Clinical Neuropathology practice guide 6-2013: morphology and an appropriate immunohistochemical screening panel aid in the identification of synovial sarcoma by neuropathologists.

AIMS: Pathologists are under increasing pressure to accurately subclassify sarcomas, yet neuropathologists have limited collective experience with rare sarcoma types such as synovial sarcoma. We reviewed 9 synovial sarcomas affecting peripheral nerve diagnosed by neuropathologists and explored the morphologic and immunohistochemical differences between these and MPNST. Our goal was to make practical recommendations for neuropathologists regarding which spindle cell tumors affecting nerve should be sent for SYT-SSX testing. METHODS: Clinical records and genetics were reviewed retrospectively and central pathology review of 9 synovial sarcomas and 6 MPNST included immunohistochemistry for SOX10, S100, BAF47, CK (lmw, pan, CK7, CK19), EMA, CD34, bcl2, CD99, and neurofilament. RESULTS: Common synovial sarcoma sites were brachial plexus, spinal and femoral nerve, none were "intra-neural", all had the SYTSSX1 translocation, and 6/9 were monophasic with myxoid stroma and distinct collagen. Half of the monophasic synovial sarcomas expressed CK7, CK19 or panCK in a "rare positive cells pattern", 8/9 (89%) expressed EMA, and all were SOX10 immunonegative with reduced but variable BAF47 expression. CONCLUSIONS: We recommend that upon encountering a cellular spindle cell tumor affecting nerve neuropathologists consider the following: 1) SYT-SSX testing should be performed on any case with morphology suspicious for monophasic synovial sarcoma including wiry or thick bands of collagen and relatively monomorphous nuclei; 2) neuropathologists should employ a screening immunohistochemical panel including one of CK7, panCK or CK19, plus EMA, S100 and SOX10, and 3) SYT-SSX testing should be performed on any spindle cell tumor with CK and/or EMA immunopositivity if SOX10 immunostaining is negative or only labels entrapped nerve elements.

NY-ESO-1 expression in synovial sarcoma and other mesenchymal tumors: significance for NY-ESO-1-based targeted therapy and differential diagnosis.

A promising targeted therapy against NY-ESO-1 (CTAG 1B) using genetically modified T-cells in synovial sarcomas was recently demonstrated in a clinical trial at the NCI. To investigate the role of NY-ESO-1 immunohistochemistry in patient selection and gain better insight into the incidence of NY-ESO-1 expression in synovial sarcomas and other mesenchymal tumors, we evaluated NY-ESO-1 expression by immunohistochemistry in 417 tumors. This collection of samples included: 50 SS18/SSX1/2 fusion positive synovial sarcomas, 155 gastrointestinal stromal tumors (GIST), 135 other spindle cell sarcomas as well as 77 other sarcomas (chondrosarcoma, osteosarcoma, dedifferentiated liposarcoma, alveolar soft part sarcoma, rhabdomyosarcoma, angiosarcoma, malignant mesothelioma, and Ewing's sarcoma). We report that 76% of synovial sarcomas expressed NY-ESO-1 in a strong and diffuse pattern (2-3+, >50-70% of tumor cells). In contrast, only rare cases of other spindle cell mesenchymal tumor expressed NY-ESO-1 (GIST (2/155), malignant peripheral nerve sheath tumors (1/34), and dermatofibrosarcoma protuberans (2/20)). Individual cases of other sarcomas (angiosarcoma, malignant mesothelioma, chondrosarcoma, osteosarcoma, dedifferentiated liposarcoma, alveolar soft part sarcoma, and Ewing's sarcoma) were positive for NY-ESO-1. However, no positive cases were identified amongst our cohort of leiomyosarcomas (0/24), hemangiopericytoma/solitary fibrous tumors (0/40), and cellular schwannomas (0/17). In summary, we find that NY-ESO-1 is strongly and diffusely expressed in a majority of synovial sarcomas, but only rarely in other mesenchymal lesions. Beyond its role in patient selection for targeted therapy, immunohistochemistry for NY-ESO-1 may be diagnostically useful for the distinction of synovial sarcoma from other spindle cell neoplasms.

[Cystic renal neoplasms. New entities and molecular findings]. / Zystische Nierentumoren. Neue Tumortypen und aktuelle molekulare Erkenntnisse.

Renal neoplasms with dominant cysts represent a broad spectrum of known as well as novel renal tumor entities. Established renal tumors with dominant cysts include cystic nephroma, mixed epithelial and stromal tumor, synovial sarcoma and multilocular cystic renal cancer (WHO classification 2004). Novel tumor types have recently been reported, which are also characterized by marked cyst formation. Examples are tubulocystic renal cancer and renal cancer in end-stage renal disease. These tumors are very likely to be included in a future WHO classification due to their characteristic phenotype and molecular features. Cysts and clear cell renal cell carcinoma frequently coexist in the kidneys of patients with von Hippel-Lindau disease. Cysts are also a component of many sporadic clear cell renal cell carcinomas. Multilocular cystic renal cell carcinoma is composed almost exclusively of cysts and is regarded as a specific subtype of clear cell renal cancer. Recent molecular findings suggest that clear cell renal cancer may develop via a cyst-dependent mechanism in von Hippel-Lindau syndrome as well as via cyst-independent molecular pathways in sporadic clear cell renal cancer.

Synovial sarcoma of the extremities: prognostic factors for 20 nonmetastatic cases and a new histologic grading system with prognostic significance.

PURPOSE: To evaluate 20 cases of nonmetastatic synovial sarcoma of the extremities regarding prognostic factors, and to propose a histologic grading system with prognostic significance. METHODS: The cases of 20 patients (14 females and 6 males) with nonmetastatic synovial sarcomas of the extremities treated between 1985 and 1998, were retrospectively evaluated regarding prognostic factors. A histologic grading system with prognostic significance is proposed. RESULTS: The mean follow-up period was 48.4 months (range, 16-116 months). There was local recurrence in 3 cases (15%), microscopic surgical margin being the only prognostic factor identified. Seven patients (35%) died of the disease in a mean postoperative period of 31.7 months (range, 16-53 months), all with pulmonary or brain metastasis. The survival rate was 65% in 48.4 months of follow-up. CONCLUSION: The unfavorable prognostic factors identified regarding survival were high histologic grade, tumors proximal to the knee or elbow, and spontaneous tumor necrosis over 25%. Local recurrence did not have influence on survival in this study. The presence of mast cells appears to have a positive influence on survival, although statistical significance was not reached (P = 0.07). The oncologic and functional result was good in 6 cases (30%), regular in 7 (35%), and poor in 7 cases (35%).

Genome-wide analysis of gene expression in synovial sarcomas using a cDNA microarray.

Among a histologically heterogeneous group of soft tissue sarcomas, synovial sarcoma (SS) is regarded as a "miscellaneous" entity of uncertain origin. Although recent molecular analysis has disclosed involvement of a specific chromosomal translocation in the pathogenesis of SS, its genetic features remain largely unclear. In the work reported here we examined genome-wide gene expression profiles of 13 SS cases and 34 other spindle-cell sarcoma cases by cDNA microarray consisting of 23,040 genes. A hierarchical clustering analysis grouped SS and malignant peripheral nerve sheath tumor into the same category, and these two types of tumor shared expression patterns of numerous genes relating to neural differentiation. Several genes were up-regulated in almost all SS cases, and the presumed functions of known genes among them were related to migration or differentiation of neural crest cells, suggesting the possibility of neuroectodermal origin of SS. Moreover, we identified a set of genes that divided SS cases into two putative subclasses, a feature that may shed light on novel biological aspects of SS in addition to those having to do with epithelial differentiation. These data have provided clues for understanding the origin and tumorigenesis of SS.

Classification and grading of soft-tissue sarcomas.

This article provides an overview of the classification of soft-tissue sarcomas as influenced by modern histopathologic techniques. The overview is followed by a practical grading system for these tumors based on a study of 282 eligible patients. The primary tumors of this trial were adequately treated. The quantitative data (mitotic count and size of the tumor) were based on the results of the statistical analysis.

Soft-tissue sarcoma of undetermined histogenesis: an ultrastructural study.

A certain proportion of soft-tissue sarcomas are difficult to classify accurately. In this case report, initial light microscope observations of a soft-tissue tumor suggested a diagnosis of a monophasic synovial sarcoma. However, critical evaluation of the histologic features, results of studies with special stains, and ultrastructural observations indicated that this tumor is best categorized as an undifferentiated soft-tissue sarcoma of "undetermined histogenesis."

Gene expression profiling of synovial sarcoma: distinct signature of poorly differentiated type.

Poorly differentiated type synovial sarcoma (PDSS) is a variant of synovial sarcoma characterized by predominantly round or short-spindled cell morphology. Although accumulating evidence from clinicopathologic studies suggests a strong association between this variant of synovial sarcoma and poor prognosis, little has been reported on the molecular basis of PDSS. To gain insights into the mechanism(s) that underlie the emergence of PDSS, we analyzed the gene expression profiles of 34 synovial sarcoma clinical samples, including 5 cases of PDSS, using an oligonucleotide microarray. In an unsupervised analysis, the 34 samples fell into 3 groups that correlate closely with histologic subtypes: monophasic, biphasic, and poorly differentiated types. PDSS was characterized by down-regulation of genes associated with neuronal and skeletal development and cell adhesion. Moreover, upregulation of genes on a specific chromosomal locus, 8q21.11, was identified. This locus-specific transcriptional activation in PDSS was confirmed by reverse transcriptase-PCR analysis of 9 additional synovial sarcoma samples. Our results indicate that PDSS tumors constitute a distinct group based on expression profiles.

[Problematic zones in the classification of soft tissue tumors]. / Problemzonen der Tumorklassifikation bei Weichgewebstumoren.

The classification of soft tissue tumors is based on the recognition of the resemblance to normal tissue or cells. Nowadays, molecular pathologic findings essentially may contribute to the diagnosis. In daily practice, however, the evaluation of HE sections and immunohistochemical findings are most important because these methods are widely available. Nevertheless, misinterpretations are possible if certain rules and limitations in data utilization for diagnosis are not considered. There are some problematic zones referring to this in which especial attention is mandatory. By means of examples difficulties are explained which may result from overlapping morphological features between soft tissue tumors, between nerve sheath tumors and melanocytic neoplasms, and between soft tissue tumors and sarcomatoid carcinomas. The necessity of a careful interpretation of immunohistochemical findings is underscored with selecting actin positivity as example. Finally, difficulties in determining the dignity of a soft tissue tumor are discussed. Moreover, tumor heterogeneity may under certain conditions render more difficult the classification of a soft tissue tumor.

Monophasic synovial sarcoma--a histological entity?

Consideration is given to the concept of a histologically identifiable monophasic type of synovial sarcoma. It is accepted that a sarcomatous tumour may be encountered where the spindle cells assume a somewhat epithelioid appearance associated with a reticulin pattern unlike that of most other spindle cell sarcomas. The appearance should alert a hsitopathologist to the possibility of a synovial sarcoma and prompt the examination of multiple additional sections in an attempt to find the pathognomonic biphasic pattern. It is not, however, believed that an entire tumour composed of cells of a single type could be identified with certainty as a synovial sarcoma by light microscopy. The term monophasic synovial sarcoma is worthy of retention, but only as a guide towards the establishment of a definite diagnosis by further sampling of the specimen. Other features suggestive of this diagnosis are discussed.

Two categories of synovial sarcoma defined by divergent chromosome translocation breakpoints in Xp11.2, with implications for the histologic sub-classification of synovial sarcoma.

Molecular analysis of a new series of synovial sarcomas confirms that t(X;18)(p11.2;q11.2) breakpoints occur at two distinct regions on Xp designated SS1 and SS2. Breakpoint position correlates with tumor phenotype. Monophasic tumors with no evidence of glandular components have breakpoints within the SS2 region in Xp11.21, and biphasic tumors with a focal poorly differentiated or extensive glandular structure have breakpoints within the SS1 region in Xp11.23.

Synovial sarcoma--identification of favorable and unfavorable histologic types: a Scandinavian sarcoma group study of 104 cases.

Synovial sarcoma has traditionally been regarded as a high-grade sarcoma and treated as such. Recently, specific types of poorly differentiated synovial sarcoma have been defined and shown to affect prognosis adversely. We studied 104 primary synovial sarcomas of the extremities and trunk wall without metastasis at diagnosis that were retrieved from the Scandinavian Sarcoma Group Registry (SSG) and the Swedish Cancer Registry from 1986 to 1994. Follow-up was available in all patients, median 6 (3-11) years for the survivors. There were local recurrences in 15% of patients and metastases in 33%. Histologically, the tumors were divided into favorable and unfavorable types. The favorable type had no significant cytologic atypia, and in most instances, no necrosis and a mitotic count of < 10/10 hpf. The unfavorable type included so-called poorly differentiated synovial sarcomas as well as recognizable biphasic and monophasic synovial sarcomas with prominent nuclear atypia, extreme cellularity and nuclear crowding. Designation of a tumor as having favorable vs. unfavorable histology conveyed more prognostic information than any single histologic factor. Kaplan-Meier estimates of metastasis-free survival at 5 years were 83% for patients with histologically favorable tumors and 31% for patients with histologically unfavorable tumors (95% confidence intervals 72-92% and 13-51%, respectively). These findings may influence future treatment protocols for synovial sarcoma.

Molecular classification of synovial sarcomas, leiomyosarcomas and malignant fibrous histiocytomas by gene expression profiling.

In this study, we have used genome-wide expression profiling to categorise synovial sarcomas, leiomyosarcomas and malignant fibrous histiocytomas (MFHs). Following hierarchical clustering analysis of the expression data, the best match between tumour clusters and conventional diagnosis was observed for synovial sarcomas. Eight of nine synovial sarcomas examined formed a cluster that was characterised by higher expression of a set of 48 genes. In contrast, sarcomas conventionally classified as leiomyosarcomas and MFHs did not match the clusters defined by hierarchical clustering analysis. One major cluster contained a mixture of both leiomyosarcomas and MFHs and was defined by the lower expression of a set of 202 genes. A cluster containing a subgroup of MFHs was also detected. These results may have implications for the classification of soft tissue sarcomas, and are consistent with the view that sarcomas conventionally defined as MFHs do not represent a separate diagnostic category.

Synovial sarcomas. True carcinosarcomas?

The histogenesis of synovial sarcomas remains controversial. An origin from epithelium, synovium, or synovial-related cells and neural tissue has been advanced. Using a combination of a cytokeratin (epithelial marker) antibody and a vimentin (mesenchymal marker) antibody, this study suggests that a synovial sarcoma might be regarded as a carcinosarcoma. It also highlights the diagnostic utility of those antibodies in the diagnosis of synovial sarcomas.

The ultrastructural spectrum of synovial sarcomas: a study of the epithelial type differentiation of primary tumors, recurrences, and metastases.

Synovial sarcomas (SS) are malignant soft tissue tumors of unknown origin. Their classification as carcinomas (monophasic synovial sarcomas, MSS) or carcinosarcomas (biphasic synovial sarcomas, BSS) still raises controversy. In an attempt to settle this controversy, an ultrastructural study was undertaken of 25 primary SS (12 BSS and 13 MSS), 5 recurrences (3 BSS and 2 MSS), and 2 metastases (2 BSS) based upon precise selection of different aspects of BSS and MSS on numerous semithin sections from each case. Ultrastructural markers of epithelial type differentiation of neoplastic cells were found in every type of cellular component of SS regardless of the tumoral pattern (biphasic or not). No major differences were found between MSS and the nonglandular areas of BSS (not even regarding the presence of abortive glandular lumina). Cytoarchitectural transitions were frequently observed; these included spindle to epithelioid cell types and fascicular to solid (MSS and BSS) or fascicular to glandular (BSS) patterns. These findings support the assumption that spindle cells of SS are neoplastic and may evolve to glandular cells in SS. Based on the cytogenetic data pointing to a common pathogenesis of both phenotypes (BSS and MSS), SS may represent true carcinomas of soft tissues with a biphasic and/or monophasic pattern depending on the degree of differentiation.

Clear cell sarcoma of tendons and aponeuroses: a comparative study of 13 cases with a provisional subgrouping into the melanotic and synovial types.

Electron microscopy of two cases of clear cell sarcoma of tendons and aponeuroses showed different fine structures. On the basis of these differences a proposed division is made of melanotic and synovial types of the tumor. A subsequent comparative histological study carried out on these tumors showed that there were histological criteria to separate the melanotic and synovial types of sarcoma. Using these histological criteria eleven further cases of clear cell sarcoma in the files of the Tumor Registry were subdivided. Review of the Tumor Registry material showed that eight were melanotic type tumors and one was a further synovial type tumor. Using these histological criteria there are two further cases in the Tumor Registry which are not clearly classifiable into either group. The present observations indicate that the majority of the so-called clear cell sarcomas are in reality "melanomas of soft parts" with a minority of this type of tumor being of "synovial type".