Soft tissue sarcomas are malignant tumors of non-epithelial, extraskeletal tissue of the body, including the muscle, fat, fibrous tissue, vessels and peripheral nervous system. They form a diverse group of mesenchymal malignancies, classified on a histologic basis according to the adult tissue they resemble or are supposed to derive from. These tumors are rare. With an annual incidence of around 2-3/100,000, they account for less than 1% of all malignant tumors and 2% of all cancer-related deaths, although in children soft tissue sarcomas represent about 8% of all malignancies.
An Important Note:
This article gives a description of pathological findings, clinical features and treatment options for patients with synovial sarcoma and provides an introduction for physicians not familiar with this disease. The authors are involved in the daily management of children and adolescents with soft tissue sarcomas. Therefore, in particular regarding treatment, the discussion represents mainly the point of view of a paediatric oncologist.
Synovial sarcoma (SS) represents one of the most frequent malignant tumors of soft tissues, accounting for about 8% of all soft tissue sarcomas. Weiss reports that SS is the most frequent non-rhabdomyosarcomatous soft tissue sarcoma in adolescents and young adults, accounting for 15-20% of cases.1 The peak of incidence is in the 3rd decade (approximately 30% of cases occur in patients less than twenty years of age), and males are affected more often than females (male/female ratio around 1.2:1). A recent paper describes clinical findings and outcome of 1268 cases (213 children/adolescents, i.e.less than 18 years, and 1055 adults) registered in the North-American Surveillance, Epidemiology, and End Results (SEER) 17 database from 1983 to 2005.2
Despite its name, synovial sarcoma does not arise from synovial tissue. As with most soft tissue sarcomas, the pathogenesis of SS is still unknown and there are no well-established risk factors; therefore, no screening program has been evaluated or could be recommended.
Pathology and Biology of Synovial Sarcomas
SS is clinically, morphologically and genetically a distinct sarcoma, characterized by the specific chromosomal translocation t(X;18) (p11;q11). In the last ‘WHO Classification of Soft Tissue and Bone Tumours’ SS is classified among malignant tumours of uncertain differentiation, lacking a precise normal tissue counterpart.3 Even if typical of soft tissues, SS are described also in other sites, such as the kidney, lung, and pleura.
SSs are classified based on their morphological appearance as:
- Biphasic SS
- Monophasic SS bu
- Monophasic epithelial SS (exceptional)
- Poorly differentiated SS
Biphasic SS shows both spindle and epithelial cells in varying proportions (Figure 1).
Monophasic SS shows only the spindle cell component. (Figure 2). The monophasic purely glandular epithelial SS is a theoretical entity and requires molecular genetics to be distinguished from adenocarcinoma.
Poorly differentiated SS shows one of three morphologic patterns: a large cell / epithelioid / rhabdoid pattern, a small cell pattern, and a high grade spindle cell pattern (Figure 3).
Among the different grading systems available, the French system, FNCLCC (French Federation of Cancer Centers Sarcoma Group), is the most often used for adult-type soft tissue sarcomas.4 It is a score system in which the sum of D (differentiation; ‘D3’ by default in SS), M (mitoses: below 10/10HPF; between 10 and 19/10HPF; more than 19/HPF) and N (necrosis: absent; less than 50%; more than 50%) gives the grade 1, 2 or 3. Even if in therapeutic protocols SS is considered among high-grade sarcomas by definition, the FNCLCC grade is reported as the most predictive histological factor for metastasis in SS. Less than 10 mitoses/10HPF, absence of necrosis, absence of poorly differentiated areas, pediatric age, size smaller than 5 cm, and eradicated localized tumors resulted in a better prognosis.5
Translocations: The online Atlas of Genetics and Cytogenetics in Oncology and Haematology contains a webpage summarizing classification and other information about Synovial Sarcoma. Also, see the sidebar "Molecular Genetics", below.
Gross Findings: The diameter of SSs varies from 3 to 10 centimetres (cm). Tumors tend to be multinodular and can be cystic. When they grow slowly, they tend to have pushing margins and are circumscribed by a fibrous pseudocapsule. Poorly differentiated SS grows rapidly with infiltrative margins, showing haemorrhage and necrosis.
Histological Findings: SSs are composed of two morphologically and immunophenotypically distinct cell types: spindle cells, uniform and relatively small, with oval nuclei and scarce cytoplasm, forming solid sheets, and epithelial cells, characterized by true epithelial differentiation.
Poorly Differentiated Synovial Sarcoma is considered as a form of progression, with a more aggressive behavior and a higher percentage of metastase.1 In the less cellular areas there can be hyalinization, myxoid changes and calcifications, with or without ossification and rarely chondroid changes. Focal tumoral calcification, with or without ossification, is present in about one third of SSs. The authors have prepared a table of the clinical and pathological characteristics of synovial sarcoma.
Molecular genetics: SS are characterized as a group by the presence of a specific translocation t(X;18), that fuses the SYT gene from chromosome 18 with SSX1 (about 2/3 of cases), SSX2 (about 1/3 of cases) or SSX4 (rare cases) gene from X chromosome. As a consequence of the translocation, a fusion transcript is formed at mRNA level, detectable by PCR tecniques. Cases with both SYT/SSX1 and SYT/SSX2 fusion transcripts have been described. SYT/SSX1 is reported significantly associated with biphasic SS. The association between SYT/SSX1 with reduced metastasis-free survival in localized tumors was not confirmed in all series, and the prognostic relevance of the fusion gene typing is still uncertain.6,7
Clinical Features and Diagnosis of Synovial Sarcoma
SS can arise anywhere in the soft part of the body, generally as a progressively expanding mass. The most common clinical presentation is a slow-growing mass in the soft tissues of the lower extremity, especially around the knee and the ankle. The tumor is often near a joint, tendon or bursa. Head and neck region, abdominal wall, retroperitoneum, mediastinum, pleura, lungs and other organs are less common locations.
Various symptoms may be related to these locations, although the painless mass remains the most frequent presentation. Difficulty in swallowing and breathing, or alteration of voice, for example, might be associated with SS of the head and neck region. Pain may be related to the involvement of nerves. Because the tumor grows slowly, symptoms may be present for a long time before the diagnosis is made. This may delay diagnosis.
As it is a high-grade sarcoma, SS is characterised by local invasiveness and a propensity to metastasize. At the time of diagnosis, less than 10% of cases present with metastases (particularly to the lung), but metastatic spread can successively occur in 25-50% of cases.
In order to determine local and distant extent of disease, a complete set of staging studies is necessary at diagnosis. Imaging studies are critical in determining tumor size and local extent. Ultrasonogram is often the first instrumental assessment to be used. Computed Tomography (CT) scan or Magnetic Resonance Imaging (MRI) of the primary site are mandatory for local extension assessment before any treatment. MRI of an extremity is usually considered superior in defining soft tissue extension (Figure 4).
After the accurate description of the local extent of the tumor, pathological assessment is necessary to define the histological diagnosis. The initial biopsy has the aim to define the diagnosis, but also should provide enough material for immunochemistry, cytogenetics, biological studies and central pathology review for patients to be included in multicenter clinical trials.
In the case of a large and deep soft tissue mass, biopsy should be always the initial surgical procedure, in order to avoid inadequate surgery. Open biopsy (incisional biopsy) or core needle biopsy (tru-cut, guided by ultrasound or CT scan) is preferred to fine needle aspirates that could establish the presence of malignancy, but rarely identify the subtype or provide the tissue required for additional studies. In any case, the initial biopsy should be carefully planned by an experienced surgeon, taking into account the possible subsequent definitive surgery, that must include the scar and the biopsy tract. For example, in SS of the extremities, the incision must be longitudinal to the limb and not traverse multiple compartments; very careful hemostasis must be ensured to minimize the risk of post-surgical hematoma and need for drains. In all cases, tissue should be sent fresh to the laboratory. When this is not possible, formalin-based fixative must be used.
After the radiological evaluation of tumor extent and biopsy, the diagnostic work-up is completed by staging investigations, aimed to detect regional and distant metastases. Chest CT scan, Technetium bone scan and abdominal ultrasound have been generally required to identify lung, bone, and abdominal metastases, respectively. Attention to regional lymph nodes of the primary site is also important. Positron emission tomography (PET) is not yet considered a standard staging investigation for SS.
A recent study from European pediatric groups on 258 SS patients less than 21 years old discussed whether staging diagnostic procedures are really necessary in all patients.8 The analysis showed that 5.8% of cases had distant metastases at diagnosis, and 86% localized at lung. The presence of metastases was unassociated with patients’ gender or age, tumor grade or site, but it was influenced by T-status, and especially primary tumor size: the risk of metastases was 32 times higher in cases of tumor > 5 cm than for tumors £ 5 cm. These findings would suggest that tumor diameter can be used as a variable for identifying patients at greater risk of metastases and warranting more accurate radiological investigations, and patients at low risk for which ionizing radiation exposures with carcinogenic potential may be avoided, at staging as well as at follow-up. According to these results, chest CT scanning may be omitted for patients with tumors less than 5 cm and, given the very low risk of bone metastases, bone scans may be recommended only in cases with evidence of lung metastases or symptoms suspected for bone lesions.
A risk-adapted treatment strategy is based on pre-treatment staging and post-surgical clinical status. Pediatric oncologists usually stage SS according to the clinical TNM classification (based on local invasiveness, T1 and T2, and tumor size, A or B, i.e. less or more than 5 cm; absence or presence of nodal and distant involvement: N0 and N1, M0 and M1, respectively.9 The Intergroup Rhabdomyosarcoma Study (IRS) post-surgical grouping system is based on the degree of surgical resection10:
- Group I - completely-excised tumors with negative microscopic margins
- Group II - grossly-resected tumors with microscopic residual disease and/or regional lymph nodal spread
- Group III - gross residual disease after incomplete resection or biopsy
- Group IV - metastases at onset
Adult oncologists often stage using the American Joint Committee on Cancer Staging system which incorporates the histological grade (which is presumably high in all SS patients) in addition to size and depth (most SS are deep-seated).
A recent study of the Associazione Italiana Ematologia Oncologia Pediatrica – Soft Tissue Sarcoma Committee (AIEOP-STSC) on 115 pediatric SS cases evidenced the prognostic role of tumor site: the outcome of patients with axial/non-extremity SS (e.g. head–neck, trunk, lung-pleura, retroperitoneum) was worse than that of patients with limb tumors (5-year OS of 55% and 84% respectively), mainly due to local failure.11 This study suggests that tumor site should be considered when defining a risk-adapted treatment strategy for SS.
The current protocol of the European pediatric Soft Tissue Sarcoma Study Group (EpSSG) stratify patients according to surgical stage (IRS), tumor size and tumor site.
The prognosis of SS patients is related to the feasibility of surgical resection, tumor size, and local invasiveness. Patients with small tumors that can be completely removed at diagnosis have an excellent prognosis. For tumors larger than 5 cm, the risk of developing distant metastases is higher. Pediatric series11-16 reported survival higher than 80% for IRS Group I-II patients, but around 60-70% for cases > 5 cm. For patients with unresectable disease at diagnosis (IRS group III), survival has been reported between 50 and 60%,17 but it clearly is less for cases localized in head-neck region, lung and mediastinum, abdomen. The prognosis is particularly poor for SS patients with distant metastases at onset2 and for patients whose tumors relapse. A recent analysis of the Italian pediatric group on 44 relapsing cases (out of a series of 118 patients) showed that overall survival of recurrent disease was 29.7% and 21.0% 5 and 10 years after relapsing, respectively. The variables influencing survival were the timing and type of relapse (late and local relapse had a better survival) and the chances of a secondary remission, which correlated strongly with the feasibility of complete surgery. These findings permit to identify a possible risk-adapted stratification enabling a better planning of second-line treatment. An aggressive surgical approach should be recommended, while experimental therapies can be offered to patients with little chance of salvage.18
The optimal treatment approach to SS remains to be determined. As in other soft tissue sarcomas, the standard treatment for localized disease is surgery, and radiotherapy has a role in improving local control after less than compartmental resections. The role of chemotherapy is still not clear and the rarity of these tumors hinders the accrual of adequate numbers for a randomized trial. However, it is possible to say that surgical resection plus or minus adjuvant radiotherapy and/or doxorubicin/ifosfamide based chemotherapy are the current mainstays of treatment.
Sarcoma Centers: Synovial sarcoma is a rare tumor and its treatment is necessarily multidisciplinary and complex. Patients should be referred to selected institutions with adequate experience in treating patients with soft tissue sarcomas, and with multidisciplinary skills in enrolling patients in clinical trials.
Surgery is the keystone of treatment for SS. It aims to obtain adequate margins with little or no long-term sequelae, and should be attempted as the primary approach only if complete and non-mutilating resection is considered feasible. Otherwise, after diagnostic biopsy, chemotherapy and/or radiotherapy should be given to shrink the tumor and make it more amenable to subsequent surgery. Achieving "adequate margins" is a crucial issue, strictly influenced by the type of healthy tissue surrounding the tumor. It is very difficult to apply a metric definition of a "safe distance" between tumor and resection margins.19 The June 2004 Milan Consensus Conference on Adult Soft Tissue Sarcomas suggested a definition to which adequate margins are "those > 1 cm of healthy tissue around the tumor, in all directions, when the tissue is a muscle, and > 1 mm of healthy tissue around the tumor when the tissue is periostium, vessel sheath, epineurium, or muscular fascia." Inadequate surgical margins adversely affect local outcome — and consequently also overall survival — though some studies on adult soft tissue sarcomas failed to find a strong correlation between quality of surgery and final outcome. However, adequate surgery could be defined an R0 resection that renders the patient classified as IRS Group I. This includes both compartment resections (en bloc resection of the tumor and the entire compartment of origin, where tumor was entirely anatomically confined) and wide excisions (en bloc excisions through normal tissue, beyond the reactive zone but within the muscular compartment, removing the tumor with its pseudocapsule).
Surgery: When and Where - The quality of the surgical operation is crucial. Patients with deep and large soft part masses, i.e. in excess of 5 cm (highly suspect of being sarcomas) should be referred to specialist centers for local treatment, preferably before undergoing biopsy.
Concerning the role of chemotherapy, it is quite surprising that, over the years, completely different strategies have been developed in pediatric oncology protocols compared with the adult setting. Since quite high rates of response to chemotherapy have been recorded in pediatric series, pediatric oncologists have considered SS as a "rhabdomyosarcoma-like" tumor, in other words a chemosensitive tumor. Therefore pediatric patients have received adjuvant chemotherapy regardless of stage, even after the complete excision of very small tumors.11-15,20-21 Differently, adjuvant chemotherapy has generally only been used in adult patients in trials that included all soft tissue sarcoma histotypes and a no-therapy control arm.22-27
Only recently adult oncologists have recognized a possible role for adjuvant chemotherapy for high-risk cases, i.e. large tumor size.26 While some studies on adult SS showed no any evidence of a survival benefit for adjuvant chemotherapy and stated that chemotherapy should not be delivered outside a clinical trial setting,24,27-29 others suggested that SS may be considered more chemosensitive than other adult soft tissue sarcomas, with a survival benefit from neoadjuvant/adjuvant chemotherapy, especially when patients were selected according to risk factors.30-32
It remains to be understood whether the different historical approaches of pediatric versus adult medical oncologists in treating SS patients had determined differences in outcome. In the large SEER series, the estimated 5-year cancer-specific survival was 83% for children/adolescents and 62% for adults (P < .001).2 However, on one side it is possible that this difference in outcome might be related to biological variables and different incidence of prognostic factors, on the other side the survival rates of adult patients in the most recent adult series published by major referral institutions or cooperative groups did not differ substantially from what reported by pediatric groups, though chemotherapy was used in a lower proportion of cases.
It remains to be demonstrated whether the worse outcome of adult synovial sarcoma reported in epidemiological analyses relates to a different access to care, since it has been variously reported that adults with cancer may have fewer chances of being enrolled in clinical trials and, more in general, of being treated at referral centers than children.33,34
Concerning pediatric series, the multicenter retrospective multivariate analysis coordinated by the M. D. Anderson Cancer Center which included the updated results of the previously published pediatric series examined the clinical history and treatment strategy of children and adolescents with SS.15 Overall survival (OS) of the 219 patients was 80% at 5 years, higher than that reported in adult series, and chemotherapy response rate was 60%, higher than that usually obtained in adult sarcomas. However, the analysis suggested that adjuvant chemotherapy had no impact on survival in IRS Group I-II patients, event-free survival (EFS) was 84% for the 37 patients treated without and 78% for 122 patients treated with adjuvant chemotherapy.15
A study from the Istituto Nazionale Tumori of Milan of 271 patients compared the clinical findings, treatment modalities and outcomes of SS at different ages.35 No major differences in clinical presentation were noted, except a tendency for larger tumor size for older patients, suggesting in principle no major biological differences correlated with age. However, when patients with grossly-resected disease were considered, significant differences in the use of adjuvant chemotherapy were seen, with a strong correlation of survival rates with age groups and use of chemotherapy. The metastases-free survival (MFS) was 60% in patients given chemotherapy and 48% in those who were not. Likewise, MFS dropped from 69% to 53% to 43% for the 0-16 year-old (78% given chemotherapy), 17-30 year-old (21% given chemotherapy) and >30 year-old (15% given chemotherapy) age brackets, respectively; see Figure 5.35 Of course, this retrospective analysis cannot be construed as a formal demonstration of the efficacy of adjuvant chemotherapy in SS, but would nonetheless suggest that it has a role.
Response to Chemotherapy
The biology of synovial sarcoma probably falls between most typical adult soft tissue sarcomas and paediatric small round cell tumors such as rhabdomyosarcoma or Ewing’s sarcoma. The response rate to chemotherapy, in fact, is approximately 60% for synovial sarcoma, less than 40% for adult soft tissue sarcomas and 80% for rhabdomyosarcoma.
Though it may be true that unfavorable clinical findings may affect adult patients more than children (and age "per se" could probably be considered a prognostic factor for soft tissue sarcomas), a different biology of SS when arising in adults as opposed to children is, at the very least, unlikely, and therefore, there is no reason to treat the same disease at the same stage in different ways according to the age of the patient.
A further analysis comes from the Italian and German pediatric soft tissue sarcoma cooperative groups in which retrospective data on 150 pediatric patients with grossly-resected SS were reviewed.16 This study was unable to cast any light on the role of adjuvant chemotherapy, however, because nearly all but very few patients received chemotherapy. Nevertheless, it pointed to a subset of patients at very low risk of metastases: four local relapses and no metastatic relapses were seen among the 48 IRS group I patients with tumors < 5 cm. For this group, the use of adjuvant chemotherapy, as required in previous European pediatric trials, could be considered an over treatment.
The above discussed data were considered in the development of the recently-established protocol from the European pediatric Soft Tissue Sarcoma Study Group (EpSSG), the first European protocol that is specifically tailored for non-rhabdomyosarcoma soft tissue sarcomas. This protocol will recruit patients over all Europe. Its treatment rationale is influenced by previous pediatric experiences, but have taken suggestions from adult experiences and moved towards a treatment concept partially similar to that adopted in the adult setting36: the ifosfamide-doxorubicin chemotherapy is currently adopted as standard regimen, and its indication is given according to the patient’s risk stratification, based on tumor size and site and surgical stage, see Figure 6.37 In low-risk patients (completely resected tumors under 5 cm in size), chemotherapy is omitted.16
Radiotherapy plays a well-defined role in local control in soft tissue sarcomas. In adult patients with soft tissue sarcoma, radiotherapy is usually recommended after incomplete resection, but often also after wide excision, especially in case of large tumour. Certainly, the indication for radiotherapy has to be stricter in children and young adolescents with SS than in adults, given the higher risk of severe late effects of radiotherapy.
The above quoted INT Milan series reported only a favorable trend for the addition of radiotherapy in patients who initially had complete resection: in IRS group I patients, 5-year local relapse free survival (LRFS) was 78% in patients treated with and 67% in those treated without post-operative radiotherapy. However, a clear benefit was observed for patients whose initial resection was marginal: IRS Group II patients had a 5-year LRFS of 57% when radiotherapy was delivered and 7% when it was not.35 According to the EpSSG protocol, surgery could be considered as the sole local treatment for group I patients (though the need of irradiation in case of tumor > 5 cm is still an open question), while post-operative radiotherapy is required for IRS Group II patients.37
The local treatment strategy is more complicated in patients whose tumors are considered unresectable at diagnosis, and thus receive initial chemotherapy. For these patients, delayed surgery is the treatment of choice and every effort should be done to obtain complete resection. However, the need for additional radiotherapy in case of delayed complete resection remains an open question. Likewise, there are relative merits of pre-operative versus post-operative radiotherapy: post-operative radiotherapy carries a lower risk of complications, but pre-operative irradiation can improve the chances of achieving free margins at the secondary resection, may reduce the risk of intra-operative contamination, and smaller radiotherapy fields and lower doses can often be used. We believe that the choice of local treatment should be discussed in a multidisciplinary setting and the decision should be customized. Various factors should be considered, i.e. anatomical site, tumor size, and patient’s age, with the aim to give to all patients the "best possible local treatment."
As with other soft tissue sarcomas, in the next years we expect to improve our understanding of SS, and we particularly need novel therapeutic approaches. The specific chromosomal translocation and fusion proteins occurring in SS38 and the proteins overexpressed by the tumor cells (epidermal growth factor receptor EGFR, HER-2/neu, Bcl-2),39,40 may become the targets of new molecular agents specifically designed to influence the tumor’s biology.41 Clinical investigative trials on targeted therapy are ongoing. Investigations are underway on the role of new drugs, such as trabectidine, multi-target anti-tyrosine kinases inhibitors, and on monoclonal antibody against frizzled homologue 10 (FZD10), a cell-surface receptor in the Wnt pathway, or adoptive immunotherapy using tumor-infiltrating lymphocytes against NY-ESO-1 cancer/testis antigen (expressed in 80% of SS).42-45 Similarly, further studies are needed to investigate the role of the Bcl-2 antisense oligonucleotide therapy, as most SS overexpress the anti-apoptotic protein Bcl-2, that correlates with tumor growth, chemoresistance and poor outcome in various cancers.6
Targeted Therapy: Synovial sarcoma is a particular tumor with important promise for targeted therapy directed against the fusion protein produced by the specific translocation or against tyrosine kinases receptors overexpressed by tumor cells.
The developing of cooperative trials involving both pediatric and adult patients with SS could be the right strategy to increase biological studies and obtain, in a rare disease as SS, the large accrual of cases necessary to design adequate clinical trials.