INVITED REVIEW ARTICLE
Synovial Sarcoma in Children and Adolescents Anna Kerouanton, MD,* Irene Jimenez, MD,* Cecile Cellier, MD,w Valerie Laurence, MD,*z Sylvie Helfre, MD,y Stephanie Pannier, MD,8 Pierre Mary, MD,z Paul Freneaux, MD,# and Daniel Orbach, MD*
Summary: Synovial sarcoma (SS) is a high-grade soft tissue sarcoma characterized by local invasiveness and a propensity to metastasize, affecting pediatric, adolescent, and adult populations. The peak incidence is observed in the third decade of life and SS is the most common nonrhabdomyosarcoma soft tissue sarcoma in childhood and adolescence. Although pediatric and adult SS appear clinically and radiologically identical, treatment modalities may differ according to the patient’s age. For many years, pediatric oncologists have treated SS as a chemosensitive tumor according to the “rhabdomyosarcoma philosophy.” In contrast, adult oncologists generally treat this tumor as a poorly chemosensitive tumor and focus on local control. The authors propose an update of SS in the pediatric population and analyze their results to those obtained in adults. Key Words: synovial sarcoma, pediatric, adolescent
(J Pediatr Hematol Oncol 2014;36:257–262)
S
ynovial sarcoma (SS) is a high-grade soft tissue sarcoma (STS) characterized by local invasiveness and a propensity to metastasize, affecting pediatric, adolescent, and adult populations. The peak incidence is observed in the third decade of life and SS is the most common nonrhabdomyosarcoma STS (NRMS-STS) in childhood and adolescence.1–5 Thirty percent of SSs occur in patients younger than 20 years of age.4 SS accounts for about 8% to 10% of all pediatric STSs. In children and adolescents younger than 20 years of age, the annual incidence rate is 0.5 to 0.7 per million.6,7 Biologically, SS is unique in terms of its differentiation into 2 distinct elements, epithelial cells with glandular components and spindle cells. Moreover, translocation between chromosomes 18 and X, t(X;18) (p11.2;q11.2), that may result in 2 different fusion genes (SYT-SSX1 and SYT-SSX2), is a characteristic molecular marker present in 90% to 95% of cases.8 Although pediatric and adult SS appear clinically and radiologically identical, treatment modalities may differ according to the patient’s age. For many years, pediatric oncologists have treated SS as a chemosensitive tumor with systematic use of chemotherapy, neoadjuvant chemotherapy in the case of Received for publication January 22, 2014; accepted February 19, 2014. From the *Pediatric, Adolescent and Young Adult Department; Departments of wRadiology; zMedical Oncology; #Pathology; yRadiotherapy Department, Institut Curie; 8Pediatric Orthopedic Department, Necker Hospital—Assistance Publique, Universite´ Paris Descartes—Sorbonne Paris; and zPediatric Orthopedic Department, Armand Trousseau Hospital—Assistance Publique, Paris, France. The authors declare no conflict of interest. Reprints: Daniel Orbach, MD, Pediatric Adolescent and Young Adult Department, Institut Curie, 26 rue d’Ulm, Paris 75005, France (e-mail: [email protected]). Copyright r 2014 by Lippincott Williams & Wilkins
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extensive tumor, and local therapy adapted to tumor response and to initial extension.2,6 In contrast, adult oncologists generally treat this tumor as a poorly chemosensitive tumor and focus on local control.1 A review of the literature reveals differences in term of prognosis between adults and children with SS, possibly correlated with clinical and biological somatic differences.3,8–10 Despite the complexities inherent to these tumors, all pediatric and adult SS specialists agree that more prospective studies are needed to more clearly understand these diseases in both children and adults. The authors propose an updated review of SS in the pediatric population and compare their results to those obtained in adults.
CLINICAL PRESENTATION SS arises in soft tissues of the extremities in 66% of cases, especially adjacent to large joints, but can occur anywhere in the body in primary including sites situated away from joint spaces.2 The main presenting complaint is the discovery of a slowly growing soft tissue mass.11 Despite its name, SS does not appear to arise from the synovial membrane but rather from primitive mesenchymal cells. Distant metastases are rare at diagnosis and are identified in only about 5.8% of cases, involving the lungs in about 85% of cases.12 Like most other NRMS-STS, SS rarely spread to regional lymph nodes (< 1% of children).2,7 SS is frequently initially misdiagnosed as a benign lesion because of its small size, slow growth, and well-defined appearance.13,14
RADIOLOGIC PRESENTATION Radiography is often the first-line examination performed to assess SS. In 50% of patients with SS, standard radiographic findings are interpreted as normal. When an abnormality is present, the radiograph may reveal a welldefined, round, or lobulated soft tissue mass. Approximately 30% of patients have detectable calcifications. Calcifications may be focal or disseminated throughout most of the tumor and may have a fine, stippled, or opaque appearance. SS tumors may be small, especially when they involve the hands or head and neck (Fig. 1).15 Ultrasonography does not play a significant role in evaluation of SS. Imaging characteristics cannot be used to establish a precise diagnosis, but a real-time imaging technique may be useful to guide diagnostic needle biopsy, especially in the case of large heterogenous tumors. Doppler ultrasonography reveals blood flow in solid soft tissue masses.16 This technique may also be useful to monitor regression of tumor neovascularization after chemotherapy or radiotherapy, but this technique is not used routinely. As for all sarcomas, magnetic resonance imaging (MRI) is the modality of choice because of its excellent tissue contrast www.jpho-online.com |
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FIGURE 1. Radiologic presentation of a patient with a small indolent well-defined synovial sarcoma with SYT-SSX transcript present of the leg (magnetic resonance imaging, right image, arrow). Calcifications are visible on standard radiography (left image; arrow).
and its ability to depict the lesion in multiple planes allowing evaluation of the extent of the tumor.11 SS tumors tend to be large, with a mean diameter of approximately 8 cm in the largest dimension, which is usually parallel to the long axis of the body (Fig. 2). Approximately 91% of patients have a well-defined, ovoid lesion with rounded or gently lobulated margins.17 The tumor usually causes displacement of adjacent structures, rather than invasion or destruction. Most tumors display a heterogenous intermediate signal intensity on T1-weighted sequences. Lesions 30 y).3 The median age of the pediatric SS population is 13 years (range, 1 to 20 y), with a sex ratio of 1.16 (male/ female); tumor site is mostly limb-based (85%); median maximum tumor size is between 5 and 10 cm; 3% of patients have distant metastases; and 40% to 60% of tumors correspond to the monophasic subtype and harbor SYT-SSX1 or SYT-SSX2 fusion transcripts in 70% and 30% of cases, respectively.2,7,27 In comparison, a study including 120 adults and 45 patients under the age of 25 years showed that the median age was 35 years; the sex ratio was 1.3; a limb primary was present in 67% of cases; median tumor diameter was 7 cm; and 16% of patients presented distant metastases, with 72% of monophasic tumors, and SYT-SSX1 or SYT-SSX2 fusion transcripts in 68% and 32% of cases, respectively.1
PROGNOSTIC FACTORS Compared with rhabdomyosarcoma, SS has traditionally been considered to be associated with a poor overall outcome in children. Reported 5-year survival rates in children range from 62.8% to 84%6,27,28 and 10-year survival rates range from 61% to 69%.4,6 However, it has recently emerged that not all SS present the same poor outcome. Various factors have been reported to have an adverse prognostic significance, although this impact still needs to be confirmed in prospective studies. Published data indicate a strong association between death from malignancy and advanced tumor stage at diagnosis.1,2,6,27 Prognosis largely depends on the feasibility of surgical resection, which is correlated with the IRS grading system and the presence of metastases.5 IRS IV group has a dismal outlook with only a minority of survivors in this population (5-year overall survival [OS], 13%).2,6,27 A primary tumor in an extremity is correlated with a better OS compared with axial lesions.2,28,29 In adults, bone and/or neurovascular invasion impact negatively on survival.28 According to the literature, tumor size is an important prognostic factor for both OS and event-free survival,9,10,26 The cut-off most frequently used is 5 cm in children and 7 cm in adults. Large tumors are associated with poorer outcome.2,7,30 Some data have suggested a possible relationship between somatic chromosomal instabilities and clinical outcomes. Pediatric patients are known to have excellent clinical outcomes compared with adults, although both populations harbor exactly the same histologic features and translocations. A 67-gene signature related to chromosome integrity, mitotic control, and genome complexity, called CINSARC (Complexity Index in Sarcoma), has been analyzed as a tool to predict the risk of metastatic spread and potentially the response to chemotherapy in SS. Moreover, a recent study showed that metastatic outcomes are strongly associated with chromosomal complexity in both age strata and that this instability is frequent in adult but not in pediatric SS.8 Given that the initial genetic driver event (t(X;18) translocation) is the same for both situations, this difference in terms of instability tends to suggest that an independent, as yet unknown, mechanism is permissive to chromosome instability in adult patients and resistant in pediatric patients. However, no genomic alteration or significantly differentially expressed genes have been identified for such mechanisms.8
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TREATMENT The approach currently adopted by the European Paediatric Soft Tissue Sarcoma Group (EpSSG) study for NRMS-STS uses a multimodal therapeutic strategy adapted to already known risk factors in this tumor: IRS group, site of primary, and tumor size. Complete resection with clear margins remains the treatment of choice for localized SS in children.31 If complete surgical resection is not immediately possible, a simple biopsy is recommended, followed by a delayed surgery after tumor reduction with neoadjuvant chemotherapy.2 Cooperative groups encourage first-line biopsy to reduce the number of initial positivemargin resections (IRS group II) and therefore increase the number of group III patients, in whom tumors may subsequently be completely removed after chemotherapy. Indeed, high response rates to chemotherapy in SS have been well documented in pediatric series, and pediatric oncologists tend to consider SS as an intermediate chemosensitive tumor and have designed treatments around this concept.2,3,29 In children, the response rate to neoadjuvant chemotherapy has been estimated to be between 60% and 65%.2,3,29 Moreover, a retrospective analysis on 271 patients of all ages performed at the Istituto Nazionale Tumori in Milan reported better outcomes for children, most of whom received adjuvant chemotherapy, with a strong correlation between use of chemotherapy and survival.3,9 Moreover, patients with tumors >5 cm, even after gross resection (IRS groups I to II), may have more metastatic disease progression leading to the proposal of systematic adjuvant chemotherapy in the presence of large tumors.3,30 However, no prospective study has formally demonstrated the absolute benefit of chemotherapy in children with SS in terms of survival gain. The place of chemotherapy remains controversial in adults and is only mandatory in the case of metastatic or initially unresectable tumor.32,33 Many drugs are active on this tumor, but the most commonly used regimens include doxorubicin and/or ifosfamide.2,7 The role of local adjuvant radiotherapy in grossly resected tumors is controversial and may be omitted in tumors presenting favorable features.2,7 Total radiotherapy dose ranges between 50.4 to 59 Gy according to initial IRS staging. Because of the low rate of nodal involvement in this tumor, prophylactic radiotherapy to regional nodes is not recommended. As an example, EpSSG recommendations in the NRSTS 2005 protocol for localized SS tumors are as follows: For limb primary, IRS group I: no radiotherapy, chemotherapy only if tumor size >5 cm. For limb primary, IRS group II: try to avoid this situation and propose an immediate primary reexcision if feasible; systematic chemotherapy with ifosfamide-doxorubicin regimen; radiotherapy can be omitted in young patients. For IRS III and axial primary: systematic chemotherapy with ifosfamide-doxorubicin regimen; delayed surgery as possible, and systematic local radiotherapy.
CONCLUSIONS In a unique prospective study based on 44 relapsing cases out of a series of 118 consecutive patients younger than 21 years of age with nonmetastatic SS, Ferrari et al described the pattern of recurrence, salvage rates, and prognostic variables influencing survival.27 Relapses were predominantly metastatic (sometimes combined with local r
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relapse). Time to relapse was fairly short, ranging from 4 to 108 months (median: 20 mo). Five-year and 10-year overall survivals after relapse were only 29.7% and 21.0%, respectively. Univariate analysis showed that patients in whom relapse was local and occurred later (> 18 mo after the initial diagnosis) had a reasonable chance of cure, with a 10-year OS of 68.6%, whereas patients with multiple metastases had a dismal outcome. The efficacy of secondline therapy strongly influenced the final outcome of the patients.27 Patients with SS should be followed for at least 10 years because of the tendency for late recurrence and metastasis.4 Recurrence and metastasis appear occurring earlier in pediatric patients.4,34 More aggressive multimodality treatment, including new radiotherapy techniques, and new drugs should be studied in patients with initial poor prognostic factors, metastatic tumors, or after relapse.6 Recent data show that pazopanib, a potent and selective multi-targeted receptor tyrosine kinase inhibitor, may be effective in adult SS and should be tested in children.35 ACKNOWLEDGMENTS The authors thank “La Ligue contre le Cancer” for their financial support and Anthony Saul for editorial assistance. REFERENCES 1. 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. 2004;22:4040–4050. 2. Orbach D, Mc Dowell H, Rey A, et al. Sparing strategy does not compromise prognosis in pediatric localized synovial sarcoma: experience of the International Society of Pediatric Oncology, Malignant Mesenchymal Tumors (SIOPMMT) Working Group. Pediatr Blood Cancer. 2011;57: 1130–1136. 3. 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. 2004;101:627–634. 4. Speth BM, Krieg AH, Kaelin A, et al. Synovial sarcoma in patients under 20 years of age: a multicenter study with a minimum follow-up of 10 years. J Child Orthop. 2011;5: 335–342. 5. Ferrari A, Casanova M. New concepts for the treatment of pediatric nonrhabdomyosarcoma soft tissue sarcomas. Expert Rev Anticancer Ther. 2005;5:307–318. 6. Brennan B, Stevens M, Kelsey A, et al. Synovial sarcoma in childhood and adolescence: a retrospective series of 77 patients registered by the Children’s Cancer and Leukaemia Group between 1991 and 2006. Pediatr. 2010;55:85–90. 7. Okcu MF, Munsell M, Treuner J, et al. Synovial sarcoma of childhood and adolescence: a multicenter, multivariate analysis of outcome. J Clin Oncol. 2003;21:1602–1611. 8. Lagarde P, Przybyl J, Brulard C, et al. Chromosome instability accounts for reverse metastatic outcomes of pediatric and adult synovial sarcomas. J Clin Oncol. 2013;31:608–615. 9. Sultan I, Rodriguez-Galindo C, Saab R, et al. Comparing children and adults with synovial sarcoma in the Surveillance, Epidemiology, and End Results program, 1983 to 2005: an analysis of 1268 patients. Cancer. 2009;115:3537–3547. 10. Ferrari A, Miceli R, Casanova M, et al. Adult-type soft tissue sarcomas in paediatric age: a nomogram-based prognostic comparison with adult sarcoma. Eur J Cancer. 2007;43: 2691–2697. 11. Kransdorf MJ, Jelinek JS, Moser RP Jr, et al. Soft-tissue masses: diagnosis using MR imaging. Am J Roentgenol. 1989;153:541–547. r
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12. Ferrari A, De Salvo GL, Oberlin O, et al. Synovial sarcoma in children and adolescents: a critical reappraisal of staging investigations in relation to the rate of metastatic involvement at diagnosis. Eur J Cancer. 2012;2012:7. 13. Berquist TH, Ehman RL, King BF, et al. Value of MR imaging in differentiating benign from malignant soft-tissue masses: study of 95 lesions. Am J Roentgenol. 1990;155: 1251–1255. 14. Murphey MD, Gibson MS, Jennings BT, et al. From the archives of the AFIP: imaging of synovial sarcoma with radiologic-pathologic correlation. Radiographics. 2006;26: 1543–1565. 15. Hirsch RJ, Yousem DM, Loevner LA, et al. Synovial sarcomas of the head and neck: MR findings. Am J Roentgenol. 1997;169:1185–1188. 16. Van der Woude HJ, Vanderschueren G. Ultrasound in musculoskeletal tumors with emphasis on its role in tumor follow-up. Radiol Clin North Am. 1999;37:753–766. 17. Jones BC, Sundaram M, Kransdorf MJ. Synovial sarcoma: MR imaging findings in 34 patients. Am J Roentgenol. 1993; 161:827–830. 18. van Rijswijk CS, Hogendoorn PC, Taminiau AH, et al. Synovial sarcoma: dynamic contrast-enhanced MR imaging features. Skeletal Radiol. 2001;30:25–30. 19. Charest M, Hickeson M, Lisbona R, et al. FDG PET/CT imaging in primary osseous and soft tissue sarcomas: a retrospective review of 212 cases. Eur J Nucl Med Mol Imaging. 2009;36:1944–1951. 20. Ferrari A, Miceli R, Rey A, et al. Non-metastatic unresected paediatric non-rhabdomyosarcoma soft tissue sarcomas: results of a pooled analysis from United States and European groups. Eur J cancer. 2011;47:724–731. 21. Skapek SX, Chui CH. Cytogenetics and the biologic basis of sarcomas. Curr Opin Oncol. 2000;12:315–322. 22. Ladanyi M, Antonescu CR, Leung DH, et al. Impact of SYTSSX fusion type on the clinical behavior of synovial sarcoma: a multi-institutional retrospective study of 243 patients. Cancer Res. 2002;62:135–140. 23. Ren T, Lu Q, Guo W, et al. The clinical implication of SS18SSX fusion gene in synovial sarcoma. Br J Cancer. 2013;109:2279–2285. 24. Wittekind C, Compton CC, Greene FL, et al. TNM residual tumor classification revisited. Cancer. 2002;94:2511–2516. 25. Maurer HM, Beltangady M, Gehan EA, et al. The Intergroup Rhabdomyosarcoma Study-I. A final report. Cancer. 1988; 61:209–220. 26. Sleijfer S, Ray-Coquard I, Papai Z, et al. Pazopanib, a multikinase angiogenesis inhibitor, in patients with relapsed or refractory advanced soft tissue sarcoma: a phase II study from the European organisation for research and treatment of cancer-soft tissue and bone sarcoma group (EORTC study 62043). J Clin Oncol. 2009;27:3126–3132. 27. Stanelle EJ, Christison-Lagay ER, Healey JH, et al. Pediatric and adolescent synovial sarcoma: multivariate analysis of prognostic factors and survival outcomes. Ann Surg Oncol. 2013;20:73–79. 28. Ferrari A, Bleyer A. Participation of adolescents with cancer in clinical trials. Cancer Treat Rev. 2007;33:603–608. 29. Ferrari A, De Salvo GL, Dall’Igna P, et al. Salvage rates and prognostic factors after relapse in children and adolescents with initially localised synovial sarcoma. Eur J Cancer. 2012;48:3448–3455. 30. Ferrari A, Bisogno G, Alaggio R, et al. Synovial sarcoma of children and adolescents: the prognostic role of axial sites. Eur J Cancer. 2008;44:1202–1209. 31. 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. 2006;46:11–17. 32. Andrassy RJ, Corpron CA, Hays D, et al. Extremity sarcomas: an analysis of prognostic factors from the Intergroup Rhabdomyosarcoma Study III. J Pediatr Surg. 1996;31:191–196.
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33. Italiano A, Penel N, Robin YM, et al. Neo/adjuvant chemotherapy does not improve outcome in resected primary synovial sarcoma: a study of the French Sarcoma Group. Ann Oncol. 2009;20:425–430. 34. Eilber FC, Brennan MF, Eilber FR, et al. Chemotherapy is associated with improved survival in adult patients with
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primary extremity synovial sarcoma. Ann Surg. 2007;246: 105–113. 35. Krieg AH, Hefti F, Speth BM, et al. Synovial sarcomas usually metastasize after > 5 years: a multicenter retrospective analysis with minimum follow-up of 10 years for survivors. Ann Oncol. 2011;22:458–467.
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Synovial Sarcoma in Children and Adolescents Anna Kerouanton, MD,* Irene Jimenez, MD,* Cecile Cellier, MD,w Valerie Laurence, MD,*z Sylvie Helfre, MD,y Stephanie Pannier, MD,8 Pierre Mary, MD,z Paul Freneaux, MD,# and Daniel Orbach, MD*
Summary: Synovial sarcoma (SS) is a high-grade soft tissue sarcoma characterized by local invasiveness and a propensity to metastasize, affecting pediatric, adolescent, and adult populations. The peak incidence is observed in the third decade of life and SS is the most common nonrhabdomyosarcoma soft tissue sarcoma in childhood and adolescence. Although pediatric and adult SS appear clinically and radiologically identical, treatment modalities may differ according to the patient’s age. For many years, pediatric oncologists have treated SS as a chemosensitive tumor according to the “rhabdomyosarcoma philosophy.” In contrast, adult oncologists generally treat this tumor as a poorly chemosensitive tumor and focus on local control. The authors propose an update of SS in the pediatric population and analyze their results to those obtained in adults. Key Words: synovial sarcoma, pediatric, adolescent
(J Pediatr Hematol Oncol 2014;36:257–262)
S
ynovial sarcoma (SS) is a high-grade soft tissue sarcoma (STS) characterized by local invasiveness and a propensity to metastasize, affecting pediatric, adolescent, and adult populations. The peak incidence is observed in the third decade of life and SS is the most common nonrhabdomyosarcoma STS (NRMS-STS) in childhood and adolescence.1–5 Thirty percent of SSs occur in patients younger than 20 years of age.4 SS accounts for about 8% to 10% of all pediatric STSs. In children and adolescents younger than 20 years of age, the annual incidence rate is 0.5 to 0.7 per million.6,7 Biologically, SS is unique in terms of its differentiation into 2 distinct elements, epithelial cells with glandular components and spindle cells. Moreover, translocation between chromosomes 18 and X, t(X;18) (p11.2;q11.2), that may result in 2 different fusion genes (SYT-SSX1 and SYT-SSX2), is a characteristic molecular marker present in 90% to 95% of cases.8 Although pediatric and adult SS appear clinically and radiologically identical, treatment modalities may differ according to the patient’s age. For many years, pediatric oncologists have treated SS as a chemosensitive tumor with systematic use of chemotherapy, neoadjuvant chemotherapy in the case of Received for publication January 22, 2014; accepted February 19, 2014. From the *Pediatric, Adolescent and Young Adult Department; Departments of wRadiology; zMedical Oncology; #Pathology; yRadiotherapy Department, Institut Curie; 8Pediatric Orthopedic Department, Necker Hospital—Assistance Publique, Universite´ Paris Descartes—Sorbonne Paris; and zPediatric Orthopedic Department, Armand Trousseau Hospital—Assistance Publique, Paris, France. The authors declare no conflict of interest. Reprints: Daniel Orbach, MD, Pediatric Adolescent and Young Adult Department, Institut Curie, 26 rue d’Ulm, Paris 75005, France (e-mail: [email protected]). Copyright r 2014 by Lippincott Williams & Wilkins
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extensive tumor, and local therapy adapted to tumor response and to initial extension.2,6 In contrast, adult oncologists generally treat this tumor as a poorly chemosensitive tumor and focus on local control.1 A review of the literature reveals differences in term of prognosis between adults and children with SS, possibly correlated with clinical and biological somatic differences.3,8–10 Despite the complexities inherent to these tumors, all pediatric and adult SS specialists agree that more prospective studies are needed to more clearly understand these diseases in both children and adults. The authors propose an updated review of SS in the pediatric population and compare their results to those obtained in adults.
CLINICAL PRESENTATION SS arises in soft tissues of the extremities in 66% of cases, especially adjacent to large joints, but can occur anywhere in the body in primary including sites situated away from joint spaces.2 The main presenting complaint is the discovery of a slowly growing soft tissue mass.11 Despite its name, SS does not appear to arise from the synovial membrane but rather from primitive mesenchymal cells. Distant metastases are rare at diagnosis and are identified in only about 5.8% of cases, involving the lungs in about 85% of cases.12 Like most other NRMS-STS, SS rarely spread to regional lymph nodes (< 1% of children).2,7 SS is frequently initially misdiagnosed as a benign lesion because of its small size, slow growth, and well-defined appearance.13,14
RADIOLOGIC PRESENTATION Radiography is often the first-line examination performed to assess SS. In 50% of patients with SS, standard radiographic findings are interpreted as normal. When an abnormality is present, the radiograph may reveal a welldefined, round, or lobulated soft tissue mass. Approximately 30% of patients have detectable calcifications. Calcifications may be focal or disseminated throughout most of the tumor and may have a fine, stippled, or opaque appearance. SS tumors may be small, especially when they involve the hands or head and neck (Fig. 1).15 Ultrasonography does not play a significant role in evaluation of SS. Imaging characteristics cannot be used to establish a precise diagnosis, but a real-time imaging technique may be useful to guide diagnostic needle biopsy, especially in the case of large heterogenous tumors. Doppler ultrasonography reveals blood flow in solid soft tissue masses.16 This technique may also be useful to monitor regression of tumor neovascularization after chemotherapy or radiotherapy, but this technique is not used routinely. As for all sarcomas, magnetic resonance imaging (MRI) is the modality of choice because of its excellent tissue contrast www.jpho-online.com |
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FIGURE 1. Radiologic presentation of a patient with a small indolent well-defined synovial sarcoma with SYT-SSX transcript present of the leg (magnetic resonance imaging, right image, arrow). Calcifications are visible on standard radiography (left image; arrow).
and its ability to depict the lesion in multiple planes allowing evaluation of the extent of the tumor.11 SS tumors tend to be large, with a mean diameter of approximately 8 cm in the largest dimension, which is usually parallel to the long axis of the body (Fig. 2). Approximately 91% of patients have a well-defined, ovoid lesion with rounded or gently lobulated margins.17 The tumor usually causes displacement of adjacent structures, rather than invasion or destruction. Most tumors display a heterogenous intermediate signal intensity on T1-weighted sequences. Lesions 30 y).3 The median age of the pediatric SS population is 13 years (range, 1 to 20 y), with a sex ratio of 1.16 (male/ female); tumor site is mostly limb-based (85%); median maximum tumor size is between 5 and 10 cm; 3% of patients have distant metastases; and 40% to 60% of tumors correspond to the monophasic subtype and harbor SYT-SSX1 or SYT-SSX2 fusion transcripts in 70% and 30% of cases, respectively.2,7,27 In comparison, a study including 120 adults and 45 patients under the age of 25 years showed that the median age was 35 years; the sex ratio was 1.3; a limb primary was present in 67% of cases; median tumor diameter was 7 cm; and 16% of patients presented distant metastases, with 72% of monophasic tumors, and SYT-SSX1 or SYT-SSX2 fusion transcripts in 68% and 32% of cases, respectively.1
PROGNOSTIC FACTORS Compared with rhabdomyosarcoma, SS has traditionally been considered to be associated with a poor overall outcome in children. Reported 5-year survival rates in children range from 62.8% to 84%6,27,28 and 10-year survival rates range from 61% to 69%.4,6 However, it has recently emerged that not all SS present the same poor outcome. Various factors have been reported to have an adverse prognostic significance, although this impact still needs to be confirmed in prospective studies. Published data indicate a strong association between death from malignancy and advanced tumor stage at diagnosis.1,2,6,27 Prognosis largely depends on the feasibility of surgical resection, which is correlated with the IRS grading system and the presence of metastases.5 IRS IV group has a dismal outlook with only a minority of survivors in this population (5-year overall survival [OS], 13%).2,6,27 A primary tumor in an extremity is correlated with a better OS compared with axial lesions.2,28,29 In adults, bone and/or neurovascular invasion impact negatively on survival.28 According to the literature, tumor size is an important prognostic factor for both OS and event-free survival,9,10,26 The cut-off most frequently used is 5 cm in children and 7 cm in adults. Large tumors are associated with poorer outcome.2,7,30 Some data have suggested a possible relationship between somatic chromosomal instabilities and clinical outcomes. Pediatric patients are known to have excellent clinical outcomes compared with adults, although both populations harbor exactly the same histologic features and translocations. A 67-gene signature related to chromosome integrity, mitotic control, and genome complexity, called CINSARC (Complexity Index in Sarcoma), has been analyzed as a tool to predict the risk of metastatic spread and potentially the response to chemotherapy in SS. Moreover, a recent study showed that metastatic outcomes are strongly associated with chromosomal complexity in both age strata and that this instability is frequent in adult but not in pediatric SS.8 Given that the initial genetic driver event (t(X;18) translocation) is the same for both situations, this difference in terms of instability tends to suggest that an independent, as yet unknown, mechanism is permissive to chromosome instability in adult patients and resistant in pediatric patients. However, no genomic alteration or significantly differentially expressed genes have been identified for such mechanisms.8
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TREATMENT The approach currently adopted by the European Paediatric Soft Tissue Sarcoma Group (EpSSG) study for NRMS-STS uses a multimodal therapeutic strategy adapted to already known risk factors in this tumor: IRS group, site of primary, and tumor size. Complete resection with clear margins remains the treatment of choice for localized SS in children.31 If complete surgical resection is not immediately possible, a simple biopsy is recommended, followed by a delayed surgery after tumor reduction with neoadjuvant chemotherapy.2 Cooperative groups encourage first-line biopsy to reduce the number of initial positivemargin resections (IRS group II) and therefore increase the number of group III patients, in whom tumors may subsequently be completely removed after chemotherapy. Indeed, high response rates to chemotherapy in SS have been well documented in pediatric series, and pediatric oncologists tend to consider SS as an intermediate chemosensitive tumor and have designed treatments around this concept.2,3,29 In children, the response rate to neoadjuvant chemotherapy has been estimated to be between 60% and 65%.2,3,29 Moreover, a retrospective analysis on 271 patients of all ages performed at the Istituto Nazionale Tumori in Milan reported better outcomes for children, most of whom received adjuvant chemotherapy, with a strong correlation between use of chemotherapy and survival.3,9 Moreover, patients with tumors >5 cm, even after gross resection (IRS groups I to II), may have more metastatic disease progression leading to the proposal of systematic adjuvant chemotherapy in the presence of large tumors.3,30 However, no prospective study has formally demonstrated the absolute benefit of chemotherapy in children with SS in terms of survival gain. The place of chemotherapy remains controversial in adults and is only mandatory in the case of metastatic or initially unresectable tumor.32,33 Many drugs are active on this tumor, but the most commonly used regimens include doxorubicin and/or ifosfamide.2,7 The role of local adjuvant radiotherapy in grossly resected tumors is controversial and may be omitted in tumors presenting favorable features.2,7 Total radiotherapy dose ranges between 50.4 to 59 Gy according to initial IRS staging. Because of the low rate of nodal involvement in this tumor, prophylactic radiotherapy to regional nodes is not recommended. As an example, EpSSG recommendations in the NRSTS 2005 protocol for localized SS tumors are as follows: For limb primary, IRS group I: no radiotherapy, chemotherapy only if tumor size >5 cm. For limb primary, IRS group II: try to avoid this situation and propose an immediate primary reexcision if feasible; systematic chemotherapy with ifosfamide-doxorubicin regimen; radiotherapy can be omitted in young patients. For IRS III and axial primary: systematic chemotherapy with ifosfamide-doxorubicin regimen; delayed surgery as possible, and systematic local radiotherapy.
CONCLUSIONS In a unique prospective study based on 44 relapsing cases out of a series of 118 consecutive patients younger than 21 years of age with nonmetastatic SS, Ferrari et al described the pattern of recurrence, salvage rates, and prognostic variables influencing survival.27 Relapses were predominantly metastatic (sometimes combined with local r
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relapse). Time to relapse was fairly short, ranging from 4 to 108 months (median: 20 mo). Five-year and 10-year overall survivals after relapse were only 29.7% and 21.0%, respectively. Univariate analysis showed that patients in whom relapse was local and occurred later (> 18 mo after the initial diagnosis) had a reasonable chance of cure, with a 10-year OS of 68.6%, whereas patients with multiple metastases had a dismal outcome. The efficacy of secondline therapy strongly influenced the final outcome of the patients.27 Patients with SS should be followed for at least 10 years because of the tendency for late recurrence and metastasis.4 Recurrence and metastasis appear occurring earlier in pediatric patients.4,34 More aggressive multimodality treatment, including new radiotherapy techniques, and new drugs should be studied in patients with initial poor prognostic factors, metastatic tumors, or after relapse.6 Recent data show that pazopanib, a potent and selective multi-targeted receptor tyrosine kinase inhibitor, may be effective in adult SS and should be tested in children.35 ACKNOWLEDGMENTS The authors thank “La Ligue contre le Cancer” for their financial support and Anthony Saul for editorial assistance. REFERENCES 1. 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. 2004;22:4040–4050. 2. Orbach D, Mc Dowell H, Rey A, et al. Sparing strategy does not compromise prognosis in pediatric localized synovial sarcoma: experience of the International Society of Pediatric Oncology, Malignant Mesenchymal Tumors (SIOPMMT) Working Group. Pediatr Blood Cancer. 2011;57: 1130–1136. 3. 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. 2004;101:627–634. 4. Speth BM, Krieg AH, Kaelin A, et al. Synovial sarcoma in patients under 20 years of age: a multicenter study with a minimum follow-up of 10 years. J Child Orthop. 2011;5: 335–342. 5. Ferrari A, Casanova M. New concepts for the treatment of pediatric nonrhabdomyosarcoma soft tissue sarcomas. Expert Rev Anticancer Ther. 2005;5:307–318. 6. Brennan B, Stevens M, Kelsey A, et al. Synovial sarcoma in childhood and adolescence: a retrospective series of 77 patients registered by the Children’s Cancer and Leukaemia Group between 1991 and 2006. Pediatr. 2010;55:85–90. 7. Okcu MF, Munsell M, Treuner J, et al. Synovial sarcoma of childhood and adolescence: a multicenter, multivariate analysis of outcome. J Clin Oncol. 2003;21:1602–1611. 8. Lagarde P, Przybyl J, Brulard C, et al. Chromosome instability accounts for reverse metastatic outcomes of pediatric and adult synovial sarcomas. J Clin Oncol. 2013;31:608–615. 9. Sultan I, Rodriguez-Galindo C, Saab R, et al. Comparing children and adults with synovial sarcoma in the Surveillance, Epidemiology, and End Results program, 1983 to 2005: an analysis of 1268 patients. Cancer. 2009;115:3537–3547. 10. Ferrari A, Miceli R, Casanova M, et al. Adult-type soft tissue sarcomas in paediatric age: a nomogram-based prognostic comparison with adult sarcoma. Eur J Cancer. 2007;43: 2691–2697. 11. Kransdorf MJ, Jelinek JS, Moser RP Jr, et al. Soft-tissue masses: diagnosis using MR imaging. Am J Roentgenol. 1989;153:541–547. r
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