Expression of TLE1, INI1, ß-catenin, Claudin1, CK7, CK19, SS18 and calponin in synovial sarcoma.

BACKGROUND AND OBJECTIVES: Synovial sarcomas (SS) are enigmatic soft tissue tumors, which are yet to have a defined cell of origin. SS have a variety of differential diagnosis depending upon the age of the patient and the site of presentation. This makes diagnosis cumbersome unless the specific fusion SS18:SSX is identified by reverse transcription-polymerase chain reaction (RT-PCR) or fluorescence in situ hybridization (FISH). Immunohistochemistry is a useful tool in resource-poor settings in helping to narrow the differentials and help diagnose this tumor. This study set about assessing possible candidate immunohistochemical markers in their utility to recognize SS. METHODS: Forty cases of SS, proven by FISH were included. A tissue microarray (TMA) was constructed, and immunohistochemistry was done using antibodies - TLE1 (OTI1F5), ß-catenin (14), INI1 (MRQ-27), CK7 (OV-TL), CK19 (polyclonal), SS18 (polyclonal), calponin (CALP), and claudin1 (Polyclonal). The expression was analyzed to arrive at sensitivity and specificity. RESULTS: TLE1 had a sensitivity of 92.5% and a specificity of 100%; ß-Catenin had a sensitivity of 17.5% and specificity of 100%; Calponin had a sensitivity of 97.5% and a specificity of 81.25%; SS18 had a sensitivity of 95% and specificity of 100%; INI1 had a sensitivity of 95% and specificity of 100%; CK7 had a sensitivity of 90% and specificity of 87.5%; CK19 had a sensitivity of 90% and a specificity of 59.38%; and Claudin had a sensitivity of 85% and a specificity of 78.12%. INTERPRETATION AND CONCLUSIONS: The study showed both TLE1 and SS18 are robust diagnostic markers of synovial sarcoma with a sensitivity of 92% and 95%, respectively. INI1 can be used to discriminate SS from nonepithelioid and nonrhabdoid differentials. Calponin expression is helpful to differentiate poorly differentiated SS from its mimics. CK7 is a better marker than CK19 and can be used as a replacement for EMA in the initial screening panel. The use of claudin1 was restricted to delineating the epithelial component. ß-Catenin had poor sensitivity, restricting its utility in SS.

Birth Characteristics and Risk of Early-Onset Synovial Sarcoma.

BACKGROUND: Synovial sarcoma is a rare cancer with peak incidence in the young adult period. Despite poor outcomes of this aggressive cancer, there is little epidemiologic research addressing its etiology. METHODS: We collected birth characteristic data on synovial sarcoma cases born during 1978-2015 and diagnosed during 1988-2015 in California (n = 244), and 12,200 controls frequency-matched on year of birth. We also constructed a dataset of cancer cases in siblings of sarcoma subjects to assess familial risk. RESULTS: In multivariable logistic regression analyses, synovial sarcoma was more frequent in Hispanics compared with non-Hispanic whites [OR, 1.48; 95% confidence interval (CI), 1.06-2.08]. Higher birth weight was a risk factor in Hispanics; each 500 g increase in birth weight was associated with a 22% increase in disease risk (OR, 1.22; 95% CI, 1.00-1.48). Also, a strong role for birth order was suggested, with highest risk for the first born (second child compared with first: OR, 0.61; 95% CI, 0.44-0.84; third or later compared with first: OR, 0.53; 95% CI, 0.36-0.77). Siblings of patients with synovial sarcoma did not display elevated cancer incidence, suggesting the low likelihood that strong familial predisposition alleles play a significant role in this disease. CONCLUSIONS: The associations with birth weight and birth order suggest that nutritional, developmental, and environmental factors may play a role in the etiology of synovial sarcoma. IMPACT: Further epidemiologic research on synovial sarcoma should evaluate epigenetic and developmental mechanisms and the formation of the archetypical t(X;18) translocation that defines this disease.

Intrapelvic Retroperitoneal Synovial Sarcoma in a 15-Year-Old Adolescent Girl: A Case Report and Review of the Literature.

Synovial sarcomas are a rare subtype of soft tissue sarcomas mostly located in the lower extremities. The authors report a case of synovial sarcoma in a 15-year-old adolescent girl with several unusual features including age, intrapelvic retroperitoneal location of the primary tumor, and presentation with right abdominal tenderness and compression of the iliac vessels with thrombosis of the right iliac and femoral vein.

Laryngeal synovial sarcoma: Report of 2 cases.

Synovial sarcoma is a malignant mesenchymal tumor. It most commonly occurs in the lower extremities of young adults. The head and neck are rare sites, accounting for less than 10%. The larynx is an extremely rare site. We report two cases of 27 and 18 year-old men who developed a synovial sarcoma of the larynx. They presented with hoarseness of voice and hemoptysis. Endoscopy detected a mass in the supraglottic region. The biopsy concluded a synovial sarcoma. Immunohistochemistry conveyed diagnostic certainty. They had been treated with total laryngectomy and post-operative radiotherapy. The 2 patients are seen for regular follow-ups in our department and they remained recurrence-free for 10 years and 24 months, respectively. Synovial sarcoma is a very rare tumor of the larynx. A multidisciplinary therapeutic approach is essential for the management of this malignancy. Long-term follow-up is required to monitor for recurrence and improve disease-free survival.

The role of TLE1 in synovial sarcoma.

The treatment outcome of synovial sarcoma is poor owing to its resistance to radiation and chemotherapy. The transducin-like enhancer of split 1 (TLE1) is a co-repressor that involves many signaling pathways like cell survival, hematopoiesis and differentiation. Although TLE1 is uniquely expressed in synovial sarcomas, the biological role of TLE1 is not completely understood. This study evaluated the function of TLE1 in synovial sarcomas using knock-down of TLE1, and examined whether the inhibition of TLE1 suppresses the proliferation of synovial sarcomas and enhances the cytotoxicity caused by doxorubicin (doxo). The over-expression of TLE1 was first confirmed in synovial sarcoma cells (HS-SYII). When the HS-SYII cells and normal fibroblast were transiently transfected with TLE1 siRNA, the MTT assay revealed growth inhibition in the HS-SY-11 cells but not in the normal fibroblast. TLE1 silencing also potentiated the cytotoxic effects of doxo against HS-SYII cells. This effect of TLE1 silencing was attributed mainly to the induction of apoptosis. Subsequent analysis revealed that Bcl-2 is a possible downstream target of TLE1 signaling. This study demonstrated that TLE1 is a critical factor for the survival of synovial sarcomas. Overall, the inhibition of TLE1 affects cell proliferation and the apoptosis pathway by suppressing the expression of Bcl-2.

Tight junctions in cancer metastasis.

Tight Junctions (TJ) are well known to function as a control for the paracellular diffusion of ions and certain molecules, it has however, become evident that the TJ has a vital role in maintaining cell to cell integrity. Loss of cohesion of the TJ structure can lead to invasion and ultimately to the metastasis of cancer cells. This review will discuss how modulation of expression of TJ molecules results in key changes in TJ barrier function leading to the progression of cancer and progression of metastasis.

A multidisciplinary approach to fertility-sparing therapy for a rare vulvar tumor.

OBJECTIVE: Case report of a young woman with a rare vulvar malignancy who received treatment with a personalized multidisciplinary approach to balance management of her malignancy without compromising survival with her desire for future pregnancy. DESIGN: Case report. SETTING: University hospital. PATIENT(S): A 33-year-old woman, gravida 2, para 1-0-1-1, who had a diagnosis of synovial cell sarcoma of the vulva and who desired future fertility. INTERVENTION(S): At multiple steps, treatment was planned to try to maximize fertility preservation without potentially affecting initial treatment, which included a radical hemivulvectomy with bilateral lymph node dissection, brachytherapy with interstitial needles (20 Gy), and external beam radiation therapy (50 Gy). MAIN OUTCOME MEASURE(S): Treatment and eradication of the malignancy and achievement of a successful subsequent pregnancy and live birth. RESULT(S): The patient had no evidence of disease for 2 years after treatment. During that time she received preconception counseling by both a perinatologist and a reproductive endocrinologist. She conceived with the use of ultrasound monitoring to time intercourse specifically with ovulation from the contralateral ovary and had an uncomplicated pregnancy with a term delivery. CONCLUSION(S): By using several disciplines and subspecialists, this patient received personalized treatment for a rare cancer, focused at curing her cancer and optimizing her future fertility.

Expression of CD133 in synovial sarcoma.

The development of synovial sarcoma, a translocationally defined soft tissue tumor of unknown histogenesis with considerable resistance to systemic therapy and a poor prognosis, may involve cancer stem-like cells. Recent studies suggest that synovial sarcoma arises from a primitive progenitor-type cell and have shown that synovial sarcomas contain subpopulations with enhanced tumorigenic potential; however, little is known about cancer stem-like cells in synovial sarcoma. Histologic and gene expression studies have reported features of synovial sarcoma that are reminiscent of neural development, suggesting that a neural cancer stem-like cell marker, such as CD133, may mark cancer stem-like cells in synovial sarcoma, allowing for further characterization. Here, the immunohistochemical expression of CD133 in primary synovial sarcoma tumor tissue and synovial sarcoma cell lines is determined. Subpopulations of CD133 expressing cells are present in all primary synovial sarcomas (5/5) and synovial sarcoma cell lines (3/3) examined. Histologically, CD133 positive cells are dispersed and seem to have dendritic processes. This study demonstrates the presence of CD133 expressing cells in synovial sarcoma for the first time and validates 3 synovial sarcoma cell lines as models for further study of the CD133+ subpopulation. The relationship between CD133 expression and cancer stem-like cells suggests that CD133 expressing synovial sarcoma cells may represent cancer stem-like cells in synovial sarcoma, which has significant implications for understanding the pathogenesis of this tumor and developing effective therapies.

Primary endobronchial synovial sarcoma confirmed by SYT-SSX1 fusion gene transcript by reverse transcriptase polymerase chain reaction.

Primary sarcomas of lung are rare compared to metastatic sarcomas. Herein, we report a rare case of primary pulmonary synovial sarcoma with polypoid endobronchial growth in a 35-year-old lady who presented with cough and dyspnea. A malignant pulmonary tumor was suspected and left pneumonectomy was performed. Grossly, a non-encapsulated polypoidal endobronchial tumor measuring 6 cm in greatest diameter, with a solid, tan-white cut surface was identified. Microscopically, tumor was characterized by a proliferation of oval to spindle-shaped cells arranged in sheets and fascicles. Focal hemangiopericytomatous pattern was noted. Immunohistochemically, tumor cells were positive for vimentin, BCL-2, MIC-2 and calponin and focally positive for pancytokeratin and epithelial membrane antigen. A subsequent molecular analysis performed using reverse transcriptase-polymerase chain reaction with RNA extracted from paraffin-embedded tissue, revealed SYT/SSX1 fusion gene which confirmed the diagnosis of synovial sarcoma. The utility of immunohistochemistry and molecular techniques in diagnosis of such a rare case is stressed and the relevant literature is discussed.

A phase II study of gefitinib for patients with advanced HER-1 expressing synovial sarcoma refractory to doxorubicin-containing regimens.

RATIONALE: Advanced synovial sarcomas (SyS) refractory to doxorubicin and ifosfamide are highly resistant to the currently available cytotoxic agents. Based on a report showing a specific overexpression of HER-1 in SyS, we investigated an HER-1 inhibitor, gefitinib, in refractory SyS. SUBJECTS AND METHODS: To establish the efficacy and safety of gefitinib in HER-1 - positive SyS refractory to one or two lines of doxorubicin- and ifosfamide-based chemotherapy, a phase II study was conducted from December 2002 to October 2005 by 12 centers of the European Organization for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group. Gefitinib was given at a 500-mg/day oral dose until progression or intolerance. RESULTS: Forty-eight patients were included (46 eligible). All patients had previously received chemotherapy for metastatic disease, with a median number of two lines (range, 1-4). The most frequent metastatic sites were the lungs (n = 44, 92%), lymph nodes (n = 11, 23%), and soft tissues (n = 10, 21%). The median duration of treatment was 43 days (range, 13-315). Treatment was interrupted in five patients (10%). Treatment was halted for progression in 45 (94%) patients. The best response was stable disease in 10 patients (21%). Disease progression occurred in 32 patients (70%), with a median time to disease progression of 6 weeks. Progression-free survival at 4 and 6 months was 21% and 6%, respectively. CONCLUSION: The results show that gefitinib monotherapy in advanced SyS refractory to conventional chemotherapy did not demonstrate sufficient activity to warrant further investigation in this setting. This may suggest that HER-1 is not a critical protein in tumor progression in this disease.

Synovial sarcoma of the extremities and trunk: a long-lasting disease.

Synovial sarcoma (SS) of an extremity or trunk is relatively rare and is approached by limb sparing surgery (LSS), radiation therapy (RT) and chemotherapy. We conducted a retrospective analysis of the clinical and histopathological data of 73 patients with proven SS. At a median follow-up time of 6 years, local recurrence was seen in 17.8 and systemic recurrence 35.6% of patients (local-only, 6.8; systemic-only, 24.6; combined, 11%). The 10-year local recurrence-free survival (LRFS), systemic recurrence-free survival (SRFS) and overall survival (OS) rates were 78, 68 and 61%, respectively. LRFS was significantly better in patients treated with isolated limb perfusion (ILP); SRFS was influenced by the delay until diagnosis. The practical aspects of our observations are the need for long-term follow-up in order to diagnose recurrences, the fact that not all local or distant recurrences are necessarily associated with a shortening of OS time and the important role of induction ILP with TNF in cases of extremity SS.

Molecular alterations of monophasic synovial sarcoma: loss of chromosome 3p does not alter RASSF1 and MLH1 transcriptional activity.

Differential diagnosis of monophasic synovial sarcoma requires the detection of specific biological markers. In this study we evaluated the presence of molecular alterations in 15 monophasic synovial sarcomas. Multiple changes affecting chromosome arms were detected by CGH-array in all microdissected cases available, and an association between gain or loss of specific regions harbouring cancer progression-associated genes and aneuploid status was found. The most frequent alteration was loss of 3p including 3p21.3-p23 region that, however, did not involve the promoter regions of the corresponding genes, RASSF1 and MLH1. Using Real-Time PCR, mRNA levels of both resulted moderately high compared to normal tissue; however, the weak to absent protein expression suggests RASSF1 and MLH1 post-transcription deregulation. Moreover, immunohistochemical analysis revealed that both mesenchymal and epithelial antigens were present in diploid tumours. These findings confirm the genetic complexity of monophasic synovial sarcoma and underline the need to integrate different analyses for a better knowledge of this tumour, essential to investigate new diagnostic and prognostic markers.

Estudo do valor prognóstico de fatores clínico-patológicos e moleculares relacionados à regulação do ciclo celular, proliferação e angiogênese em portadores de sarcomas sinoviais de extremidades / Prognostic analysis of clinical, pathological and molecular factors related to cell regulation, proliferation and angiogenesis in patients with localized extremity synovial sarcoma

Para testar a hipótese de que pacientes portadores de sarcomas sinoviais de extremidades com características clínicas similares podem apresentar evoluções distintas em decorrência de alterações moleculares tumorais, reações imuno-histoquímicas para p53, Ki67, EGFR, c-erbB-2, e sintases do óxido nítrico 1,2 e 3 foram realizadas em tecidos de 57 pacientes para análise de sua positividade como valor prognóstico. Fatores prognósticos adversos para recidiva local, metástases e morte por tumor na análise multivariada foram apresentação como recidiva (p=0,014) e Ki67 score ≥5 por cento (p<0,001); Ki67 score ≥5 por cento (p<0,001) e negatividade para c-erb-B2 (p=0,01); e o tamanho do tumor >8 cm (p=0,047), respectivamente. Verificou-se que o Ki67 e c-erbB2 são marcadores de prognóstico independentes de fatores clínicos / To test the hypothesis that extremity synovial sarcoma patients with similar clinical scenarios can have distinct outcomes due to tumor molecular alterations, immunohistochemical reactions for p53, Ki67, EGFR, c-erbB-2, and nitric oxide sinthases 1,2 and 3 were performed in tissues of 57 patients to analyze their positivity as prognostic factors. Adverse prognostic factors for local recurrence, metastasis and tumor related death on multivariate analysis were presentation as local recurrence (p=0.014) and Ki67 score ≥5 per cent (p<0.001); Ki67 score ≥5 per cent (p<0.001) and negativity for c-erb-B2 (p=0.01); and tumor size >8 cm (p=0.047), respectively. It was verified that both Ki67 and c-erbB2 are prognostic factors independent of clinical variables...

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.

Sarcoma sinovial primario de corazón

El sarcoma sinovial es una neoplasia bastante rara, que deriva su nombre de su origen mesenquimal y por que en las imágenes microscópicas recuerda a los sinoviocitos. Su sitio de presentación más frecuente son los tejidos blandos de extremidades, cabeza y cuello. Su localización primaria en corazón es bastante exótica, conociéndose hasta la fecha tan sólo 6 casos en la literatura mundial. Todos estos con un pobre pronóstico a pesar de diferentes medidas terapéuticas utilizadas. El promedio de presentación es en la 2-4 década de la vida y el promedio de vida son entre 6 y 9 meses. Se presenta, el caso de un paciente de 30 años cuya patología evidencia la presencia de sarcoma sinovial, se descarta compromiso metastásico y se confirma el origen primario de corazón. Se relata su forma de presentación clínica, evolución, hallazgos histológicos y esquema terapéutico utilizado. Además se realiza una revisión de la literatura en lo referente a sarcomas primarios de corazón

Synovial sarcoma: oncological and functional results.

AIM: To evaluate the oncological and functional result of the treatment of patients with a synovial sarcoma. This paper gives a retrospective review of 20 patients (15 male and five female) treated for synovial sarcoma at the Nijmegen University Hospital, The Netherlands. METHODS: The median age of the patients was 30 years (range: 14-71, mean 37 years). RESULTS: The tumour locations were: lower extremity in 12 patients; upper extremity in three; pelvic and groin region in four; and the retroperitoneal space in one. Surgical stages according to Enneking (Clin Orthop 1986; 204: 9-24) were IIA in five cases; IIB in seven; and IIIB in eight. The surgical margin was intralesional in three cases; marginal in three; wide in six; and radical in six. In one case the surgical margin could not be assessed and one patient was not operated. One patient developed a recurrent tumour and one developed nodal metastases. Eight patients who did not have metastases at the time of diagnosis developed metastase during follow-up. Fourteen patients died of metastatic disease; one patient died of diabetes; one is alive with disease; and four presently do not have evidence of disease. CONCLUSIONS: The outcome was poor, especially due to the occurrence of pulmonary metastases. The functional result according to the MSTS was 100% in four patients; in one the result was 93% because of the scar and venous insufficiency.

Tumor-induced hypercalcemia in a patient with extensive soft tissue sarcoma: effects of bisphosphonate therapy and surgery.

Tumor-induced hypercalcemia (TIH) is a frequent complication of advanced cancer, but it has been rarely reported in patients with sarcoma. We describe the case of a young female patient with TIH and with an extensive synoviosarcoma of the left lower limb destroying the bony structures. Hypercalcemia was severe (18.3 mg/dl) and accompanied by low serum Pi and suppressed parathyroid hormone (PTH) and 1,25(OH)2 vit D3 serum concentrations. Hypercalcemia was successfully treated with ibandronate, a new third-generation bisphosphonate, and radical surgery was performed when the patient was normocalcemic. Circulating levels of PTH-related protein (PTHrP) were elevated at 22.5 pmol/L (NI < 9). PTHrP levels did not change after successful therapy of TIH, in contrast with PTH, which increased sharply. PTHrP levels were normalized after radical surgery. Moreover, low serum Pi with reduced threshold for phosphate excretion and increased tubular calcium reabsorption supported the notion that PTHrP was indeed the essential mediator of paraneoplastic hypercalcemia in this case despite the extensive bone destruction.

Synovial sarcoma in children and adolescents: the St Jude Children's Research Hospital experience.

PURPOSE AND METHODS: We reviewed the clinical records and pathologic findings of 37 children and adolescents with synovial sarcoma treated at our institution over a 30-year period to evaluate the prognostic significance of tumor size, invasiveness, histology, and other features. RESULTS: The 20 male and 17 female patients with synovial sarcoma had a median age of 13.7 years at diagnosis. Primary tumor sites were the extremities (n = 27), trunk (n = 8), and head and neck (n = 2). Disease stage (clinical group) was as follows: group I, n = 21; group II, n = 7; group III, n = 4; and group IV, n = 5. Nineteen patients had invasive (T2) lesions, 20 had tumors more than 5 cm in diameter, and 14 had histologic grade 3 lesions. The estimated 5-year survival rate (+/- SE) for patients with group I or II disease was 80% +/- 9%, compared with 17% +/- 15% for those with group III or IV tumors (P = .0003). An exact log-rank test, adjusted for clinical group, showed that tumor invasiveness and grade independently predicted overall and progression-free survival (P < .05); tumor size was significantly correlated with progression-free survival. A borderline significant relationship with overall survival was found for both tumor size and histologic subtype (P = .09). CONCLUSION: A controlled trial of adjuvant chemotherapy is merited in children with resected synovial sarcoma (clinical group I or II) who present with unfavorable clinicopathologic features such as large, invasive, or grade 3 lesions. Children with unresected or metastatic disease fare poorly despite multimodality therapy and require novel treatment approaches.