Nonrhabdomyosarcoma Soft Tissue Sarcomas and Other Soft Tissue Tumors

Local Control

Surgical resection is typically the initial therapy for operable nonmetastatic NRSTS. Complete resection of small (<5 cm) NRSTS results in a 5-year OS in excess of 80%. However, large, high-grade or incompletely resected tumors have a significant chance of local recurrence. Tumor location (e.g., abdomen vs. extremity) and invasion may limit the ability to perform a wide local excision necessary to achieve tumor-free margins. For these patients, external-beam radiation therapy has been used to reduce the risk for local recurrence based on adult studies. Pediatric studies seem to confirm that radiation therapy reduces the risk for local recurrence associated with an inability to achieve a wide surgical margin (>1 cm) for high-grade disease. The impact of postoperative radiation therapy may be most significant for IRS group II patients, although grade and size may mitigate this effect. Higher radiation doses are associated with increased rates of local control in NRSTS. However, these doses are associated with abnormalities of bone development, complicating the delivery of this modality to growing children.

Brachytherapy—interstitial, intercavitary or surface placement of radioisotopes—constitutes an alternative approach to deliver radiotherapy. Brachytherapy can precisely deliver high doses of radiation to the tumor or resection site while sparing normal tissue. Brachytherapy can also be administered concurrently with external-beam radiation, and a study of adult STS suggests that the combination may result in increased rates of local control when surgical margins are positive. Other techniques to augment local control include radiofrequency ablation, cryoablation, and embolization. Strategies for local control that incorporate site-directed chemotherapy include intralesional chemotherapy followed by electroporation at accessible sites and intraperitoneal chemotherapy infusion.

Chemotherapy

Because complete resection of NRSTS is associated with a high rate of cure, chemotherapy is principally employed when tumors are unresectable, incompletely resected, or metastatic. The infrequency of each of the heterogeneous tumors that constitute the class of NRSTS makes clinical trials of chemotherapy particularly challenging. To enable multicenter groups to accrue sufficient subjects, the nonselective inclusion of NRSTS complicates the interpretation and extrapolation of most trials. Nonetheless, several consistent themes emerge. In contrast to the striking successes of chemotherapy for Ewing sarcoma and rhabdomyosarcoma, NRSTS tend to be relatively chemoresistant, with synovial sarcoma and extraosseous Ewing sarcoma as exceptions. For patients with fully resected tumors, the inclusion of chemotherapy fails to increase survival. The impact of chemotherapy may be most significant for patients harboring tumors with the highest risk for metastatic spread. For high grade, grossly resected tumors, chemotherapy was associated with a 5-year metastasis-free survival of 49.5% compared with 0% for untreated patients. Chemotherapy may also be beneficial for patients with unresectable tumors. For both chemotherapy-sensitive and chemotherapy-resistant tumors, neoadjuvant treatment may permit the subsequent surgical resection of initially nonresectable tumors. Patients with unresected or metastatic tumors have a poor outcome, although 40% to 50% of patients with advanced disease demonstrate some response (partial + complete response) to a regimen containing either ifosfamide and doxorubicin or cyclophosphamide and doxorubicin. Treatment with doxorubicin, cyclophosphamide, and vincristine alternating with ifosfamide and etoposide together with aggressive local control for incompletely resected tumors or those metastatic at presentation, resulted in a partial + complete response of 80%. Approximately 40% of children and adolescents with NRSTS responded to ifosfamide and doxorubicin, results similar to those for cyclophosphamide and doxorubicin. Based on the principle that advanced sarcomas may respond to intensive therapies, the feasibility of dose-intensified neoadjuvant chemotherapy has been an end point of several trials using doxorubicin, ifosfamide, and dacarbazine in adults and doxorubicin, cyclophosphamide, ifosfamide, etoposide, and vincristine in children. However, evidence in support of high-dose chemotherapy with autologous stem cell infusion remains limited.

Regarding specific chemotherapeutic agents, topoisomerase 1 inhibitors may also have activity against these tumors. Topotecan with high-dose cyclophosphamide as well as irinotecan demonstrated limited efficacy against recurrent NRSTS, and the effect of irinotecan together with temozolomide is currently being studied. The combination of vinorelbine with low-dose cyclophosphamide may also have activity against these tumors. Gemcitabine and docetaxel, both of which have some activity against adult sarcomas, were more effective together than gemcitabine alone in adult patients with metastatic sarcoma. In adults, advanced disease may also respond to the combination of gemcitabine and vinorelbine. In children, however, the efficacy of gemcitabine or docetaxel administered individually in the setting of relapsed pediatric solid tumors seems small. As previously mentioned, synovial sarcoma is considered an exception to the general chemoresistance of NRSTS. Children and adolescents exhibit a 5-year EFS of about 70% with decreased EFS, progression-free survival (PFS), and OS associated with tumor size (>5 cm), local invasion, and IRS grouping (III and IV). Another exception is extraosseous Ewing sarcoma, which is generally grouped with bony Ewing sarcoma for treatment purposes (see Chapter 61, “Ewing Sarcoma” ).

Insights regarding the biology of STS are beginning to identify novel targetable pathways. The management of GISTs in adults has been altered by treatment with KIT and PDGFR-targeted tyrosine kinase inhibitors. Multitargeted tyrosine kinase inhibitors have demonstrated efficacy in nonadipocytic STS in adults, and sorafenib has activity against desmoid tumors. Insulin-like growth factor 1 (IGF-1) inhibition has demonstrated efficacy in a fraction of patients with DSRT. Targeting the mammalian target of rapamycin (mTOR) pathway demonstrated a significant, although brief, delay in disease progression in a large adult trial of sarcomas previously treated with cytotoxic chemotherapy.

Desmoid Tumor

Desmoid tumor, also known as deep musculoaponeurotic fibromatosis, presents from infancy through adulthood with a median age at diagnosis in the early 30s and a twofold higher incidence in women. Although most tumors occur spontaneously, FAP patients, and in particular those with Gardner syndrome, have reported incidences of desmoid tumors ranging from 3.5% to 32%. Desmoid tumors in the pediatric population tend to occur in the second decade and are located in the extremities and head and neck, in contrast to the adult population in whom abdominal and truncal sites are common. Abdominal desmoids are more common in FAP patients, whereas limb and trunk locations predominate in non-FAP patients.

The tumors consist of an infiltrating, uniform, spindled cell proliferation lacking nuclear pleomorphism and mitotic activity ( Fig. 60-3 ). Although desmoid tumors have a high potential for local invasion and recurrence, they never metastasize. Surgery is the primary treatment; however, tumors have a significant chance of local recurrence even if negative margins can be achieved. Achieving negative margins without severe disfigurement or functional impairment may be impossible. In these circumstances, preoperative chemotherapy or partial resection and postoperative chemotherapy should be considered, although, given a highly variable clinical course, close observation may be justified. Multiple drug regimens have been shown to shrink or stabilize desmoid tumor growth. These include methotrexate with vinblastine or tamoxifen with diclofenac. Other potentially active treatments include the combination of doxorubicin, vincristine, dactinomycin, and cyclophosphamide or the combination of doxorubicin and dacarbazine. Responses to imatinib and sorafenib have been observed in about half of desmoid patients.

Although most desmoid tumor cells are karyotypically diploid, abnormalities of the Y chromosome and 5q and gains in chromosome 8 and 20 may be noted. Abnormalities have been identified in a subset of tumor cells, and the finding of trisomy 8 may suggest an increased risk for recurrence. Gardner syndrome, which is associated with colonic polyposis and abdominal desmoid tumors, is a phenotypic variant of FAP, which is caused by mutation of APC. APC regulates β-catenin, the downstream mediator of WNT signaling. Stabilized β-catenin forms a multiprotein complex with members of the T-cell factor/lymphoid enhancer factor family (TCF-LEF) resulting in transcriptional activation of TCF-LEF target genes. APC mutations resulting in increased β-catenin or stabilizing mutations in the β-catenin gene ( CTNNB1) have been implicated in the proliferation of sporadic desmoid tumors. Eighty-five to 90 percent of sporadic desmoid tumors are associated with somatic mutation of CTNNB1. Mice expressing either mutant APC or stabilized β-catenin develop aggressive fibromatoses.

Infantile Myofibroma/Myofibromatosis and Hemangiopericytoma

In recent World Health Organization (WHO) classifications of soft tissue tumors, the term hemangiopericytoma is no longer used; instead, a majority of these tumors are currently classified as solitary fibrous tumors. Infantile hemangiopericytoma, recognized as a distinct category of benign hemangiopericytoma by Enzinger, is currently regarded in the category of infantile myofibroma/myofibromatosis. Infantile myofibromatosis is a benign proliferation of myofibroblastic cells affecting almost exclusively young children. The tumors are solitary or multicentric and may involve the skin, muscle, viscera, or bone. Sixty percent are noted at birth, and 88% occur before the age of 2. More commonly found in males, solitary lesions typically develop in the soft tissues of the head and neck and trunk. In contrast, the multicentric form is more common in females and in addition to affecting soft tissues it can develop in bones and viscera. Histopathologically, infantile myofibroma and myofibromatosis have similar features. They are multinodular and biphasic with alternating hemangiopericytoma-like, densely cellular areas and less cellular areas with smooth muscle differentiation immunoreactive to actin ( Fig. 60-4 ). Solitary lesions can rarely recur. Multicentric lesions undergo spontaneous regression; however, multiple visceral lesions may increase in size and number prior to regression, compromising vital structures and, rarely, leading to death. Optimal initial therapy involves complete surgical excision. Life-threatening multifocal disease has been treated successfully with low-dose vincristine and dactinomycin or low-dose vinblastine and methotrexate. Urinary basic fibroblast growth factor has been shown to be elevated in an infant during the proliferative phase, and connective tissue growth factor is expressed in both tumor and stromal cells. An autosomal dominant pattern of inheritance has been associated with mutations in the growth factor receptor PDGFRB.

Infantile myofibroma/myofibromatosis should be distinguished from pericytoma with t(7;12), a distinct tumor with histologic, immunohistochemical, and ultrastructural features of pericytic differentiation and a translocation involving t(7;12)(p22;q13). Although typically developing in soft tissue, this entity can develop in bone. The translocation brings together the β-actin gene (ACTB) with the zinc finger transcription factor GLI1. Originally identified based on amplification in human glioma, GLI1 is activated by Sonic hedgehog signaling through the transmembrane receptor PTCH. In t(7;12) pericytoma the carboxyl terminus of GLI1 is fused with the amino-terminal domain of ACTB. Intriguingly, GLI1 has also been found to be amplified in a subset of rhabdomyosarcoma and osteosarcoma that lack typical markers of differentiation.

Infantile Fibrosarcoma

Infantile (congenital) fibrosarcoma is one of the most common NRSTS in young children. In contrast to fibrosarcoma in adults, this low-grade tumor displays a benign clinical behavior and is typically cured by surgical excision. However, large tumors for which surgical excision would result in significant morbidity may be treated with preoperative chemotherapy ( Fig. 60-5, A ). Regimens with activity against these tumors include vincristine and dactinomycin alone or together with either cyclophosphamide, ifosfamide, or doxorubicin.

Histopathologically, the tumor is characterized by intersecting bundles with a herringbone pattern composed of cellular spindle to ovoid cells with a high proliferative rate, frequent mitoses, and areas of necrosis (see Fig. 60-5, B and C ). Some tumors may have a hemangiopericytoma-like pattern of growth. Scattered chronic inflammatory cells are frequently present. Tumor cells have a fibroblastic and myofibroblastic ultrastructure (see Fig. 60-5, D ) and immunophenotype with variable positivity for desmin and actin. Aberrant cytokeratin expression is observed in 15% to 20% of the tumors.

Infantile fibrosarcoma is characterized by t(12;15)(p13;q25). This translocation fuses the amino-terminal helix-loop-helix oligomerization domain of the ETV6 transcription factor (also known as TEL ) with the carboxyl-terminal tyrosine kinase domain of the neurotrophic tyrosine kinase receptor, type 3 ( NTRK3, also known as TRKC ). The detection of ETV6-NTRK3 by reverse-transcriptase PCR is highly specific and can distinguish infantile fibrosarcoma from more aggressive spindle cell sarcomas. Intriguingly, the same translocation also occurs in congenital mesoblastic nephroma, secretory breast carcinoma, and acute myeloid leukemia.

Chimerism results in constitutive activation by autophosphorylation of NTRK3 tyrosine residues. Translocation also results in aberrant NTRK3 expression. ETV6 is widely expressed whereas NTRK3 is normally restricted to neuronal cells and fetal kidney. ETV6-NTRK3 expression can transform NIH3T3 cells as assayed by growth in soft agar and in xenografts in immunocompromised mice. ETV6-NTRK3 is associated with several signaling pathways that may be important in oncogenesis. ETV6-NTRK3 activates both the MAPK and AKT pathways, with AKT activation mediated by direct interaction of ETV6-NTRK3 with SRC. Activation of signaling also leads to phosphorylation of YAP1 and WWTR1, Hippo pathway transcriptional coactivators, and a characteristic transcriptional profile. ETV6-NTRK3–mediated fibroblast transformation also requires the insulin-like growth factor receptor (IGF1R) possibly through directly interacting with the IGF1R substrate IRS-1. The ETV6-NTRK3 fusion may also act by suppressing transforming growth factor-β (TGF-β) signaling through interaction with the type II TGF-β receptor.

Fibrosarcoma Arising in Dermatofibrosarcoma Protuberans and Giant Cell Fibroblastoma

Dermatofibrosarcoma protuberans (DFSP) is a rare cutaneous fibrohistiocytic tumor characterized by locally aggressive behavior. DFSP may begin as a plaquelike, raised red-blue lesion followed by a rapid growth phase that may be associated with the development of one or more nodules. DFSP appears as a cellular, spindle cell proliferation, frequently with a distinct storiform pattern that infiltrates the surrounding dermis and subcutaneous fat ( Fig. 60-6, A ). Tumor cells are typically immunoreactive for apolipoprotein D and CD34 (see Fig. 60-6, B ). The Bednar tumor refers to an uncommon DFSP variant with scattered dendritic cells containing melanin. The majority of the tumors develop on the trunk and upper extremity. Although typically diagnosed during the fourth and fifth decades, DFSP may occur in children and adolescents. Inadequate resection of the tumor is associated with a significant risk for local recurrence. Radiation therapy can be used effectively as an adjuvant for the treatment of resection sites with positive margins. Rarely, DFSP can evolve into a high-grade fibrosarcoma often associated with a loss of CD34 staining and an increased risk for metastasis ( Fig. 60-7, A and B ). Giant cell fibroblastoma, a rare tumor predominantly of males younger than 10 years of age, is in the spectrum of DFSP. Histopathologically, giant cell fibroblastoma is composed of variably cellular spindle or stellate cells often in a myxoid background containing pseudovascular spaces and multinucleated giant cells (see Fig. 60-7, C ).

Like DFSP, giant cell fibroblastoma is characteristically immunoreactive for CD34 and apolipoprotein D. Both lesions also harbor a pathognomonic translocation between the collagen, type I, alpha 1, gene (COL1A1) and the platelet-derived growth factor-β gene (PDGFB). In contrast to the other sarcoma-associated translocations, the translocated COL1A1 - PDGFB locus may be present as a low-level amplification on a ring chromosome. Detection of the resulting COL1A1-PDGFB transcript can provide confirmation of the diagnosis. The fusion of PDGFB with COL1A1 preserves the full coding region of PDGFB, and the resulting chimeric polypeptide is subject to intracellular processing that results in the secretion of a native PDGFB molecule that is capable of activating its receptor, PDGFR. Although the mechanisms for autocrine-activated PDGFR signaling are not known, it may function through STAT3 and ERK activation. Presumably through the inhibition of autocrine PDGFR activation, the growth of xenografted primary human DFSP cells can be inhibited with the kinase inhibitor imatinib (Gleevec). Treatment with imatinib has also been shown to be effective in children and in patients with metastatic or unresectable disease. Imatinib-resistant DFSP may respond to sorafenib or sunitinib. Response to vinblastine and methotrexate has also been reported.

Low-Grade Fibromyxoid Sarcoma

Low-grade fibromyxoid sarcoma (LGFMS) typically develops in the lower extremities of young adults and occasionally in adolescents ( Fig. 60-8 ). Described by Evans in 1987, it is characterized by bland, uniform spindle cells with a short fascicular or whorly pattern of growth in a dense collagenous or variably myxoid stroma ( Fig. 60-9 ). An abrupt transition between cellular myxoid and hypocellular collagenous areas is frequently present. Dense collagenous areas mimic desmoid tumor. Myxoid areas contain characteristic arcades of curvilinear vessels that may be sclerotic or be surrounded by more densely cellular spindle cells. Mitotic count is characteristically low. Occasionally there are giant collagenous rosettes (hyalinizing spindle cell tumor with giant rosettes). Vimentin is the only constant marker present in tumor cells. Some tumors may be focally immunoreactive for actin, CD34, cytokeratins, or epithelial membrane antigen (EMA). MUC4 reactivity is common in LGFMS and can distinguish it from other histologically similar tumors. A superficial location occurs more frequently in children. Although primary resection typically results in disease control, local recurrences and pulmonary metastases can develop in 5% to 10% of patients after many years. However, resection of recurrent disease can result in long-term remission. LGFMS seems to be chemoresistant, although limited responses to trabectedin have been reported.

LGFMS is associated with t(7;16)(q34;p11) or t(11;16)(p11;p11), which results in the fusion of FUS (TLS) with CREB3L2 or CREB3L1. These translocations are also found in sclerosing epithelioid fibrosarcoma, suggesting that these tumors may be related. EWSR1 - CREB3L1 has also been noted. Native CREB3L2 is a member of the CREB basic leucine zipper family of transcription factors and acts as a transducer of endoplasmic reticulum (ER) stress signals. Normally tethered through a transmembrane domain to the ER, ER stress results in cleavage of the cytoplasmic amino terminal b-ZIP domain, enabling it to translocate to the nucleus and to activate transcription from cyclic adenosine monophosphate (AMP)–responsive elements. Chimerism with FUS, a translocation partner with CHOP in myxoid liposarcoma, likely deregulates CREB3L2 transcriptional activity. PCR-based identification of the fusion gene product from paraffin sections can be used to confirm the diagnosis. LGFMS is associated with a gene expression profile that distinguishes it from similar tumors and is marked by the expression of FOXL1.

Myxofibrosarcoma

Myxofibrosarcoma (MFS) is one of the most common sarcomas of the elderly but has been reported in adolescents and young adults. Typically developing in the sixth and seventh decades of life, MFS exhibits a predilection for the dermal or subcutaneous tissues of the extremities. MFS may be alternatively referred to as low-grade myxoid malignant fibrous histiocytoma or fibrosarcoma, myxoid type. Histopathologically, it is characterized by a multinodular growth of spindled or stellate cells in a myxoid stroma ( Fig. 60-10 ). MFS grading has prognostic value and is based on cellularity, nuclear pleomorphism, and mitotic activity. Resection is typically curative for low- or intermediate-grade tumors; however, recurrent tumors may show morphologic and molecular multistep tumor progression. Large tumor size, necrosis, and decreased myxoid stroma in low-grade tumors are associated with a significant risk for local and distant recurrence. Intermediate- and high-grade tumors have a significant risk for recurrence and metastasis. In a study of adults, 23% of patients with intermediate- or high-grade tumors developed metastases, most commonly to the lung and lymph nodes and rarely to the brain. A subset of intermediate- or high-grade tumors exhibiting an epithelioid morphology seems to behave more aggressively than other high-grade histologies. In addition to grade, an initial incomplete resection and infiltrative MRI T2-weighted signal correlates with an increased risk for local recurrence. Combined chemotherapy and irradiation has efficacy for MFS. Cytogenetically, MFS may be diploid but is typically complex. Numerous chromosomal gains and losses as well as ring chromosomes have been observed. Large-scale 7q gains were associated with increased expression of the hepatocyte growth factor receptor MET and CDK6, and increased expressed of these proteins was associated with lower metastasis-free survival. Ezrin expression also correlates with decreased metastasis-free survival. Isolated chromosomal translocations have been noted.