominantly affects adults and involves the axial skeleton and proximal sites. The tumor is highly aggressive and has a propensity for lymph node metastases. The proximal type has a more aggressive clinical behavior. In a review of 30 pediatric patients with epithelioid sarcoma, the median age at presentation was 12 years, responses to chemotherapy were reported in 40% of patients using sarcoma-based regimens, and 60% of patients were alive at 5 years following initial diagnosis.[37]

Inflammatory myofibroblastic tumor

Inflammatory myofibroblastic tumor (IMT) is an incompletely characterized neoplasm of intermediate biologic potential. It recurs frequently but metastasizes rarely.[38] Roughly half of IMTs exhibit a clonal mutation that activates the anaplastic lymphoma kinase (ALK)-receptor tyrosine kinase gene at chromosome 2p23.[39] There are no well-documented responses to chemotherapy. A case report described a partial response in a patient with recurrent IMT who was treated with crizotinib, an ATP-competitive inhibitor of the ALK and MET tyrosine kinases.[40] There are case reports of response to either steroids or nonsteroidal anti-inflammatory drugs.

Leiomyosarcoma

A 24-year retrospective analysis of the Italian cooperative group identified one child with leiomyosarcoma.[41] A retrospective analysis of the St. Jude Children’s Research Hospital experience from 1962 to 1996 identified 40 children with NRSTS; none had leiomyosarcoma.[42] Among 43 children with HIV/AIDS who developed tumors, eight developed Epstein-Barr virus–associated leiomyosarcoma.[43] Survivors of hereditary retinoblastoma have a statistically significant increased risk of developing leiomyosarcoma and 78% of these were diagnosed 30 years and older after the initial diagnosis of retinoblastoma.[44]

Liposarcoma

Liposarcoma is rare in the pediatric population. Liposarcomas can be roughly divided into the following four large groups:

• Atypical lipomatous neoplasm/well-differentiated liposarcoma. These tumors do not metastasize unless they undergo dedifferentiation.
• Myxoid liposarcoma. Pure myxoid liposarcomas are characterized by a t(12;16)(q13;p11) translocation and can metastasize but usually have an excellent outcome in the absence of a round cell component.
• Dedifferentiated liposarcoma.
• Pleomorphic liposarcoma.

In a review of 182 pediatric patients with adult-type sarcomas, only 14 had a diagnosis of liposarcoma.[45] In another review, the characteristics of 82 cases of pediatric liposarcoma were reported. The median age was 15.5 years and females were more commonly affected. Myxoid liposarcoma was the predominant histologic subtype, and 94% of these patients were alive following surgical resection. In contrast, seven of ten patients with pleomorphic myxoid liposarcoma in this series died of their disease.[46]

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 no longer includes MFH as a distinct diagnostic category but rather as a subtype of an undifferentiated pleomorphic sarcoma.[47] (Refer to the Osteosarcoma and Malignant Fibrous Histiocytoma of Bone ¹⁶ summary for information on MFH of bone.)

Malignant peripheral nerve sheath tumor

MPNST arises in children with type 1 neurofibromatosis (NF1), and it arises sporadically.[48] Features with favorable prognosis have been reported to include localized disease, absence of NF1, smaller tumor size, lower stage, and an extremity as the primary site.[48-50] 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.[51] 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. A retrospective review of 140 patients with MPNST from the MD Anderson Cancer Center included children and adolescents. The disease-specific survival at 10 years was 32%. In this series, presence of metastatic disease was associated with a much worse prognosis. For patients with localized disease, there was no significant difference in outcome between patients with and without NF1. In a multivariate analysis, only tumor size and nuclear p53 expression were found to be independent predictors of disease-specific survival.[50]

Mesenchymal chondrosarcoma

Mesenchymal chondrosarcoma is a highly malignant tumor with a propensity to spread to the lungs. A review of 15 patients aged younger than 26 years from the German Cooperative Soft Tissue Sarcoma (11 with soft-tissue lesions) and German-Austrian-Swiss Cooperative Osteosarcoma Study Group (four with primary bone lesions) protocols suggests that complete surgical removal, or incomplete resection followed by radiation therapy, is necessary for local control.[10][Level of evidence: 3iiA] Multiagent chemotherapy may decrease the likelihood of lung metastases: OS at 10 years was 67%, compared with approximately 20% in an earlier series of young patients.[52]

Perivascular epithelioid cell neoplasms (PEComas)

PEComas include angiomyolipoma, lymphangioleiomyomatosis, and clear cell "sugar" tumor. Benign PEComas are common in tuberous sclerosis, an autosomal dominant syndrome that also predisposes to renal cell cancer and brain tumors. Tuberous sclerosis is caused by germline inactivation of either TSC1 (9q34) or TSC2 (16p13.3), and the same tumor suppressor genes are inactivated somatically in sporadic PEComas.[53] Inactivation of either gene results in stimulation of the mTOR pathway, providing the basis for the treatment of non-surgically curable PEComas with mTOR inhibitors.[54,55]

PEComas occur in various rare gastrointestinal, pulmonary, gynecologic, and genitourinary sites. Soft tissue, visceral, and gynecologic PEComas are more commonly seen in middle-aged female patients and are usually not associated with the tuberous sclerosis complex.[56] Most PEComas have a benign clinical course, but malignant behavior has been reported and can be predicted based on the size of the tumor, mitotic rate, and presence of necrosis.[57]

Plexiform histiocytic tumor

Plexiform histiocytic tumor is a low to intermediate grade tumor. It most commonly arises in the skin or subcutaneous tissue of children and young adults.[58-60] Treatment is limited to surgical resection. There are rare reports of spread to regional lymph nodes or the lung. The majority of patients are cured by surgery, but local recurrence has been reported in 10% to 40% of cases.

Synovial sarcoma

Synovial sarcoma is considered to be more chemotherapy responsive than many other soft tissue sarcomas. There is ample documentation of objective response of synovial sarcoma to systemic chemotherapy.[41,61-63] 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.[62,64-66]

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.[67,68] 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.[69]

Undifferentiated soft tissue sarcoma

Patients with undifferentiated sarcoma were eligible for participation in rhabdomyosarcoma (RMS) trials coordinated by the Intergroup Rhabdomyosarcoma Study Group and the Children’s Oncology Group (COG) from 1972 to 2006. The rationale was the observation that patients with undifferentiated sarcoma had similar sites of disease and outcome compared with those with alveolar RMS. Therapeutic trials for adults with soft tissue sarcoma include patients with undifferentiated sarcoma and other histologies, which are treated similarly, utilizing ifosfamide and doxorubicin, sometimes with other chemotherapy agents, surgery, and radiation therapy. The COG is studying the use of a combination of surgery and/or radiation therapy, with or without ifosfamide and doxorubicin, for patients with undifferentiated sarcoma of soft tissue in its open protocol COG-ARST0332 ¹⁷ for patients with non-rhabdomyosarcoma soft tissue sarcoma (NRSTS).

Vascular tumors

Angiosarcoma: A review of 20 years of experience in the Italian and German Soft Tissue Sarcoma Cooperative Group identified 12 children with angiosarcoma.[70] Only one objective response to chemotherapy was observed, and the overall behavior of this tumor was identical to angiosarcoma in adults. A subsequent retrospective study performed by the Polish and German Cooperative Paediatric Soft Tissue Sarcoma Study Groups identified four chemotherapy responses in ten children treated (total 14 children with angiosarcoma).[71] Another review of 15 patients demonstrated a 33% survival rate.[72] A review of 222 patients (median age, 62 years; range, age 15–90 years) showed an overall disease-specific survival (DSS) rate of 38% at 5 years. Five-year DSS was 44% in 138 patients with localized, resected tumors but only 16% in 43 patients with metastases at diagnosis.[73] Anti-angiogenesis therapy may prove useful in the treatment of this group of neoplasms.[74]

Hemangioendothelioma: Hemangioendotheliomas are tumors found in infants that arise within the liver or elsewhere and usually remain benign.[75] The tumors are sometimes associated with consumptive coagulopathy, also known as the Kasabach-Merritt syndrome (or phenomenon).[76-78] In older children and adults, hemangioendotheliomas may occur elsewhere in the body and can metastasize to lungs, lymph nodes, bones, and within the pleural or peritoneal cavities. The preferred pathologic designation for these lesions in older persons is epithelioid hemangioendothelioma, which connotes the possibility of distant spread. These latter lesions are considered of intermediate malignant potential, between benign hemangioma and angiosarcoma.[79,80]

Biopsy Technique for Soft Tissue Sarcoma

When a suspicious lesion is identified it is crucial that a complete workup followed by adequate biopsy be performed. Generally, it is better to image the lesion prior to any interventions. A core-needle biopsy or limited open biopsy that obtains an adequate amount of tissue for histopathology, immunohistochemistry, and molecular genetics is mandatory, given the diagnostic importance of translocations. Needle biopsy techniques must obtain an adequate tissue sample and usually require obtaining multiple cores of tissue. Image guidance using ultrasound, computed tomography scan, or magnetic resonance imaging may be necessary to ensure a representative biopsy.[81] Incisional biopsies are acceptable but should not compromise subsequent wide local excision, and extensive dissection around the lesion must be avoided. Transverse extremity incisions should be avoided to reduce skin loss, as should extensive surgical procedures prior to definitive diagnosis.

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.  [PUBMED Abstract]
   
   
3. Sandberg AA: Translocations in malignant tumors. Am J Pathol 159 (6): 1979-80, 2001.  [PUBMED Abstract]
   
   
4. Slater O, Shipley J: Clinical relevance of molecular genetics to paediatric sarcomas. J Clin Pathol 60 (11): 1187-94, 2007.  [PUBMED Abstract]
   
   
5. 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.  [PUBMED Abstract]
   
   
6. Ladanyi M: The emerging molecular genetics of sarcoma translocations. Diagn Mol Pathol 4 (3): 162-73, 1995.  [PUBMED Abstract]
   
   
7. Antonescu CR, Dal Cin P, Nafa K, et al.: EWSR1-CREB1 is the predominant gene fusion in angiomatoid fibrous histiocytoma. Genes Chromosomes Cancer 46 (12): 1051-60, 2007.  [PUBMED Abstract]
   
   
8. 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.  [PUBMED Abstract]
   
   
9. Jain S, Xu R, Prieto VG, et al.: Molecular classification of soft tissue sarcomas and its clinical applications. Int J Clin Exp Pathol 3 (4): 416-28, 2010.  [PUBMED Abstract]
   
   
10. Dantonello TM, Int-Veen C, Leuschner I, et al.: Mesenchymal chondrosarcoma of soft tissues and bone in children, adolescents, and young adults: experiences of the CWS and COSS study groups. Cancer 112 (11): 2424-31, 2008.  [PUBMED Abstract]
    
    
11. Rekhi B, Jambhekar NA, Puri A, et al.: Clinicomorphologic features of a series of 10 cases of malignant triton tumors diagnosed over 10 years at a tertiary cancer hospital in Mumbai, India. Ann Diagn Pathol 12 (2): 90-7, 2008.  [PUBMED Abstract]
    
    
12. 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.  [PUBMED Abstract]
    
    
13. Alaggio R, Collini P, Randall RL, et al.: Undifferentiated high-grade pleomorphic sarcomas in children: a clinicopathologic study of 10 cases and review of literature. Pediatr Dev Pathol 13 (3): 209-17, 2010 May-Jun.  [PUBMED Abstract]
    
    
14. Williams A, Bartle G, Sumathi VP, et al.: Detection of ASPL/TFE3 fusion transcripts and the TFE3 antigen in formalin-fixed, paraffin-embedded tissue in a series of 18 cases of alveolar soft part sarcoma: useful diagnostic tools in cases with unusual histological features. Virchows Arch 458 (3): 291-300, 2011.  [PUBMED Abstract]
    
    
15. 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.  [PUBMED Abstract]
    
    
16. 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.  [PUBMED Abstract]
    
    
17. Fanburg-Smith JC, Miettinen M, Folpe AL, et al.: Lingual alveolar soft part sarcoma; 14 cases: novel clinical and morphological observations. Histopathology 45 (5): 526-37, 2004.  [PUBMED Abstract]
    
    
18. Casanova M, Ferrari A, Bisogno G, et al.: Alveolar soft part sarcoma in children and adolescents: A report from the Soft-Tissue Sarcoma Italian Cooperative Group. Ann Oncol 11 (11): 1445-9, 2000.  [PUBMED Abstract]
    
    
19. Pennacchioli E, Fiore M, Collini P, et al.: Alveolar soft part sarcoma: clinical presentation, treatment, and outcome in a series of 33 patients at a single institution. Ann Surg Oncol 17 (12): 3229-33, 2010.  [PUBMED Abstract]
    
    
20. Argani P, Antonescu CR, Illei PB, et al.: Primary renal neoplasms with the ASPL-TFE3 gene fusion of alveolar soft part sarcoma: a distinctive tumor entity previously included among renal cell carcinomas of children and adolescents. Am J Pathol 159 (1): 179-92, 2001.  [PUBMED Abstract]
    
    
21. 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.  [PUBMED Abstract]
    
    
22. 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.  [PUBMED Abstract]
    
    
23. Stacchiotti S, Tamborini E, Marrari A, et al.: Response to sunitinib malate in advanced alveolar soft part sarcoma. Clin Cancer Res 15 (3): 1096-104, 2009.  [PUBMED Abstract]
    
    
24. Speleman F, Delattre O, Peter M, et al.: Malignant melanoma of the soft parts (clear-cell sarcoma): confirmation of EWS and ATF-1 gene fusion caused by a t(12;22) translocation. Mod Pathol 10 (5): 496-9, 1997.  [PUBMED Abstract]
    
    
25. Coindre JM, Hostein I, Terrier P, et al.: Diagnosis of clear cell sarcoma by real-time reverse transcriptase-polymerase chain reaction analysis of paraffin embedded tissues: clinicopathologic and molecular analysis of 44 patients from the French sarcoma group. Cancer 107 (5): 1055-64, 2006.  [PUBMED Abstract]
    
    
26. 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.  [PUBMED Abstract]
    
    
27. 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.  [PUBMED Abstract]
    
    
28. Lewis JJ, Boland PJ, Leung DH, et al.: The enigma of desmoid tumors. Ann Surg 229 (6): 866-72; discussion 872-3, 1999.  [PUBMED Abstract]
    
    
29. Lazar AJ, Tuvin D, Hajibashi S, et al.: Specific mutations in the beta-catenin gene (CTNNB1) correlate with local recurrence in sporadic desmoid tumors. Am J Pathol 173 (5): 1518-27, 2008.  [PUBMED Abstract]
    
    
30. Faulkner LB, Hajdu SI, Kher U, et al.: Pediatric desmoid tumor: retrospective analysis of 63 cases. J Clin Oncol 13 (11): 2813-8, 1995.  [PUBMED Abstract]
    
    
31. Leuschner I, Radig K, Harms D: Desmoplastic small round cell tumor. Semin Diagn Pathol 13 (3): 204-12, 1996.  [PUBMED Abstract]
    
    
32. Kushner BH, LaQuaglia MP, Wollner N, et al.: Desmoplastic small round-cell tumor: prolonged progression-free survival with aggressive multimodality therapy. J Clin Oncol 14 (5): 1526-31, 1996.  [PUBMED Abstract]
    
    
33. Saab R, Khoury JD, Krasin M, et al.: Desmoplastic small round cell tumor in childhood: the St. Jude Children's Research Hospital experience. Pediatr Blood Cancer 49 (3): 274-9, 2007.  [PUBMED Abstract]
    
    
34. Gerald WL, Ladanyi M, de Alava E, et al.: Clinical, pathologic, and molecular spectrum of tumors associated with t(11;22)(p13;q12): desmoplastic small round-cell tumor and its variants. J Clin Oncol 16 (9): 3028-36, 1998.  [PUBMED Abstract]
    
    
35. Chbani L, Guillou L, Terrier P, et al.: Epithelioid sarcoma: a clinicopathologic and immunohistochemical analysis of 106 cases from the French sarcoma group. Am J Clin Pathol 131 (2): 222-7, 2009.  [PUBMED Abstract]
    
    
36. Hornick JL, Dal Cin P, Fletcher CD: Loss of INI1 expression is characteristic of both conventional and proximal-type epithelioid sarcoma. Am J Surg Pathol 33 (4): 542-50, 2009.  [PUBMED Abstract]
    
    
37. Casanova M, Ferrari A, Collini P, et al.: Epithelioid sarcoma in children and adolescents: a report from the Italian Soft Tissue Sarcoma Committee. Cancer 106 (3): 708-17, 2006.  [PUBMED Abstract]
    
    
38. Kovach SJ, Fischer AC, Katzman PJ, et al.: Inflammatory myofibroblastic tumors. J Surg Oncol 94 (5): 385-91, 2006.  [PUBMED Abstract]
    
    
39. Coffin CM, Hornick JL, Fletcher CD: Inflammatory myofibroblastic tumor: comparison of clinicopathologic, histologic, and immunohistochemical features including ALK expression in atypical and aggressive cases. Am J Surg Pathol 31 (4): 509-20, 2007.  [PUBMED Abstract]
    
    
40. Butrynski JE, D'Adamo DR, Hornick JL, et al.: Crizotinib in ALK-rearranged inflammatory myofibroblastic tumor. N Engl J Med 363 (18): 1727-33, 2010.  [PUBMED Abstract]
    
    
41. 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.  [PUBMED Abstract]
    
    
42. 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.  [PUBMED Abstract]
    
    
43. Pollock BH, Jenson HB, Leach CT, et al.: Risk factors for pediatric human immunodeficiency virus-related malignancy. JAMA 289 (18): 2393-9, 2003.  [PUBMED Abstract]
    
    
44. Kleinerman RA, Tucker MA, Abramson DH, et al.: Risk of soft tissue sarcomas by individual subtype in survivors of hereditary retinoblastoma. J Natl Cancer Inst 99 (1): 24-31, 2007.  [PUBMED Abstract]
    
    
45. Ferrari A, Casanova M, Collini P, et al.: Adult-type soft tissue sarcomas in pediatric-age patients: experience at the Istituto Nazionale Tumori in Milan. J Clin Oncol 23 (18): 4021-30, 2005.  [PUBMED Abstract]
    
    
46. Alaggio R, Coffin CM, Weiss SW, et al.: Liposarcomas in young patients: a study of 82 cases occurring in patients younger than 22 years of age. Am J Surg Pathol 33 (5): 645-58, 2009.  [PUBMED Abstract]
    
    
47. 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.  [PUBMED Abstract]
    
    
48. 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.  [PUBMED Abstract]
    
    
49. 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.  [PUBMED Abstract]
    
    
50. Zou C, Smith KD, Liu J, et al.: Clinical, pathological, and molecular variables predictive of malignant peripheral nerve sheath tumor outcome. Ann Surg 249 (6): 1014-22, 2009.  [PUBMED Abstract]
    
    
51. 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.  [PUBMED Abstract]
    
    
52. Dabska M, Huvos AG: Mesenchymal chondrosarcoma in the young. Virchows Arch A Pathol Anat Histopathol 399 (1): 89-104, 1983.  [PUBMED Abstract]
    
    
53. Martignoni G, Pea M, Reghellin D, et al.: Molecular pathology of lymphangioleiomyomatosis and other perivascular epithelioid cell tumors. Arch Pathol Lab Med 134 (1): 33-40, 2010.  [PUBMED Abstract]
    
    
54. Bissler JJ, McCormack FX, Young LR, et al.: Sirolimus for angiomyolipoma in tuberous sclerosis complex or lymphangioleiomyomatosis. N Engl J Med 358 (2): 140-51, 2008.  [PUBMED Abstract]
    
    
55. Davies DM, Johnson SR, Tattersfield AE, et al.: Sirolimus therapy in tuberous sclerosis or sporadic lymphangioleiomyomatosis. N Engl J Med 358 (2): 200-3, 2008.  [PUBMED Abstract]
    
    
56. Folpe A, Inwards C, eds.: Bone and Soft Tissue Pathology: A Volume in the Foundations in Diagnostic Pathology. Philadelphia, Pa: WB Saunders Co, 2010. 
    
    
57. Armah HB, Parwani AV: Perivascular epithelioid cell tumor. Arch Pathol Lab Med 133 (4): 648-54, 2009.  [PUBMED Abstract]
    
    
58. Moosavi C, Jha P, Fanburg-Smith JC: An update on plexiform fibrohistiocytic tumor and addition of 66 new cases from the Armed Forces Institute of Pathology, in honor of Franz M. Enzinger, MD. Ann Diagn Pathol 11 (5): 313-9, 2007.  [PUBMED Abstract]
    
    
59. Billings SD, Folpe AL: Cutaneous and subcutaneous fibrohistiocytic tumors of intermediate malignancy: an update. Am J Dermatopathol 26 (2): 141-55, 2004.  [PUBMED Abstract]
    
    
60. Remstein ED, Arndt CA, Nascimento AG: Plexiform fibrohistiocytic tumor: clinicopathologic analysis of 22 cases. Am J Surg Pathol 23 (6): 662-70, 1999.  [PUBMED Abstract]
    
    
61. 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.  [PUBMED Abstract]
    
    
62. 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.  [PUBMED Abstract]
    
    
63. 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.  [PUBMED Abstract]
    
    
64. 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.  [PUBMED Abstract]
    
    
65. Raney RB: Synovial sarcoma in young people: background, prognostic factors, and therapeutic questions. J Pediatr Hematol Oncol 27 (4): 207-11, 2005.  [PUBMED Abstract]
    
    
66. 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.  [PUBMED Abstract]
    
    
67. 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.  [PUBMED Abstract]
    
    
68. Krsková L, Sumerauer D, Stejskalová E, et al.: A novel variant of SYT-SSX1 fusion gene in a case of spindle cell synovial sarcoma. Diagn Mol Pathol 16 (3): 179-83, 2007.  [PUBMED Abstract]
    
    
69. 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.  [PUBMED Abstract]
    
    
70. 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.  [PUBMED Abstract]
    
    
71. Bien E, Kazanowska B, Dantonello T, et al.: Factors predicting survival in childhood malignant and intermediate vascular tumors : retrospective analysis of the Polish and German cooperative paediatric soft tissue sarcoma study groups and review of the literature. Ann Surg Oncol 17 (7): 1878-89, 2010.  [PUBMED Abstract]
    
    
72. Deyrup AT, Miettinen M, North PE, et al.: Angiosarcomas arising in the viscera and soft tissue of children and young adults: a clinicopathologic study of 15 cases. Am J Surg Pathol 33 (2): 264-9, 2009.  [PUBMED Abstract]
    
    
73. Lahat G, Dhuka AR, Hallevi H, et al.: Angiosarcoma: clinical and molecular insights. Ann Surg 251 (6): 1098-106, 2010.  [PUBMED Abstract]
    
    
74. Park MS, Ravi V, Araujo DM: Inhibiting the VEGF-VEGFR pathway in angiosarcoma, epithelioid hemangioendothelioma, and hemangiopericytoma/solitary fibrous tumor. Curr Opin Oncol 22 (4): 351-5, 2010.  [PUBMED Abstract]
    
    
75. Daller JA, Bueno J, Gutierrez J, et al.: Hepatic hemangioendothelioma: clinical experience and management strategy. J Pediatr Surg 34 (1): 98-105; discussion 105-6, 1999.  [PUBMED Abstract]
    
    
76. Lyons LL, North PE, Mac-Moune Lai F, et al.: Kaposiform hemangioendothelioma: a study of 33 cases emphasizing its pathologic, immunophenotypic, and biologic uniqueness from juvenile hemangioma. Am J Surg Pathol 28 (5): 559-68, 2004.  [PUBMED Abstract]
    
    
77. Hu B, Lachman R, Phillips J, et al.: Kasabach-Merritt syndrome-associated kaposiform hemangioendothelioma successfully treated with cyclophosphamide, vincristine, and actinomycin D. J Pediatr Hematol Oncol 20 (6): 567-9, 1998 Nov-Dec.  [PUBMED Abstract]
    
    
78. Deb G, Jenkner A, De Sio L, et al.: Spindle cell (Kaposiform) hemangioendothelioma with Kasabach-Merritt syndrome in an infant: successful treatment with alpha-2A interferon. Med Pediatr Oncol 28 (5): 358-61, 1997.  [PUBMED Abstract]
    
    
79. Makhlouf HR, Ishak KG, Goodman ZD: Epithelioid hemangioendothelioma of the liver: a clinicopathologic study of 137 cases. Cancer 85 (3): 562-82, 1999.  [PUBMED Abstract]
    
    
80. Pinet C, Magnan A, Garbe L, et al.: Aggressive form of pleural epithelioid haemangioendothelioma: complete response after chemotherapy. Eur Respir J 14 (1): 237-8, 1999.  [PUBMED Abstract]
    
    
81. Chowdhury T, Barnacle A, Haque S, et al.: Ultrasound-guided core needle biopsy for the diagnosis of rhabdomyosarcoma in childhood. Pediatr Blood Cancer 53 (3): 356-60, 2009.  [PUBMED Abstract]