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Synovial Sarcoma
by
Andrea Ferrari, M.D. Pediatric Oncology Unit
and
Paola Collini, M.D. Pathology Department
Istituto Nazionale per lo Studio e la Cura dei Tumori, Milano, Italy. Via G. Venezian, 1 -20133 Milano MI, Italy
Important Note This manuscript 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 the treatment, the discussion represents mainly the point of view of a paediatric oncologist.
Introduction 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.
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 (Weiss 2001). 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).
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 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 (WHO 2002). 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 shows both spindle and epithelial cells in varying proportions (Figure 1).
Figure 1: This is a picture of a biphasic synovial sarcoma, in which we can see the coexistence of both the epithelial glandular component and the spindle cell component.
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
Figure 2: This is a picture of a monophasic synovial sarcoma, in which only the spindle cell component is present.
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).
Figure 3: This is a poorly differentiated synovial sarcoma, small cell type, characterized by a prominent hemangiopericytomatous pattern formed by dilated vascular structures, between which there are cells that are roundish and small, like those seen in a small round cell tumor, i.e. Ewing's sarcoma. In these cases molecular genetic analyses could be required to differentiate between these two entities.
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 (Guillou 1997). 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 (Guillou 2004).
Clinical features and diagnosis 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).
Figure 4: Magnetic Resonance Imaging (MRI) of a 17-year old boy with a synovial sarcoma of the proximal thigh: MRI is mandatory for the adequate assessment of the local extension of the tumor. MRI seems superior to CT scans in defining soft tissue extension.
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. Wwhen this is not possible, formalin-based fixative must be used.
Staging 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 are required to identify lung, bone, and abdominal metastases, respectively. Attention to regional lymph nodes of the primary site are also important. Positron emission tomography (PET) is not yet considered a standard staging investigation for SS.
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 (Harmer 1982). The Intergroup Rhabdomyosarcoma Study (IRS) post-surgical grouping system is based on the degree of surgical resection (Maurer 1988):
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).
Prognosis 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 series (Ladenstein 1993, Pappo 1994, Ferrari 1999, Okcu 2003, Brecht in press) 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 70% (but it clearly is less for cases localized in head-neck region, lung and mediastinum, abdomen). For patients with distant metastases, overall results are poor.
Treatment 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.
Surgery 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 (Gronchi 2005). 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).
Chemotherapy 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 (Ladenstein 1993, Pappo 1994, and Ferrari 1999). 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 (Sarcoma Meta Analysis Collaboration 2997, Bergh 1999, Lewis 2000, Spillane 2000, Frustaci 2001, and Trassard 2001). Only recently have adult oncologists recognized a possible role for adjuvant chemotherapy for high-risk cases, i.e. large tumor size (Frustaci 2001, Spurrel 2005).
A 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 (Okcu 2003). 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 (Okcu 2003).
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 (Ferrari 2004). 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 (Ferrari 2004). 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.
Figure 5: Study from the Istituto Nazionale Tumori of Milan, Italy (retrospective analysis of 271 patients of all ages): survival rates correlated with age and with the use of chemotherapy, that was clearly different in the different age groups (Ferrari A, et al. Cancer, 101:627:634; 2004).
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 (Brecht in press). 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 (in which SS was considered a “rhabdomyosarcoma-like tumor” and chemotherapy was given to all patients) and adult experiences (where ifosfamide and doxorubicin chemotherapy was given sparsely). Chemotherapy will be omitted in IRS group I, ≤ 5 cm patients, whereas for other subgroups fewer chemotherapy cycles will be administered, but with a greater dose-intensity of ifosfamide and doxorubicin, see Figure 6 (Ferrari 2005).
Figure 6: Risk-adapted treatment program for synovial sarcoma, European pediatric Soft Tissue Sarcoma Study Group EpSSG, NRSTS 2005 protocol. Click on the figure to view a larger version of it.
Radiotherapy 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 (Ferrari 2004). 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 (Ferrari 2005).
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”.
Future issues As for 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 occurring in SS (Kawaguchi 2005), as well as the tyrosine kinases receptors identified in SS, epidermal growth factor receptor EGFR and HER-2/neu (Tamborini 2004, Thomas 2005), may become the targets of new molecular agents specifically designed to influence the tumor’s biology (Albritton 2005). Clinical investigative trials on targeted therapy are ongoing. 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 (Mancuso 2000).
The developing of cooperative trials involving both pediatric and adults 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.
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V2N6 ESUN Copyright © 2005 Liddy Shriver Sarcoma Initiative.
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