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© 2000 American Society for Clinical Oncology Synovial Sarcoma: A Clinicopathologic, Staging, and Prognostic AssessmentFrom the Sarcoma Unit, Royal Marsden Hospital, London, United Kingdom. Address reprint requests to A. Spillane, FRACS, Melanoma and Sarcoma Unit, Royal Marsden National Health Service Trust, Fulham Rd, London SW3 6JJ, England; email ajspillane{at}ozemail.com.au
PURPOSE: Synovial sarcoma (SS) is a common soft tissue sarcoma (STS) with a propensity for young adults and notable sensitivity to chemotherapy (CT). This study provides a current clinicopathologic, staging, and prognostic assessment for SS. The problems with the current American Joint Committee for Cancer (AJCC) Staging System in relation to SS are discussed. METHODS: Review of a prospective database supplemented by retrospective data.
RESULTS: One hundred fifty patients were assessed; median age was 30 years and median follow-up was 52 months. Overall actuarial 5-year survival rate was 57%. Size trend, but not a cutoff of less than 5 cm versus CONCLUSION: SS tends to affect young people. In this subtype of STS, size trend is the most significant influence on stage and hence survival; however, smaller SSs have an unexpectedly poor prognosis. Adequate local control may affect survival. SS is often chemosensitive, and given its poor prognosis, multicenter trials of adjuvant therapy are warranted.
SYNOVIAL SARCOMA (SS) is a rare but distinctive soft tissue sarcoma (STS) that displays epithelial differentiation. It represents between 5% to 10% of STS,1-3 with perhaps 200 new cases a year occurring in the United Kingdom and 800 cases per year in the United States.1 SS has been described as "a clinically and morphologically well-defined entity that has been extensively described in the literature."2 However, even in more recent publications, the misconception that SS is somehow related to synovial tissues and hence arises in the vicinity of large joints is perpetuated.4 Recently SS was noted to have increased postchemotherapy survival time on univariate analysis,5 and in the last 10 years, the sensitivity of SS to ifosfamide-based chemotherapy has been documented, with encouraging results from high-dose ifosfamide therapy.6,7 No large reviews of SS have included a significant number of cases treated with ifosfamide-based chemotherapy. A modified staging system for extremity STS from the Royal Marsden National Health Service Trust (RMH) was recently published.8 The authors recommended testing it against large series of patients with STS, including those with nonextremity tumors. We have therefore assessed this case series with the modified RMH Staging System8 and the American Joint Committee on Cancer (AJCC)/International Union Against Cancer (UICC) Fifth Edition Staging Systems9,10 to evaluate their predictive value in this subtype of STS. Thus the intention of this study was to perform a clinicopathologic correlation and staging assessment and determine prognostic factors important for SS.
Information was initially gathered from the RMH’s prospectively collected database. The period of assessment started with all patients registered at RMH from April 1987 until May 1998. Information was supplemented by review of the hospital records, liaison with referring physicians, and review of the original histopathology reports from the referring hospitals when the patient presented having already had excisional biopsy, local recurrence (LR), or metastatic disease (MD). In nearly all cases, original histopathology had been reviewed at the time of referral by one anatomic pathologist with a specialized interest in this disease (C.F.). The other five cases were reviewed before inclusion in the study (two by another expert second opinion). Detailed information was recorded on tumor characteristics, including immunohistochemistry. Follow-up information was obtained from regular outpatient visits in the majority of cases or by correspondence with the referring physician in the case of distant referrals. Nine patients were seen for a second opinion only, but complete data and pathologic review were provided at the time of referral and have been updated in all cases. Up to 33 patients from this study may have been included in the 271 cases from which the proposed RMH Staging System8 was developed. Nine patients were excluded from analysis on the basis of inadequate information being available.
Definitions Persistent disease despite the primary therapy regimen was defined as local or regional recurrence or MD (or a combination) at 0 months for the purpose of calculation of the first disease-free interval, but the subgroup LR at 0 months was excluded from analysis of time to LR when relating it to surgical clearance. Survival figures were calculated from the time of the earliest histologic verification of the diagnosis of SS to the date of death or last recorded medical contact. Poorly differentiated SS (PDSS) is a recently described subtype of SS that has some typical morphologic features of monophasic or biphasic SS but also a variable proportion of poorly differentiated areas characterized by high cellularity, pleomorphism and polygonal or small round-cell morphology, numerous mitoses, and often necrosis. In each case there is, however, evidence of the diagnosis of SS made by immunohistochemical analysis, ultrastructural findings, and demonstration of the specific chromosomal translocation t(x;18)(p11.2;q11.2).11,12 This abnormality is specific for SS13 and is found in all morphologic subtypes results in rearrangement of the SYT gene on chromosome 18 with one of the subtypes (1, 2, or 4) of the SSX gene on chromosome X. Grading was assessed using the Trojani Classification.14 Unless stated otherwise in the RMH pathology report, all cases were assumed to be of high grade. Partial response to chemotherapy was defined as an objective decrease in tumor dimensions. Complete response (CR) was defined as complete pathologic or radiologic response. Survival, LR-free survival, metastasis-free survival, and disease-free survival were compared between different groups using the log-rank test, a test for trend being employed for ordered categories. Life-table curves were calculated using the Kaplan-Meier method.15 Analysis of the effect of prognostic factors on cause-specific survival was undertaken using Cox proportional hazards regression.16 The effect of LR on survival was assessed by using LR as a time-dependent covariate in Cox proportional hazards regression. Ninety-five percent confidence intervals (CI) were added to life-table curves at 5 years (5 and 10 years for overall survival).
Patient Characteristics There were 159 patients identified; nine were excluded from analysis because of inadequate information being available. The median age at diagnosis was 30 years (range, 3 to 85 years), with a median age of registration at RMH of 32 years (range, 5 to 76 years). The ratio of male to female patients was 1.08:1. The distribution of tumor locations is provided in Table 1. The most common site of disease was the proximal lower limb, but there was a broad spectrum of locations, including two intracardiac primary tumors, four primary thoracic (mediastinal, pleural, or pulmonary) tumors, a supraglottic laryngeal tumor, a hypopharyngeal tumor, and a maxillary antrum tumor. The site distribution of the 107 cases of extremity SS (excluding five buttock tumors) is further assessed in Fig 1 to test the reported relationship to large joints. There were three cases with an intra-articular component. Ninety-six patients presented to RMH during the management of their primary tumor, 26 presented to the RMH with LR, 21 presented with MD, and seven presented with MD as well as LR. Of the 96 patients who presented with localized primary disease, there were 63 patients whose presenting symptom was a mass, 26 presented with a painful mass, five had pain only, and two had other symptoms. Duration of symptoms ranged from 1 month to 15 years. Two cases occurred in radiotherapy fields 9 and 19 years after radiotherapy.
Pathology The histologic subtypes of SS were monophasic in 64 cases, biphasic in 69, and PDSS in 17. Three cases were categorized as being situated superficial to the deep fascia. Four patients were classified histologically as having low-grade disease (who clinically had histories of a mass for between 4 and 15 years before diagnosis), 12 cases were classified as intermediate grade, and the remaining cases were stated to be or assumed to be high grade. In all cases original tumor size was determined from the histopathology report, except for 28 cases for which the original size was obtained from clinical assessment or radiologic size, because no histopathologic measurement was made. The immunohistochemical profiles of the cases included in this study are listed in Table 2.
Diagnosis/Treatment The method of first histologic diagnosis was core biopsy in 38 patients (25.3%; procedure was performed at the RMH in 26 patients), incisional biopsy in 28 patients (18.7%; procedure performed at the RMH in no patients), and excisional biopsy in 84 cases (56.0%; procedure performed at the RMH in three). The first treatment modality used was surgery in 113 patients (75.3%), radiotherapy in 21 (14%), chemotherapy in 10 (6.7%), combined chemoradiotherapy in four, and isolated limb perfusion in two. The distribution of the surgical interventions performed at first referral to the RMH categorized according to the Enneking Classification17 included nine radical procedures (two amputations), 58 wide-excision procedures (20 patients underwent re-excision of the tumor bed when referred with a recent inadequate excision), 14 marginal excision procedures, and seven intracapsular removal procedures. This summary of procedures included 17 patients who were referred to the RMH with LR events chronologically separated from their primary presentation. Sixty-one patients received adjuvant postoperative radiotherapy for treatment of their primary tumor.
Chemotherapy
Outcome The median follow-up period in patients still alive was 52 months (range, 3 to 216 months). The overall 5-year survival rate was 57%(Fig 2). At final analysis, 66 patients were alive and disease-free (nine had not been seen in the last 12 months, including eight who returned home overseas). Sixteen patients were alive with disease; all except three had been seen in the last 3 months and were under frequent review at RMH. The other three patients were lost to follow-up, having returned to their country of origin for palliation and probably having died, but we were unable to confirm this. At final analysis, 67 patients had died from SS. Another patient died of an unrelated cause but had residual disease at the time of death.
Prognostic Factors Groupings of patients according to the AJCC/UICC (fifth edition) Staging Systems9,10 and the recently proposed RMH Staging System8 is provided in Table 4. Analysis of the actuarial 5-year overall survival, disease-free survival, and freedom from LR for each stage assessable from the AJCC and RMH Staging Systems is listed in Table 4, which also documents the predicted rates for survival where available. Survival plots for AJCC and RMH stages are shown in Figs 3 and 4, respectively. The other prognostic factors examined were sex; age; tumor size less than 5 cm versus  5 cm; size trend through the groups of less than 5 cm, 5 to less than 10 cm, 10 to less than 15 cm, and 15 cm; site; histologic subtype; and surgical margin after primary surgery. The univariate analysis of these factors appears in Table 5.
First Disease-Free Interval The 5-year disease-free survival rate was 33% (95% CI, 24% to 41%). Median first disease-free interval in the 103 patients who developed recurrent disease was 14 months (range, 0 to 170 months). When LR was the first site of recurrent disease (50 patients, including nine with synchronous MD), median time to LR was 23 months, with a range of 0 to 168 months; six patients had persistent local disease, ie, LR at 0 months. Of the 62 patients who developed MD (including the same nine patients with synchronous LR), median time to MD was 11 months (range, 0 to 170 months); 14 patients had MD at presentation. There were 12 other later cases of LR among the 53 patients who developed MD as a first site of disease relapse. There were a further 20 later cases of MD in the 41 patients who developed LR as a first site of disease relapse.
LR
MD The overall MD rate was 39%, with an actuarial 5-year MD rate of 53%. The first sites of MD were lung in 61 patients, lung and soft tissue or bone in eight, bone alone in four, soft tissue alone in four, bone and soft tissue in one, and lymph node in five (two synchronous with lung metastases). The actuarial 5-year survival rate after first metastasis was 6%, with a median survival of 11 months. Pulmonary metastasectomy was undertaken in 21 patients. Median postpulmonary metastasectomy survival duration was 38 months. The actuarial 5-year survival rate after pulmonary metastasectomy was 23%. When comparing the six pulmonary metastasectomy patients who were younger than 20 years of age with those who were 20 years, there was an improved survival in the younger group, but this did not reach significance.
Death
Large case series of this nature are published most often by specialist referral centers and tend to be biased by the number of cases with recurrent disease and MD at presentation to the institution. This can bias the clinical impression of the disease, with the worst cases self-selecting for referral to centers with higher levels of expertise. There are perhaps 200 cases of SS in the United Kingdom each year,1 with a rate of accrual in this series of only 14 per year. However, the rate of accrual in this series is more rapid than the other large series published.4,18-21 Acknowledging this case-mix bias, we collected data from the earliest definitive diagnosis in an attempt to give an accurate picture of the disease. SS remains a disease with poor prognosis, having an overall 5-year survival rate of 57% in this series. This is despite taking into account the sensitivity to chemotherapy that is reported in this study as well as in the literature over the last decade.5-7 The published 5-year survival figures have tended to improve slowly in the last 20 years, with Hadju et al22 reporting a 40% 5-year survival rate in 1977, Wright et al19 reporting a 55% 5-year survival rate in 1982, Brodsky et al18 reporting a 56% 5-year survival rate in 1992, and Singer et al4 reporting a 60% 5-year survival rate in 1996. However, if the inclusion dates of each study are taken into account, the trend is even less convincing.
Tumor size ( Effectively the AJCC system has only two assessable groups in SS: small high-grade and large high-grade tumors. This provides limited differentiating information on prognosis between patients. This contrasts with the RMH Staging System, which gives four groups with a stepped deterioration in prognosis with increasing stage and close approximation to the predicted survival figures (Table 4), enabling more useful discrimination of prognosis between patients. The identification of these inadequacies with the current AJCC/UICC Staging Systems in this relatively common subtype of STS as well as the important points raised in several recent editorials on the problems with the current staging systems used in STS26,28 are the basis for suggesting that future modification of the AJCC/UICC Staging Systems of STS should take these factors into account.
Other factors suggested previously to worsen prognosis in SS include male sex,19 patient age greater than 20 years,19,29 size of the tumor Adjuvant chemotherapy for localized resectable STS of adults has been shown on meta-analysis to improve the time to LR and distant recurrence and overall recurrence-free survival, but only a trend toward improved overall survival has been seen.35 The role of adjuvant chemotherapy in SS is difficult to assess in this series given that only 11 patients received it. Certainly, demonstrated sensitivity to ifosfamide and doxorubicin in combination for both therapeutic and neoadjuvant therapy in our study, the work of Rosen et al,7 and, more recently, the European Organization for Research and Treatment of Cancer analysis5 suggest that SS is usually chemosensitive. Given the overall poor prognosis in a predominantly young age group, multicenter trials of adjuvant therapy in this histologic subtype of high-risk STS patients are warranted. Therapeutic chemotherapy for STS has a documented overall response rate of approximately 24%, including doxorubicin/ifosfamide in combination, and although quality-of-life measures may demonstrate an advantage to chemotherapy, no overall survival advantage has been proven.36 The role of therapeutic chemotherapy in SS is similar, with no evidence of overall survival advantage in the literature.18 We did not try to validate this statement in this series by comparing patients who did and did not receive chemotherapy because of the nonrandomized nature of the data. However, in this series, there was a median survival duration of 11 months after first diagnosis of MD for all patients, whereas the 19 cases who received ifosfamide/doxorubicin in combination had an overall median survival of 15 months. Interestingly, five of these patients were still alive between 10 and 89 months after diagnosis of MD, including one who was disease-free. Van Glabbeke et al5 reported a median survival duration of less than 12 months after randomization (or registration) for anthracycline-containing first-line regimens of chemotherapy for metastatic STS, with no significant differences between regimens that include ifosfamide and doxorubicin (± granulocyte-macrophage colony-stimulating factor). Pisters et al37 reported a 14.8-month postmetastasis survival for SS, whereas Rosen et al7 reported a median survival duration of more than 2 years for patients with diffusely metastatic SS after high-dose ifosfamide (14 to 18 g/m2). Van Glabbeke et al5 noted a higher than average STS postmetastatic survival after chemotherapy for SS on subset univariate analysis; however, when the influence of the low rate of hepatic metastases and younger age of the patients was taken into account in the multivariate analysis, the significance of the SS subtype decreased. The tendency of SS to arise in the vicinity of large joints, especially the knee, may have been overstated in the past. In our series, 75% of cases originated in the extremity, compared with the more frequently reported distribution of 90% from the extremities with 30% around the knee joint.1,18,19 The distribution of locations in the extremities was random and bore no obvious relationship to large joints (Fig 1). Only three cases (2%) had intra-articular involvement, which has been reported in up to 5% of cases, among which the knee38,39 and temporomandibular joint40 are favored sites. There have also been several reports of a high rate (12% to 27%) of lymph node involvement in SS,22,29 but in this series, there were only five cases of lymph node metastases (3.3%), which is similar to the 3% rate reported by Brodsky et al.18 In this series, with patients with SS from all sites included, surgical excision with clear resection margins gave a recurrence rate of 18.0%. This is similar to the series by Mullen and Zagars,20 who reported that 13.4% of cases with clear margins had LR despite all cases having received radiotherapy, and Brodsky et al18 who reported a 14% LR rate for extremity lesions. The aim with patients who underwent surgery at the RMH was to achieve a wide local excision or functional compartmental excision of the tumor if at all possible.41 The high frequency of involved margins in this series (48%) reflects the pattern of referral to the RMH, in which although 96 cases were referred during the course of their primary tumor management, only 28 of these patients had their first operation at the RMH. Earlier on in the series (during the late 1980s), marginal resection and radiotherapy was occasionally accepted as adequate treatment, whereas in the later part of the series, microscopically involved margins were occasionally accepted with addition of radiotherapy if anatomic constraints made re-excision of the tumor bed limb-threatening. There were also 54 patients who were referred to the RMH with LR or MD (or both), and these represent more than one half of the patients in the group with inadequate margins after primary surgery. The high frequency of involved margins may also be a reflection of the aggressive biologic nature of many SS and demonstrates the tendency for inexperienced surgeons to underestimate local extent, which is a frequent problem with all STS.42 Radiotherapy was associated with a significant overall decrease in LR, but when patients with clear margins were compared with those with involved margins separately, the reduction in LR did not reach significance. The interpretation of these data is difficult given the nonrandom allocation of cases for radiotherapy. Patients with higher-risk tumors (obvious biologic aggressiveness) and closer margins would tend to receive radiotherapy, whereas a lower-grade tumor with a wide resection margin may not always do so. Certainly the literature demonstrates a benefit in terms of local control from either external-beam radiotherapy or brachytherapy in high-grade STS.43-45 The beneficial effect of radiotherapy on local control has not translated into an increase in disease-specific survival in previous reports.43,46 However, an LR event was at least a predictor of poorer outcome in this series, which indirectly suggests that radiotherapy may have an influence on survival. Several other authors have found microscopic involvement of surgical margins to be associated with worse survival.37,47 Pisters et al,37 in their study of 1,041 patients with STS of the extremities, found that positive resection margins and presentation with LR were both predictive of inferior survival. Whatever the significance of this finding, local control from the time of primary tumor presentation certainly improves the quality of life for patients. In conclusion, SS is a characteristic subtype of STS with a predilection for young people, but no specific relationship to large joints was found in this series. Size trend is the most useful staging discriminator, because grade and depth have little differentiating impact in SS. Therefore, more useful prognostic information comes from the RMH Staging System8 than the AJCC/UICC Staging Systems.9,10 The data presented for this subtype of STS, as well as other accumulating evidence of the importance of size as a continuous variable in STS,8 should influence the development of the next edition of the AJCC and UICC Staging Systems. Adequate surgical margins with the addition of radiotherapy give the best chance for local control in SS and may improve overall survival. SS is usually chemosensitive, and given the overall poor prognosis, multicenter trials of adjuvant therapy in this histologic subtype of high-risk, younger-age patients are warranted. Future improvements in survival from this disease will require better chemotherapy and better initial management, preferably by specialist centers.
Supported by the Melanoma and Sarcoma Unit Research Fund at the Royal Marsden Hospital.
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Pisters PWT, Harrison LB, Leung DHY, et al: Long-term results of a prospective randomized trial of adjuvant brachytherapy in soft tissue sarcoma. J Clin Oncol 14: 859-868, 1996 44. Suit HD, Russell WO, Martin RG: Management of patients with sarcoma of soft tissues in an extremity. Cancer 31: 1247-1255, 1973[Medline] 45. Suit HD, Russell WO, Martin RG: Sarcoma of soft tissue: Clinical and histopathologic parameters and response to treatment. Cancer 35: 1478-1483, 1975[Medline] 46. Rosenberg SA, Tepper J, Glatstein E, et al: The treatment of soft-tissue sarcomas of the extremities: Prospective randomized evaluations of (1) limb-sparing surgery plus radiation therapy compared with amputation and (2) the role of adjuvant chemotherapy. Ann Surg 196: 305-315, 1982[Medline] 47. Herbert SH, Corn BW, Solin LJ, et al: Limb-preserving treatment for soft tissue sarcomas of the extremities: The significance of surgical margins. Cancer 72: 1230-1238, 1993[Medline] Submitted March 12, 1999; accepted June 16, 2000.
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Copyright © 2000 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
5 cm v > 5 cm), grade, and depth are the important prognostic factors considered in the current AJCC/UICC Staging Systems for STS.
