synovial sarcoma

receptor with an important role in homing of hematopoietic stem cells and lymphocyte trafficking that has been found to promote cell migration, invasion and angiogenesis [52, 81]. The CXCR4 pathway has been shown to be associated with tumor progression and poor prognosis in many types of cancer including breast [82], lung [83], colon [84], melanoma [85] and soft tissue sar- comas [86]. CXCR4 promotes metastasis by activating activating extracellular signal-regulated kinase 1/2 (ERK1/2), Akt/PKB and Nuclear factor-κB (NF-κB), which increases the adhesion and invasive ability of can- cer cells in part by the activity of MMP2 and MMP9 [87–89]. CXCR4 has a pivotal role in the migration of cancer cells between the primary and the metastatic site in synovial sarcoma [52, 90]. Tumor cells expressing CXCR4 that detach from the primary tumor and enter the circulatory system can migrate toward organs that express its ligand CXCL12 [91]. Lung, lymph node, bone marrow, and liver, the most frequent metastatic loca- tions in SS [9], all express very high levels of CXCL12 [92]. A study of SS patients found that 5-year overall survival (OS) rates were 47% for those with positive CXCR4 staining, and 86% ( P = 0.0003) for those with negative CXCR4 staining [52]. A second study, reported that 5 year survival outcomes for SS patients with posi- tive CXCR4 staining was less than 30% [4]. Importantly, it was found that SS cultures contain a subpopulation of cells expressing high levels of CXCR4 that also express high levels stem cell markers (NANOG, OCT4, SOX2), and these cells have an increased tumor initiating cap- acity in xenographic mouse models [4]. Although no group has directly measured the metastatic risk of CXCRX4 expression in SS, perhaps due to limited pa- tient numbers, expression of this marker appears to be a key factor both for cell migration and tumor propagation at a distal site. Perhaps the use of CXCR4 antagonists, many of which are already in various stages of clinical development [93], and shown to significantly reduce lung metastasis in mouse models of osteosarcoma [94], would be a beneficial treatment option for patients with metastatic SS, particularly in cases where tumors are unresectable.

Synovial sarcoma is a high-grade soft tissue malignancy and has a specific chromosomal translocation t(X; 18), which leads to the fusion of the SS18 gene to one of three SSX genes (SSX1, SSX2 or SSX4). The 5- and 10-year dis- ease-specific survival is 62% and 52% in adults, respectively [1]. β-catenin is a key player in Wnt-signaling pathway. Oncogenic activation of Wnt-signaling pathway is mandatory for the ini- tial neoplastic transformation of intestinal epi- thelium [2]. Nuclear accumulation of β-catenin as a cell-signaling event may play an important role in the progression of synovial sarcoma [3]. Abnormal levels of β-catenin could contribute to the development and progression of synovial sarcoma, through increasing the proliferative activity of the tumour cells [4]. More important- ly, SYT-SSX2 recruits β-catenin to the nucleus and associates with it in an active complex [5]. Upregulation of the Wnt/β-catenin cascade by SYT-SSX2 correlates with its nuclear reprogra-

spindle-cell components, it contains three sub- types: monophasic, biphasic and poorly differ- entiated according to cell compositions [8]. Poorly-differentiated SS is composed of sheets of round or spindled cells showing severe nuclear atypia and high mitotic activity, and the prognosis is very poor. In biphasic SS, the epi- thelial cells usually are cuboidal or columnar and have ovoid vesicular nuclei, and are arranged in solid nests or cords. The spindle cells are relatively uniform with sparse cyto- plasm and arranged in intersecting fascicles [9]. The majority of SS are positive for Bcl-2, CD99, CD56, vimentin, and focally positive for EMA, and negative for desmin, WT-1, and S-100 [10], but these markers are not specific. Studies show that TLE1 is a promising and helpful marker for the diagnosis of synovial sarcoma [11, 12], but it is not specific for SS, and also occurs in other similar tumors.

Morphologically, synovial sarcoma can show several growth patterns and is basically divided into monophasic and biphasic subtypes. The better recognized variant is the biphasic synovial sarcoma which consists of proliferation of bland looking spindle-shaped cells in a collagenous background and hemangiopericytomatous vascular growth pattern, along with evidence of epithelial differentiation ranging from well-formed gland-like structure to aggre- gates of cudoidal cells. Monophasic tumors on the other hand can show either spindle cells only or occasionally might consist of epithelial component only [7]. A poorly differentiated variant of synovial sarcoma is also recognized [8]. Immunostains has been invaluable in supporting the diagnosis of synovial sarcoma, especially with limited bi- opsy material as in our case, when the diagnostic features are not well represented, or in the poorly differentiated variant. The expression of epithelial markers in the gland- like component and more importantly in the spindle cell component supports the diagnosis. Among all epithelial markers, EMA is the most commonly positive marker [8]. Pan-cytokeratin, cytokeratin 7, and 19 can also be positive in the epithelial-like component as well as the spindle cell component [9]. In addition; positivity for bcl-2 can be seen in some cases [10]. Recently; TLE1 has been described as a diagnostic marker for synovial sarcoma which is claimed to be more sensitive and specific than others [11].

From the molecular point of view, the current diagnostic gold standard for synovial sarcoma is to demonstrate the fusion of the SYT (Synonyms: SS18-synovial sarcoma transloca- tion, chromosome 18) gene on chromosome 18 to either SSX1 (synovial sarcoma, X break- point 1) or SSX2 (synovial sarcoma, X break- point 2) gene on chromosome Xp11 [9]. The overall clinical, histopathological, immuno- histochemical and molecular results directed toward primary synovial sarcoma of the kidney than the other differential diagnosis of leiomyo- sarcoma, sarcomatoid renal cell carcinoma, malignant solitary fibrous tumor, and dediffer- entiated liposarcoma.

Abstract: This paper presents an extremely rare case of synovial sarcoma arising from the maxillary sinus, which resulted in a clinically complete response to chemotherapy. Synovial sarcoma is a rare soft tissue malignant tumor, most commonly affecting the extremities. While ∼10% occur in the head and neck region, synovial sarcoma of the sinonasal tract is extremely rare, with only 11 cases having been reported previously. As with other sarcomas, the standard treatment is complete resection while allowing for a safe margin, but this is often difficult in the head and neck area due to the complicated anatomy there. This makes the treat- ment of head and neck sarcoma challenging and leads to the need for a multimodal approach in advanced cases. However, the exact efficacy of chemotherapy is not well understood. In this report, we present a case of unresectable maxillary sinus synovial sarcoma that was success- fully treated by chemotherapy followed by radiation therapy. A 53-year-old Japanese man was referred to our hospital with a history of left nose obstruction over the previous couple of years. Computed tomography/magnetic resonance imaging revealed a tumor arising from the maxillary sinus that extended to adjacent tissues. A biopsy was performed, and the tumor was diagnosed as synovial sarcoma. Since the tumor was unresectable, neoadjuvant chemotherapy was administered. The response was excellent, and the tumor became undetectable under endoscopy and radiological imaging. This provided us with a clinical evaluation of “complete response”. The treatment was concluded with definitive radiotherapy and two more cycles of adjuvant chemotherapy. The patient remains free of disease 12 months after treatment. Synovial sarcoma of the head and neck is a rare entity; complete resection is the treatment of choice but (neo)adjuvant chemotherapy can be considered in unresectable cases, as we show here in the present case.

In the article by Bergh et al. [33], the investigators divided patients with synovial sarcoma into low-risk and high-risk groups depending on their age, tumor size and grade as follows: low-risk group (patient age < 25 years, tumor size < 5 cm, and no histologic evidence of poorly differentiated tumor); high-risk group (patient age approximately 25 years, tumor size approximately 5 cm, and poorly differentiated tumor). The question is, can we apply the same risk factors to patients with GI synovial sarcoma? To answer such a question we need to diagnose more cases and collect more data about the already pub- lished cases to study the behavior of this disease entity in the GI tract, as well as in other parts of the body. Pre- sently, the evidence suggests adequate primary surgery is essential to both local control and outcome. The other question that one may ask: why do these tumors shift to unusual sites and different tissues? The honest answer, at least at this time, would by that we do not yet know the exact mechanism for such a shift. We are involved in a larger research study to investigate the increased inci- dence of sarcomas in the Saudi population, particularly in the northern region, which is close to the military activ- ities of both Gulf wars and the military activities in Iraq over the last decade.

Based on the results for synovial sarcoma of the extremities, surgical excision with a wide margin is the only curative therapy and offers the best outcome; however, the application to intra abdominal cases is largely unstudied [15]. Recently, the French Sarcoma group reported in their retrospective study about the effect of neo/adjuvant chemotherapy in resected SS of the extremities and stated that chemotherapy does not improve the outcome in the localized setting [4,16]. Thus, the role of adjuvant chemotherapy in patients with localized disease after local excision remains unproven [4].

tive expression rates of EMA (87%), Bcl-2 (85%), AE1/AE3 (61%), CK7 (35%) and CD99 (24%) were slightly lower than those reported in previ- ous studies [4, 17, 18, 21]. For example, Knösel T et al. [18] observed EMA positivity in 91% of synovial sarcomas, Bcl-2 positivity in 99.6%, PanCK (MNF) positivity in 73% and CK7 positiv- ity in 96%. CD99 can be detected in 60% to 70% of synovial sarcomas [4]. The main rea- sons for the differences might be that we used TMAs instead of whole sections. The focal staining patterns of epithelial markers in syno- vial sarcomas are usually displayed in the epi- thelial component rather than the spindled component. Therefore, the positive rates of the epithelial markers may have been lower, to some degree, than those observed in conven- tional tissues. In contrast, TLE1 usually dis- plays nuclear staining and a diffuse staining pattern in both the spindle and epithelial cell components, even in TMAs. Interestingly, the tissue volumes used in TMAs are very small and are thus similar to biopsy specimens to some extent. These findings imply that TLE1 is more sensitive and easier to interpret than tra- ditional markers, especially in small biopsies. Rekhi B et al. [21] investigated TLE1 expression in 42 synovial sarcomas, including 8 biopsy specimens. In their study, authors suggested that TLE1 was a useful diagnostic marker for synovial sarcomas on small biopsy samples. In our study, some synovial sarcomas did not express the traditional immunohistochemical markers but did exhibit TLE1 positivity. For example, one synovial sarcoma was negative for all of the traditional markers but displayed TLE1 2+ staining. Therefore, TLE1 is an excel- lent marker for the diagnosis of synovial sarco- ma, especially in challenging cases.

Introduction: Synovial sarcoma is a high-grade, soft-tissue sarcoma that most frequently is located in the vicinity of joints, tendons or bursae, although it can also be found in extra-articular locations. Most patients with synovial sarcoma of the hand are young and have a poor prognosis, as these tumors are locally aggressive and are associated with a relatively high metastasis rate. According to the literature, local recurrence and/or metastatic disease is found in nearly 80% of patients. Current therapy comprises surgery, systemic and limb perfusion chemotherapy, and radiotherapy. However, the 5-year survival rate is estimated to be only around 27% to 55%. Moreover, most authors agree that synovial sarcoma is one of the most commonly misdiagnosed malignancies of soft tissues because of their slow growing pattern, benign radiographic appearance, ability to change size, and the fact that they may elicit pain similar to that caused by common trauma.

Abstract: Primary mediastinal synovial sarcoma (PMSS) is a rare malignant soft tissue tumor with a poor progno- sis. Because of its rarity, the misdiagnosis rate remains high. To raise awareness of this disease, the current study presents a case of PMSS with atypical CT features. A 26-year-old male presented with a 3-day history of chest pain. Chest CT scans showed multi fusion masses with an ill-defined margin. After the mass was partially resected, patho- logical and immunochemistry examinations were performed. The patient was diagnosed with biphasic synovial sar- coma. Summary analysis was then conducted of clinical, histopathological, and CT details of cases reported in the literature (English only). Based on results, PMSS should be considered when a solitary mass in the mediastinum is observed in a man with chest pain. Moreover, PMSS is indicated when the mass measures greater than 4 cm and appears as a heterogenous mass with necrosis/cystic changes and heterogenous patterns. Prognosis of PMSS can be improved by early diagnosis.

Peripheral nerve tumors are predominantly of neuroectodermal origin and developed from two components of nerve, Schwann or perineurial cells. Schwannoma and neurofibroma represent the benign tumors and malignant peripheral nerve sheath tumor represents the malignant counterpart of tumors with schwannian origin. Contrarily, mesenchymal tumors involving peripheral nerve are infrequent and are derived mainly from epineurial connective tissue. [3] Synovial sarcoma is a class of mesenchymal tumors with no apparent relation to synovial tissue and their likely origin is from primitive undifferentiated mesenchymal cells present at any site. [1] The intraneural type of SS is a rare entity often misdiagnosed as peripheral nerve sheath tumor.

Lastly, EZH2 as a highly expressed pro-oncogenic re- gulator may also be an attractive candidate target for the future therapy of synovial sarcoma. SYT-SSX closely colla- borates with both EZH2 and HDAC in the repression of the tumor suppressor early growth response 1 (EGR1) [10]. Romidepsin (FK228), a HDAC inhibitor, reactivated EGR1 expression and caused tumor shrinkage in a preclinical synovial sarcoma model, presumably by disrupting the interactions within this complex [12,37]. It is reasonable to assume that concomitant inhibition of HDAC and EZH2 might yield a synergistic effect. Success- ful repression of EZH2 was achieved by small interfering RNA (siRNA) as well as using the small-molecule pharmacologic inhibitor 3-deazaneplanocin A in neuro- blastoma cells . Translation of these results into the treat- ment of synovial sarcoma may open novel therapeutic [38]opportunities.

in nonspecific constitutional symptoms such as short- ness of breath, weight loss, and anaemia-related fatigue and malaise [3]. However, severe thrombocytopenia has very rarely been reported in association with cardiac tumours, either benign or malignant [4]. We report one patient diagnosed with atrial myxoma with severe thrombocytopenia on admission, while the postoperative diagnosis was primary cardiac synovial sarcoma (PCSS) that severely adhered to the posterior mitral annulus. Surprisingly, the platelet counts returned rapidly to nor- mal range early after tumour excision without other

Despite intensive multi-modal treatment of sarcomas, a heterogeneous group of malignant tumors arising from connective tissue, survival remains poor. Candidate-based targeted treatments have demonstrated limited clinical success, urging an unbiased and comprehensive analysis of oncogenic signaling networks to reveal therapeutic targets and personalized treatment strategies. Here we applied mass spectrometry-based phosphoproteomic profiling to the largest and most heterogeneous set of sarcoma cell lines characterized to date and identified novel tyrosine phosphorylation patterns, enhanced tyrosine kinases in specific subtypes, and potential driver kinases. ALK was identified as a novel driver in the Aska-SS synovial sarcoma (SS) cell line via expression of an ALK variant with a large extracellular domain deletion (ALK Δ2-17 ). Functional ALK dependency was confirmed in vitro and in vivo with selective inhibitors. Importantly, ALK immunopositivity was detected in 6/43 (14%) of SS patient specimens, one of which exhibited an ALK rearrangement. High PDGFRα phosphorylation also characterized SS cell lines, which was accompanied by enhanced MET activation in Yamato-SS cells. Although Yamato-SS cells were sensitive to crizotinib (ALK/MET-inhibitor) but not pazopanib (VEGFR/PDGFR-inhibitor) monotherapy in vitro, synergistic effects were observed upon drug combination. In vivo, both drugs were

Soft tissue sarcoma (STS) is a rare malignant tumor of mesenchymal origin having an incidence of 2–3 cases per 100,000, thus contributing to less than 1% of all adult ma- lignancies [1, 2]. Synovial sarcoma (SS), or sarcoma of tis- sues adjacent to joints, is a rare type of STS, and represent 5 to10% of all STSs [1]. SS is commonly found in the proximal limb of young adults and has a male predomin- ance [3]. Other unusual sites of occurrence include the head and neck, heart, lungs, and kidneys [4]. Very few re- ports have tackled this tumor due to its rarity and diffi- culty to distinguish from other renal pathologies. The first case of primary SS of the kidney has been reported by Faria et al. in 1999 [5]. We present a case of primary syn- ovial sarcoma of the kidney, initially thought to be a

Synovial sarcoma (SS) is a distinctive entity, approxi- mately 90 % of which arise in the extremities, with a pre- dilection for the regions adjacent to large joints. Occasionally, the tumour may involve unusual sites throughout the body, including the head and neck, heart, pleura, abdomen, kidney, prostate, vulva, etc., which may be difficult to correctly diagnose [6]. Primary cardiac synovial sarcoma (PCSS) occurs infrequently. Wang et al. [5] reviewed 54 isolated literature reports before 2012 and found that there were 60 patients with PCSS, and only 16 cases of intra-cardiac biphasic SS. To date, less than 80 patients in total have been reported in the literature [7–17]. Here, we report a patient who was found to have a bloody pericardial effusion and a large right atrium mass who was diagnosed with biphasic PCSS mimicking carcinosarcoma. We arrived at our diagnosis because of the histological characteristics,

Synovial sarcoma is a rare, malignant mesen- chymal neoplasm that accounts for approxi- mately 8% of all soft tissue sarcomas. It can occur at any site and age but primarily arises in the para-articular areas of the lower extremi- ties of young adults, especially around the knee and ankle [1, 2]. Since the first case of head and neck synovial sarcoma reported by Jernstrom in 1954, only 3% to 5% of all cases were found in the head and neck region. In this region, the hypopharynx is the most common site [3]. Owing to rarity, non-specific imaging appearance and complex histological features of synovial sarcoma, its diagnosis is challeng- ing both clinically and pathologically. This tumor may occasionally appear as a well-defined, cys- tic mass associated with intralesional necrosis or hemorrhage. Such changes have been observed in patients with neck synovial sarco- mas [4, 5]. Once synovial sarcoma of the neck develops cystic degeneration, it could be easily confused with the common cystic diseases of the neck such as thyroglossal duct cyst and branchial cleft cyst. Here, we present a synovial Here, we present a case of a 21-year-old male with a cystic lesion of the left-sided neck, clini- cally masquerading as a malignant second

Some of the cases in our cases group were con- sultation cases from the other hospitals. The initial diagnosis included Wilm’s tumor, subtype undetermined; spindle renal tumor, possibly malignancy. The differential diagnosis includes sarcomatoid renal cell carcinoma (sarcomatoid RCC), Mixed epithelial and stromal tumor (MEST) [20, 21]. Here, we describe the key cri- teria for differential diagnosis of primary SS from its mimics, and list the useful diagnostic immuno-markers and molecular features in Table 2. Sarcomatoid RCC is characterized by sheets of whorled or interlacing bundles of pleomorphic spindle cells in a storiform pattern and may focal positive for epithelial markers, which mimics synovial sarcoma. Both the sar- comatoid RCC and SS may present hemangio- pericytoma like pattern. In contrast to synovial sarcoma, sarcomatoid RCC show classic RCC components with adequate sampling, which are mostly clear cell RCC, less common are chromophobe RCC, papillary RCC, unclassified RCC and collecting (Bellini) duct carcinoma, and negative for SS18-SSX. Epithelial lined tubular or cystically dilated structures admixed with spindle mesenchymal components in MEST can mimic BSS, especially when the tumor is cellular, which with increased stromal cellularity, and high mitotic index. Most of the MESTs are benign renal tumor. Bland epitheli- um, ovarian-type stromal components, and estrogen-receptor and progesterone-receptor positivity of the stromal are characteristics of MEST [22].

Gemcitabine and docetaxel combination chemotherapy has emerged as an effective salvage schedule in advanced sar- coma [3, 4, 16], particularly leiomyosarcoma and undifferen- tiated pleomorphic sarcoma. Synovial sarcoma is generally regarded as a relatively chemosensitive sarcoma subtype, although radiological response assessments in synovial sar- comas are particularly challenging [17]. However, there are few published data regarding gemcitabine/docetaxel in this subtype. Therefore, the aim of this study was to report the utility of this combination in synovial sarcoma. Our results suggest that gemcitabine/docetaxel has little efficacy with a response rate of 5% and median PFS of 2 months.