Synovial Sarcoma of Extremities: Evaluation of Prognostic Factors and Clinical Outcomes

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1 Med. J. Cairo Univ., Vol. 81, No. 1, December: , Synovial Sarcoma of Extremities: Evaluation of Prognostic Factors and Clinical Outcomes SEHAM E. ABDELKHALEK, M.D. and RASHA HAMDY, M.D. The Department of Clinical Oncology & Nuclear Medicine, Mansoura University Hospital Abstract Purpose: As synovial sarcoma has a poor prognosis. In this retrospective study we tried to evaluate its clinical outcome and to identify which prognostic factors influence its clinical outcomes. Patients and Methods: This is a retrospective study of patients with synovial sarcoma of extremities between January 2000 and January 2010 at Clinical Oncology & Nuclear Medicine, Mansoura University Hospital. Results: Of 74 patients, 44 males (59.5%) and 30 females (40.5%) with a median age of 38 (range;1-69 years). Thirty two (43.2%) had metastasis at the first diagnosis and 42 (56.75%) had only a localized tumor. The 5-year overall survival of all the patients was 37.83%; 66.7% in patients with localized disease and 0% in patients with metastasis at first diagnosis. Forty one patients (55.4%) died of the disease at a median duration of 12 months (range 4-48 months). Metastasis at first diagnosis influenced overall survival for patients with synovial sarcoma (p<0.001). According to a univariate analysis, the significant adverse factors were biphasic histological subtype and an inadequate surgical margin of the definitive surgery (p<0.05). Conclusion: Synovial sarcoma is still a disease with a poor prognosis. Distant metastasis at initial diagnosis is a significant adverse prognostic factor for overall survival. A biphasic histological subtype and an inadequate surgical margin are significant adverse prognostic factors in localized synovial sarcoma. Key Words: Synovial sarcoma Prognostic factors Extremities Clinical outcomes. Introduction SYNOVIAL sarcoma accounts for approximately 8% of all soft tissue sarcomas and is the fourth most common type of sarcoma. Synovial sarcoma can occur anywhere in the body, but it most often occurs in the paraarticular areas of the lower extremities1and they have a poor prognosis [2]. They occur predominantly in the young and the middle aged and in both genders (median age 35 Correspondence to: Dr. Seham E. Abdelkhalek, The Department of Clinical Oncology & Nuclear Medicine, Mansoura University Hospital years) [3,4]. Synovial sarcoma usually occurs in the extremities but any location may be affected and, despite its name, synovial sarcomas do not arise from synovial tissue. The histological pattern, however, resembles a developing synovium, 5 and is classified into three subtypes: Monophasic, biphasic and poorly differentiated [6]. It is aggressive and the development of distant metastasis is therefore common. The most common sites of metastasis are the lung and lymph nodes [3]. Overall survival in patients with metastasis at first diagnosis is quite low while the 5-year survival of patients with localized disease at first presentation range from 57 to 88.2% [2,4,7-10]. Surgery is the main treatment modality, with the aim to achieve adequate surgical margins, while adjuvant chemotherapy and radiotherapy are controversial [4,9,11-13]. It is well known from the literature that the key prognostic factors at diagnosis of synovial sarcoma are tumor stage [2,14], tumor size [8,15], older age [4,8,9,11], primary tumor site [9,12,16], initial surgical treatment with adequate surgical margins [8,10,14]. And adjuvant radiotherapy [17]. However, there is no consensus on which is the most useful [2,8-10]. This is a retrospective study was performed to evaluate clinical outcomes and identify which prognostic factors influenced outcome of synovial sarcoma of extremities. Patients and Methods This is a retrospective study of patients with synovial sarcoma of extremitiesthat has been treated at Clinical Oncology & Nuclear Medicine Department, Mansoura University Hospital during the period from 1 st January 2000 till 1 st January A total 79 patients were diagnosed with synovial sarcoma while five were excluded from this study five because of incomplete data. All patients had chest X-ray, chest computed tomography, bone 1093

2 1094 Synovial Sarcoma of Extremities scan and magnetic resonance imaging of the extremity involved. The patients were divided into two groups: Those with localized tumor at the time of diagnosis, and those with metastatic disease. Patient data were recoded including; age, sex, primary tumor site (upper extremity at or distal to the shoulder joint, lower extremity) and size (maximum diameter <5cm or >_5cm), previous treatment, histological subtype (monophasic, biphasic, poorly differentiated), type of surgical procedure (closed, wide excision or amputation), microscopic surgical margins (an inadequate margin was defined as are section with close (tumor present 2mm or less from the inked margins) or positive margins or a tumor at the inked margin), chemotherapy, radiotherapy and status of the patients after treatment. Statistical analysis: Disease-free survival time was calculated from the time of admission to the occurrence of a local recurrence, distant metastasis or death. Overall survival time was calculated from the time of admission to death or last follow-up visit. The survival analysis was calculated using the Kaplan- Meier method. Patients with localized disease, the following parameters were analyzed by the log-rank test for prognostic value: Age, sex, primary tumor site and size, previous treatment, histological subtype, microscopic surgical margins, chemotherapy and radiotherapy. All statistical analyses were performed using SPSS 15 statistical software (SPSS, Chicaco, IL, USA). Results Patients characteristics: Table (1) showed patients characteristics; of 74 patients, 44males (59.5%) and 30 females (40.5%) with a median age of 38 (range, 1-69 years), 32 (43.2%) had metastasis at the first diagnosis and 42 (56.75%) had only a localized tumor. The most common location of tumors was: Thigh (43 patients, 58.1%), leg and foot (15 patients; 20.3%), arm (10 patients; 13.5%), forearm and hand (six; 8.1 %). The tumor size ranged between 0.6 and 21 cm (median, 6cm). Fifteen patients (20.3%) had tumors <5cm while 59 patients (79.7%) had tumors >_5cm. There were 48 monophasic (64.8%) and 26 biphasic (35.1%) synovial sarcomas. In all, 58 patients underwent surgical treatment, twenty two (29.7%) with a wide excision, fifteen (20.2%) amputations and twenty one (28.3%) with marginal excisions. Sixteen patients (21.6%) refused all surgical procedures. Postoperative external beam irradiation was administered to 32 patients (43%); Gy over weeks according to margins. While ten patients (14%) received preoperative radiotherapy to shrink tumor size by external beam irradiation 50 Gy over 5 weeks and boost after surgery Gy over weeks according to margins. Palliative radiotherapy was given to relieve symptoms for fourteen patients (19%). Regards to chemotherapy 59 patients (79.7%) received chemotherapy while fifteen (20.3%) did not receive (nine refused and six patients had comorbidities and cannot tolerate chemotherapy). Multiple drug regimens were used based on combinations of adriamycin, mesna and ifosfamide. In eight patients the regimen was changed after the administration of chemotherapy because the tumors were not responding. Four patients received cisplatin and ifosfamide. Four patient received dacarbazine, mesna, adriamycin and ifosfamide. There were no deaths related to chemotherapy toxicity. Table (1): Baseline and tumor characteristics for the 74 patients with synovial sarcoma (n, %). Sex: Male Female Age (years) Median Localized disease (n=42) 22 (52) 20 (48) 38 (1-64) Metastases at first diagnosis (n=32) 13 (41) 19 (59) 46 (16-77) Site: Upper extremities Proximal 5 (12) 5 (16) Distal 4 (10) 2 (6) Lower extremities: Proximal 25 (60) 18 (56) Distal 8 (19) 7 (22) Size: <5cm >_5cm 9 (21) 33 (79) 6 (19) 26 (81) Histologic subtype: Monophasic 26 (62) 22 (69) Biphasic 16 (38) 10 (31) Type of definite surgery: Wide excision 13 (31) 9 (28) Radical (amputation) 9 (21) 6 (19) Marginal excision 13 (31) 8 (25) Chemotherapy: Neoadjuvant 17 (40) 13 (41) Adjuvant 18 (43) 11 (34) None 7 (17) 8 (25) Radiation: Adjuvant 21 (50) 11 (34) Neoadjuvant 10 (24) 4 (13) Palliative 4 (10) 6 (19) No 7 (17) 11 (34)

3 Seham E. Abdelkhalek & Rasha Hamdy 1095 Table (2): Statistical analysis for prognostic factors by logranktest. 5-year overall survival (%) p-value Sex: Male Female 75 Age (years): < >_35 54 Site: Proximal Distal 69 Size: <5cm cm. 44 Histological subtype: Monophasic Biphasic 37 Microscopic surgical margin: Adequate (wide excision/ amputation) Inadequate (marginal excision) 43 Chemotherapy: Yes No 40 Radiation: Yes No 52 Metastasis at first diagnosis influenced the overall survival of synovial sarcoma patients (p<0.001) (Fig. 1). The prognostic factors of death in patients with localized disease are presented in Table (2). According to the univariate analysis, the significant adverse factors were biphasic histological subtype and inadequate surgical margins in definitive surgery (p<0.05). Cum Survival Overall survival (months) Fig. (1): Kaplan-Meier estimates of overall survival in patients with only localized tumor at diagnosis (n=42). Clinical outcome: The median follow-up time was 22 months (range4-113 months). None of the patients was lost to follow-up. The overall 5-year survival for the patients was 37.83%; it was 66.7% in patients with localized disease (Fig. 1) and 0% for patients with metastasis at diagnosis. A total of 41 patients (55.4%) died from the disease at a median duration of 12 months (range 3-47 months); none died from any unrelated causes. A total of 24 patients (32.4%) have remained alive and continuously free of disease at a median follow-up time of 52 months (range months). Nine patients (12.1 %) have remained alive with disease at a median followup time of 8 months (range 5-52 months). Local recurrence after treatment in patients with localized disease occurred in eight patients (19%): The median being 12 months (range 2-62 months). Metastasis after treatment occurred in ten patients (24%): The median being 12 months (range 3-60 months). Seven patients had both lung and lymph node metastases; three had only lung metastasis and one had both lung and brain metastases. The 5-year disease-free survival was 58% (Fig. 2). Cum Survival Disease free survival (months) Fig. (2): Kaplan-Meier curve showing time from diagnosis to local recurrence or distant metastasis in patients with only localized tumor at diagnosis (n=42). Discussion Synovial sarcoma is a high-grade aggressive soft tissue tumor with high rate of local recurrence and distant metastasis in spite of aggressive treatment (i.e., wide excision plus adjuvant radiotherapy and chemotherapy) [18]. During the last 40 years, there have been many studies to determine prognostic factors in this disease. Anatomic site [19], tumor size [20], patient age [21], microscopic margins [20], and histologic subtype (monophasic v biphasic) [19,22] have all been reported to be significant determinants of outcome for patients with synovial sarcoma.

4 1096 Synovial Sarcoma of Extremities Regarding the histological subtypes of synovial sarcoma, there are mixed reports of a histological correlation with survival between monophasic and biphasic histologies [23-27]. Our study found that the monophasic type had a better overall survival than the biphasic type (p=0.01). A tumor size >5 cm had a negative influence on overall survival in many studies; [3,4,8,9] whereas in our study there was a non-statistically significant trend of tumor size affecting overall survival ( p=0.07). This is comparable to tumor size described by Taweechok et al., [28]. The rate of metastasis at the first diagnosis ranges between 9 and 54% [8,14]. In the present study distant metastases at diagnosis were found in 43.2% of all patients. The 5-year overall survival rate in this series was quite low (37.8%) because the patients who had metastasis at first presentation were included. When patients with only localized disease were considered, the 5-year overall survival rate increased to 66.7%, which is comparable to other similar studies [2,7,8]. Metastases and local recurrences in initially localized tumors after treatment were 24 and 19% respectively. This is comparable to other studies [8,23,28]. Surgery is the mainstay of treatment for local control of tumors [12,23]. A wide excisions with a limb-sparing procedure is the method of choice except when neurovascular structures are involved [29]. Ten patients in the current study underwent an amputation because of locally recurrent disease and the tumor involved a neurovascular structure. A marginal margin (excision through the pseudocapsule or the reactive tissue surrounding the tumor) is insufficient for the management of a soft tissue sarcoma. In the entire marginal margin patients in the current series the tumors were very close to neurovascular bundles and postoperative radiation and chemotherapy were given. We found that the overall survival of an inadequate surgical margin was worse than a free surgical margin (p<0.001). A wide surgical margin (excision through normal tissue) affected overall survival significantly compared to a marginal margin as described by other studies [11,28]. The benefit of chemotherapy for synovial sarcoma is controversial [2,11,13]. At our institution chemotherapy was given as neoadjuvant or/and adjuvant to patients who had tumors larger than 5cm and who could tolerate its side-effects. The usual regimen was ifosfamide-based, resembling other studies [11,13,30]. In the present study we found that chemotherapy did not improve the clin- ical outcome for patients with a localized synovial sarcoma; however, there were only 35 patients in the localized disease group so a larger study is needed. Some studies have shown that radiation improved local control of soft tissue sarcoma with a combination of surgery and radiation [12,13]. Ferrari et al., studied postoperative external-beam radiotherapy combined with adjuvant chemotherapy for synovial sarcoma patients, which resulted in high rates of local control [29]. However, local control is not always certain if adequate surgical margins are not achieved [4]. In the present study we did not find an association between radiation and survival in patients with a localized synovial sarcoma (p=0.42), as other studies have done [11,25,28]. Conclusion: Synovial sarcoma is a high-grade tumor that is associated with poor prognosis. Soft tissue sarcomas have many factors that can influence the overall survival of the patients. These factors are related to the patients, tumor and treatment. Distant metastasis at initial diagnosis is a significant adverse prognostic factor for overall survival. A biphasic histological subtype and an inadequate surgical margin are significant adverse prognostic factors in localized synovial sarcoma. 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