Premonitory Pain Preceding Swelling: A Distinctive Clinical Presentation of Synovial Sarcoma which may Prompt Early Detection

Purpose: The aim of this paper is to document the unusual presentation of long-standing pain at the tumour site before development of a swelling in patients with synovial sarcoma.Patients/methods and results: The clinical presentation of 53 patients with synovial sarcoma was compared with 56 randomly selected patients with other sarcomas of the trunk and extremities. The two groups were similar with regard to age (P = 0.980), sex (P = 0.784) duration of symptoms (P = 0.697), size (P = 0.931) and site of tumour (P = 0.288). Sixteen (30.2%) patients with synovial sarcoma had pain before development of a swelling compared to two (3.6%) patients with other sarcomas (P < 0.001, odds ratio = 11.68, 95% confidence interval 2.53, 53.83). The mean duration of such pain was 37 months (median 24, range 6-120 months). The nature of the pain was variable. Eight patients had sharply localised tenderness. Calcification seen in the X-rays of four patients was initially misdiagnosed as benign lesions. A swelling was ultimately detected by MRI, CT, ultrasound or at physical examination. The mean duration from first presentation with pain till diagnosis of synovial sarcoma was 20 months. In three patients, at explorative surgery there was friable, vascular or necrotic tissue in the absence of a well-defined tumour mass.Discussion: The occurrence of long-standing pain at the tumour site prior to development of a swelling is significantly more common with synovial sarcomas than with other sarcomas. Awareness of this unusual presentation and appropriate investigation may enable detection of synovial sarcoma at a prognostically favourable early stage.     

Angiogenesis does not correlate with prognosis or expression of vascular endothelial growth factor in synovial sarcomas.

To investigate the significance of tumour angiogenesis in synovial sarcoma on prognosis, we analysed the correlation between microvessel density (MVD) and various clinicopathological factors or immunohistochemical expression of vascular endothelial growth factor (VEGF) in 54 primary and recurrent synovial sarcomas. MVD in synovial sarcomas did not correlate with prognosis or VEGF expression. Furthermore, VEGF expression in synovial sarcomas did not have any prognostic value on overall survival. Our results indicate that angiogenesis does not play an important role in metastasis of synovial sarcoma and overall survival. Angiogenesis in synovial sarcoma may be controlled by angiogenesis activators other than VEGF.     

Diagnosis and management of primary breast sarcoma

Primary sarcoma of the breast is an extremely rare and heterogeneous disease. The rarity of this tumour limits most studies to small retrospective case reviews and case reports and has made clinicopathological study difficult. This article reviews the current literature on the diagnosis and management of breast sarcoma. The optimal treatment of breast sarcoma involves a multidisciplinary team prior to the initiation of treatment. Patients with tumours less than 5 cm that are easily resectable should undergo complete resection to the extent required to provide negative surgical margins. Negative surgical margins are more important for local recurrence and overall survival than the extent of surgical resection. Thus, neoadjuvant chemotherapy should be considered in order to shrink the tumour and help obtain negative surgical margins. Whether chemotherapy is indicated is primarily determined by tumour size. There is evidence that tumours larger than 5 cm are associated with an elevated risk of systemic failure and a poor prognosis. After surgical resection, patients with chemosensitive tumours should undergo additional adjuvant chemotherapy to treat micrometastatic disease. Radiation therapy should be used to improve local control in cases in which the tumour is larger than 5 cm and in cases with positive surgical margins. We propose to treat the patients according to the clinical practice guidelines in use for soft tissue sarcomas and address them to a reference centre for sarcoma. The appropriate treatment of breast sarcoma requires a multidisciplinary team approach necessitating experienced sarcoma surgeons, pathologists, radiotherapists and medical oncologists. Treating rare tumours in the same place should permit us to standardise pathological data and to include patients into multicentric radiotherapy or chemotherapy protocols to improve overall survival.     

The risk of angiosarcoma following primary breast cancer.

Lymphangiosarcoma of the upper extremity is a rare and aggressive tumour reported to occur following post-mastectomy lymphoedema (Stewart-Treves syndrome). Haemangiosarcoma, a related rare tumour, has occasionally been reported to occur in the breast following irradiation. We conducted a case-control study using the University of Southern California-Cancer Surveillance Program, the population-based cancer registry for Los Angeles County, to evaluate the relationship between invasive female breast cancer and subsequent upper extremity or chest lymphangiosarcoma and haemangiosarcoma together referred to as angiosarcoma. Cases were females diagnosed between 1972 and 1995 with angiosarcoma of the upper extremity (n = 20) or chest (n = 48) who were 25 years of age or older and residing in Los Angeles County when diagnosed. Other sarcomas at the same anatomic sites were also studied. Controls were females diagnosed with cancers other than sarcoma during the same time period (n = 266,444). Cases and controls were then compared with respect to history of a prior invasive epithelial breast cancer. A history of breast cancer increased the risk of upper extremity angiosarcoma by more than 59-fold (odds ratio [OR] = 59.3, 95% confidence interval [95% CI] = 21.9-152.8). A strong increase in risk after breast cancer was also observed for angiosarcoma of the chest and breast (OR = 11.6, 95% CI = 4.3-26.1) and for other sarcomas of the chest and breast (OR = 3.3, 95% CI = 1.1-1.7).     

Is there a role for sentinel lymph node biopsy in the management of sarcoma?

Is there a role for sentinel lymph node (SLN) biopsy in the management of sarcoma? Sentinel node biopsy has dramatically changed the management of melanoma and breast cancer, helping surgeons avoid radical lymphadenectomies in node negative patients who would previously have undergone a more morbid operation with little benefit, or remained pathologically unstaged. Many investigators have explored the use of lymphatic mapping for malignancies other than breast cancer or melanoma. Lymphatic mapping and sentinel node biopsy has not been investigated in the management of sarcomas, which is not surprising given that the majority of sarcomas spread by local extension or hematogenously. Regional lymph node metastases are rare; developing in about 3-10% of patients with localized disease. However, among certain subtypes of high-grade sarcomas there is a propensity for regional lymph node metastases. These include rhabdomyosarcoma, epithelioid sarcoma, clear cell sarcoma, synovial sarcoma, and vascular sarcomas. It is in these particular subtypes that there may be a benefit to SLN biopsy.     

Soft tissue sarcoma after treatment for breast cancer--a Swedish population-based study

The aim was to quantify the risk of post-treatment sarcoma in breast cancer patients. All 122,991 women with a breast cancer from 1958 to 1992 in the Swedish Cancer Register were followed up for soft tissue sarcomas and 116 were found, giving a standardised incidence ratio of 1.9 (95% CI 1.5-2.2). The absolute risk was 1.3 per 10(4) person-years. The sarcomas were located in the breast region or on the ipsilateral arm in 63% (67/106). There were 40 angiosarcomas and 76 sarcomas of other types. In a case-control study, angiosarcoma correlated significantly with lymphoedema of the arm, odds ratio (OR) 9.5 (95% CI 3.2-28.0), but no correlation with radiotherapy was observed. For other types of sarcoma there was a correlation with the integral dose. The dose-response relationship indicated that the risk increased linearly with the integral dose to 150-200 J and stabilised at higher energies. The OR was 2.4 (95% CI 1.4-4.2) for an energy of 50 J, approximately corresponding to the radiation of the breast after breast-conserving surgery. Thus, only oedema of the arm correlated with angiosarcoma, but for other types of sarcoma the integral dose of radiotherapy was a predictor of the risk.     

Primary sarcoma of the breast

BACKGROUND AND OBJECTIVES: Primary sarcoma occurring in breast is rare and comprises 0.5-1% of all breast neoplasm. Majority of the series include both stromal and cystosarcoma phyllodes, only a few hundred cases of sarcomas other then cystosarcoma are reported. PATIENTS AND METHODS: We carried out a retrospective analysis of 19 patients with primary sarcoma of the breast treated between 1982 and 2002. RESULTS: Mean age of the patients was 38.6 years (12-70 years). Gradually progressive swelling was the commonest presenting feature. There were eight cases of angiosarcoma, four cases of spindle cell sarcoma, two each of pleomorphic sarcoma and stromal sarcoma, and one each of malignant fibrous histiocytoma, embryonal rhabdomyosarcoma, and sarcoma (NOS). Eight of these were high-grade (42%). Eight patients underwent either radical or modified mastectomy, three underwent wide excisions, and one underwent quadrantectomy. Ten (52.6%) patients received postoperative adjuvant radiation. Two patients received chemotherapy. After a mean follow-up time of 34.5 months (median 25 months), eight patients failed. Failure was local in five, opposite breast in one, and both local and distant in two. The disease free survival at 3-year was 39%. In univariate analysis only the margin of first surgery was found to be a significant predictor of survival (P = 0.05). CONCLUSIONS: Primary sarcomas of the breast are aggressive tumors. Surgical treatment should consist of at least simple mastectomy. All attempts should be made to achieve a negative margin as this appears to be the only factor influencing survival in these patients.     

Transducer-like Enhancer of Split 1 as a Novel Immunohistochemical Marker for Diagnosis of Synovial Sarcoma

Background: Synovial sarcoma is a mesenchymal neoplasm that accounts for around 10% of all softtissue sarcomas. The diagnosis of synovial sarcoma can be a challenging task, particularly with small biopsyspecimens. Aim: We investigated transducer-like enhancer of split 1 (TLE1), monoclonal antibody, expressionby immunohistochemical analysis in a group of 74 synovial sarcoma cases, 20 cases of MPNST, 12 cases ofneurofibroma, 15 cases of schwannoma, 5 cases of MFH, 10 cases of lieomyosarcoma and 10 cases of solitaryfibrous tumor. Materials and Methods: Whole tissue sections were examined: (39 biphasic and 35 monophasic).Nuclear immunoreactivity was scored as negative (<5% of cells positive), 1+(mild /5-25%), 2+ (moderate/25-50%),and 3+ (strong >50%). Results: Overall, 71 (96%) of 74 synovial sarcomas were positive for TLE1, including 37biphasic (95%) and 34 monophasic (97%) tumors. Other spindle cell tumors showed very low or absent stainingof TLE1. Conclusions: We conclude that TLE1 is a sensitive marker and can be a useful diagnostic marker forsynovial sarcoma, particularly the monophasic forms.     

Sarcoma as a second malignancy after treatment for breast cancer

: Second malignant neoplasms may be a consequence of radiotherapy for the treatment of breast cancer. Prior studies evaluating sarcomas as second malignant neoplasms in breast cancer patients have been limited by the numbers of patients and relatively low incidence of sarcoma. Using data from the Surveillance, Epidemiology and End Results registries, we evaluated the influence of radiation therapy on the development of subsequent sarcomas in cases with primary breast cancer.

: Cases with primary invasive breast cancer (n = 274,572) were identified in the Surveillance, Epidemiology and End Results Cancer Incidence Public-Use Database (1973–1997). The database was then queried to determine the cases developing subsequent sarcomas (n = 263). Eighty-seven of these cases received radiation therapy, and 176 had no radiation therapy. The cumulative incidence of developing secondary sarcoma and the survival post developing secondary sarcoma were determined by the Kaplan-Meier method.

: The occurrence of sarcoma was low, regardless of whether cases received or did not receive radiation therapy: 3.2 per 1,000 (SE [standard error] = 0.4) and 2.3 per 1,000 (SE = 0.2) cumulative incidence at 15 years post diagnosis, respectively (p = 0.001). Of the sarcomas occurring within the field of radiation, angiosarcoma accounted for 56.8%, compared to only 5.7% of angiosarcomas occurring in cases not receiving radiotherapy. The cumulative incidence of angiosarcoma at 15 years post diagnosis was 0.9 per 1,000 for cases receiving radiation (SE = 0.2) and 0.1 per 1,000 for cases not receiving radiation (SE < 0.1). Overall survival was poor for cases of sarcoma after breast cancer (27–35% at 5 years), but not significantly different between patients receiving or not receiving radiation therapy for their primary breast cancer.

: Radiotherapy in the treatment of breast cancer is associated with an increased risk of subsequent sarcoma, but the magnitude of this risk is small. Angiosarcoma is significantly more prevalent in cases treated with radiotherapy, occurring especially in or adjacent to the radiation field. The small difference in risk of subsequent sarcoma for breast cancer patients receiving radiotherapy does not supersede the benefit of radiotherapy.     

Long-term risk of sarcoma following radiation treatment for breast cancer.

Between 1954 and 1983, 7620 patients were treated for breast carcinoma at Institut Gustave Roussy (France). Of these patients, 6919 were followed for at least 1 year. Out of these, 11 presented with sarcomas thought to be induced by irradiation, 2 of which were Steward-Treves Syndrome, and 9 of which were sarcomas within the irradiated fields. All histological slides were reviewed and a comparison with those of breast cancer was done. The sites of these sarcomas were: parietal wall, 1 case; second costal cartilage, 1 case; infraclavicular region, 1 case; supraclavicular region, 2 cases; internal third of the clavicle, 2 cases; axillary region 2 cases; and the internal side of the upper arm (Stewart-Treves syndrome), 2 cases. The median age of these 11 patients at the diagnosis of sarcomas was 65.8 (49-83). The mean latent period was 9.5 years (4-24). Three patients underwent radical mastectomy and nine modified radical mastectomy. Only one patient received chemotherapy. The radiation doses received at the site of the sarcoma were 45 Gy/18 fr. for 10 cases and 90-100 Gy for 1 case (due to overlapping between two fields). The histology was as follows: malignant fibrous histiocytoma, 5 cases; fibrosarcoma, 3 cases; lymphangiosarcoma, 2 cases; and osteochondrosarcoma, 1 case. The median survival following diagnosis of sarcoma was 2.4 years (4 months-9 years). Two patients are still alive: one with recurrence of her breast cancer, the other in complete remission, with 7 and 3 years follow-up, respectively. All other patients died from their sarcomas. The cumulative incidence of sarcoma following irradiation of breast cancer was 0.2% (0.09-0.47) at 10 years. The standardized incidence ratio (SIR) of sarcoma (observed n# of cases (Obs)/expected n# of cases (Exp) computed from the Danish Cancer Registry for the same period) was 1.81 (CI 0.91-3.23). This is significantly higher than one, with a p = 0.03 (One Tailed Exact Test). The mean annual excess (Obs-Exp)/100.000 person-years at risk during the same period/(100,000) was 9.92. This study suggests that patients treated by radiation for breast cancer have a risk of subsequent sarcomas that is higher than the general population. However, the benefit from adjuvant radiation therapy in the treatment of breast cancer exceeds the risk of second cancer; therefore, the potential of radiation-induced sarcomas should not be a factor in the selection of treatment for patients with breast cancer.     

Outcome of chemotherapy in advanced synovial sarcoma patients: Review of 15 clinical trials from the European Organisation for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group; setting a new landmark for studies in this entity

IntroductionPrevious studies in metastatic soft tissue sarcomas (STS) showed that synovial sarcomas tend to have better survival rates and a higher chemosensitivity than other STS subtypes. However, data are derived from relatively small subgroups and statistical significance of these observations is lacking. Larger cohorts are necessary to define and confirm the specific characteristics of this subtype.Patients and methodsPatient data were retrieved from 15 European Organisation for Research and Treatment of Cancer advanced first-line STS trials. Patient characteristics, survival and treatment response of synovial sarcoma patients were compared to other STS patients. Univariable and multivariable analyses were performed to evaluate prognostic factors.ResultsIn total, 3330 advanced STS patients were retrieved, of whom 313 had a synovial sarcoma. Synovial sarcoma patients were significantly younger (median 40 versus 52 years), more often had extremity primary tumours and had a better performance status (PS 0: 50.2 versus 43.4%) compared to other STS patients. Additionally, synovial sarcoma patients had a significantly better response to chemotherapy (responders: 27.8 versus 18.8%) and better survival rates (progression free survival [PFS]: 6.3 versus 3.7 months; Overall survival [OS]: 15.0 versus 11.7 months). Age, PS, and presence of metastatic disease were defined as prognostic factors for PFS and OS in the univariable analysis. The last two factors were confirmed in the multivariable analysis for OS.DiscussionAdvanced synovial sarcomas are a distinct subgroup of STS, with a better response to systemic chemotherapy and longer PFS and OS. These results should be taken into account in the design of future synovial sarcoma specific studies.     

Molecular pathology in sarcomas

Abstract Bone and soft tissue sarcomas are an infrequent group of tumours. Their prevalence is 4 in 100 000 people/year, making the disease quite rare. Some of these tumours, such as synovial sarcoma, Ewing tumour and osteosarcoma, are more usual in adolescents or in young adults; there are, though, some neoplasias such as leiomyosarcoma or liposarcoma that are more frequent in patients over 55 years. There are more than a hundred different types of sarcomas from the histological point of view. This is the main limitation at the time of finding major clinic essays on patients with specific types of sarcomas. From the molecular point of view, these neoplasias are grouped into two main types: (a) sarcomas showing specific genetic alterations and relatively simple karyotypes, and translocations which originate gene fusions (e.g., EWS-FLI1 in Ewing tumour); or specific genetic mutations (e.g., c-kit in the gastrointestinal stromal tumour), and (b) sarcomas showing unspecific gene alterations and very complex karyotypes, and very numerous gains and losses. This review describes diverse types of molecular alterations as well, their utility in the clinical domain, as well as implications for the pathologist in translational research in sarcomas. *Supported by an unrestricted educational grant from Sanofi-Aventis.     

Urokinase-plasminogen-activator levels and prognosis in 69 soft-tissue sarcomas

The local and systemic invasiveness of soft-tissue sarcomas may depend upon an interaction between the primary tumour and the extracellular matrix in which the proteolytic enzyme, urokinase plasminogen activator (uPA), may have an important role. We analyzed the expression of uPA in soft-tissue sarcoma using a luminescent immunoassay technique, and examined the relationships between different uPA levels and tumour characteristics and behaviour. We evaluated 69 adult patients with surgically treated soft-tissue sarcomas (MFH 43, leiomyosarcoma 8, liposarcoma 5, synovial sarcoma 4, others 9) of the extremities and trunk wall. Sixteen developed local recurrences, 26 developed metastases, and 5 had both. The median follow-up for survivors was 55 (30–80) months. The median uPA level was 1.4 (0.04–10.6) ng/mg protein. Increasing uPA levels correlated with increasing grade, malignant fibrous histiocytomas, leiomyosarcomas, DNA non-diploidy, tumour necrosis, local recurrence, and metastasis. Storiform-pleomorphic MFH had higher uPA levels than the myxoid variant. A cut-off value of 0.25 ng/mg protein was identified, above which local recurrence and metastasis occurred more frequently. High uPA levels appear to reflect the malignant phenotype in soft-tissue sarcoma, thus supporting the role of uPA as a prognostic indicator. © 1996 Wiley-Liss, Inc.     

Primary breast sarcoma: clinicopathologic series from the Mayo Clinic and review of the literature

Primary sarcomas of the breast are extremely rare, with less than 0.1% of all malignant tumours of the breast. Mayo Clinic Surgical Pathology database was searched for all breast sarcoma from 1910 to 2000. Pathology reports and slides were reviewed and tumour types were determined. Metaplastic carcinomas and phyllodes tumours were excluded. There were 25 women ranging in age 24-81 years (mean 45 years). All but one patient presented with a palpable lump. Mastectomy was performed in 19 patients and lumpectomy in five patients. Histopathological diagnoses were fibrosarcoma (six), angiosarcoma (six), pleomorphic sarcoma (six), leiomyosarcoma (two), myxofibrosarcoma (three), hemangiopericytoma (one) and osteosarcoma (one). Tumour size ranged from 0.3 to 12 cm (mean 5.7). Low-grade lesions were observed in 10 cases and high-grade in 15. Overall, mean follow-up was 10.5 years. Local recurrence was observed in 11 patients and ranged from 2 to 36 months (mean 15 m), while distant metastasis was observed in 10 patients (40%) affecting lungs, bones, liver, spleen, and skin. Of the 25 patients, 12 have died of disease and six of other causes. Five-year overall (OS) and cause-specific survival (CSS) were 66 and 70%, respectively. OS and DFS at 5 years were 91% for tumours < or =5 cm and 50% for tumours >5 cm. Tumour size was significantly associated with OS (risk ratio=1.3 per 1 cm increase; 95% CI, 1.02-1.7; P=0.036). There was no significant difference in OS or CSS between low- and high-grade lesions. In this series, tumour size was a more valuable prognostic factor than tumour grade.     

Increased risk of soft tissue sarcoma after radiotherapy in women with breast carcinoma.

BACKGROUND: Numerous studies to date have suggested an association between radiation exposure and the development of soft tissue sarcoma. The current study was performed to quantify the risk of soft tissue sarcoma in the vicinity of previously irradiated anatomic regions in women with breast carcinoma. METHODS: In this population-based, retrospective cohort study, 194,798 women who were diagnosed with invasive breast carcinoma (exclusive of those with distant metastasis) between 1973--1995 were identified, and subsequent soft tissue sarcoma cases utilizing the data from the Surveillance, Epidemiology, and End Results Program (SEER) were ascertained. Poisson regression analysis was used to calculate age standardized incidence ratios (SIR) and to model the influence of radiotherapy (RT) on the relative risk (RR) between the RT and non-RT cohorts. RESULTS: A total of 54 women in the RT cohort and 81 women in the non-RT cohort subsequently developed soft tissue sarcoma. In the RT cohort, the SIR was 26.2 (95% confidence interval [95% CI], 16.5--41.4) for angiosarcoma and was 2.5 (95% CI, 1.8--3.5) for other sarcomas; in the non-RT cohort, the SIRs were 2.1 (95% CI, 1.0--4.4) and 1.3 (95% CI, 1.0--1.7), respectively. The RT cohort demonstrated a higher risk of developing both angiosarcoma (RR: 15.9; 95% CI, 6.6--38.1) and other sarcomas (RR: 2.2; 95% CI, 1.4--3.3) compared with the non-RT cohort, and the largest increase was observed in the chest wall/breast. The elevated RR was significant even within 5 years of RT, but it reached a maximum between 5--10 years. CONCLUSIONS: The risk of soft tissue sarcoma, especially angiosarcoma, was elevated after RT in women with breast carcinoma.     

Diagnosis and management of synovial sarcoma

Synovial sarcoma accounts about 9% of soft tissue sarcomas, most commonly develops in the extremity of young adults, is considered high grade and contains a characteristic translocation (X;18;p11;q11). While surgery and radiation therapy have achieved excellent local control, distant metastasis remains the principal problem limiting survival. Although ifosfamide based chemotherapy has been associated with an improved survival in patients with synovial sarcoma, the search for less toxic and more targeted systemic therapies is ongoing.     

Translocation t(X;18) in orofacial synovial sarcoma

Cytogenetic analysis of a synovial sarcoma of the base of the tongue showed a reciprocal translocation involving chromosomes X and 18 [t(X;18)(p11.2;q11.2)]. This is a translocation recently reported to be characteristic of synovial sarcomas of the extremities. The histogenesis of synovial sarcoma is controversial. Our discovery of this translocation in an oral synovial sarcoma confirms the unity of origin of this neoplasm with the far more common synovial sarcomas of the extremity. Karyotypic analysis may prove useful in confirming the diagnosis of this uncommon neoplasm.