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This is one of the sarcomas that combine histologic features of both a carcinoma and a sarcoma. It may have epithelioid cells, mimicking carcinoma, intimately admixed with spindled sarcoma cells. Because of these features, the pathologist may have to differentiate between a poorly differentiated carcinoma and this tumor. It is a critical distinction but with the advent of immunohistochemistry, a confident distinction can now be made. These tumors are have spindle cells which are positive for vimentin and epithelial components positive for cytokeratin. More recently, molecular diagnostic studies have identified a unique translocation, t(X;18), fusing the SYT/SSX genes.
Rare variants may occur in non-soft tissue locations such as the larynx, heart, pericardium, pleura, lung, mediastinum, and peritoneal cavity. Recently cases have also been described in the kidney. Histologically, these tumors may mimic clear cell sarcomas or cellular mesoblastic nephromas. These tumors exhibit a characteristic translocation.
OUTLINE
PATHOGENESIS CHARACTERIZATION t(X;18)
SYT/SSX FUSION
Nat Genet 1994;7:502–8.
A characteristic chromosomal translocation t(X;18) (p11.2;q11.2) is present in most cases
Detailed cloning analysis of the breakpoints has revealed that the SYT gene at 18q11 is fused with the distal potion of one of two duplicated genes at Xp11, SSX1,or SSX2. This SYT-SSX fusion is present in >95% of cases and is a sensitive test for synovial sarcoma. The types of fusion transcripts may play a role in prognosis.
In a study of 19 cases, patients with SYT-SSX1 type fusion, high Ki-67 expression, and high mitotic rate correlated with shorter metastasis-free survival compared with SYT-SSX2 type fusion.
Mod Pathol 2000;13:1253-1263
Until recently, this translocation was thought to be specific for synovial sarcoma, this paper describes 15/20 (75%) of cases positive for this translocation
A Novel Type of SYT/SSX Fusion: Methodological and Biological Implications.Tornkvist M, Brodin B, Bartolazzi A, Larsson O.
Department of Cellular and Molecular Tumor Pathology, Cancer Centrum Karolinska, Karolinska Hospital (MT, BB, AB, OL), Stockholm, Sweden.
Mod Pathol 2002 Jun;15(6):679-85 Abstract quote Synovial sarcoma (SS) is a rare soft-tissue tumor that affects children and young adults. It is characterized by the chromosomal translocation t(X;18)(p11.2;q11.2), which results in the fusion of the SYT gene on chromosome 18 with a SSX gene on chromosome X. In the majority of cases, SYT is fused to exon 5 of SSX1 (64%), SSX2 (36%), or, rarely, SSX4. A novel fusion transcript variant deriving from the fusion of SYT to exon 6 of SSX4 gene (SYT/SSX4v) was found coexpressed in one of the previously reported SYT/SSX4 cases.
In the present investigation, we describe a new SS case that was previously shown to be negative for SYT/SSX1 and SYT/SSX2 expression by conventional reverse transcription polymerase chain reaction (RT-PCR) methods. By redesigning and optimizing the RT-PCR protocol, we were able to detect SYT/SSX4v as the sole fusion transcript expressed in this tumor sample.
This finding suggests that this novel fusion gene, which involves exon 6 of SSX only, is sufficient to keep the transforming function conferred by the SYT/SSX translocation of SS. In about 3% of morphologically, ultrastructurally, and immunohistochemically defined SS, the SYT/SSX fusion transcript is not detected using conventional RT-PCR. Here we demonstrate that optimization of the RT-PCR method is important for detecting different and unexpected SYT/SSX variants, which otherwise could be overlooked.
Using nine cases of SS in which SYT/SSX fusion transcripts were not detected by conventional RT-PCR methods, we demonstrate the presence of SYT/SSX transcripts in two cases using the proposed RT-PCR approach. Applications of optimized RT-PCR can contribute to reduce false-negative SYT/SSX SS cases reported in literature.
SYT-SSX Is Critical for Cyclin D1 Expression in Synovial Sarcoma Cells: A Gain of Function of the t(X;18)(p11.2;q11.2) Translocation.Xie Y, Skytting B, Nilsson G, Gasbarri A, Haslam K, Bartolazzi A, Brodin B, Mandahl N, Larsson O.
Departments of Oncology and Pathology [Y. X., K. H., A. B., B. B., O. L.] and Orthopedics [G. N.], Karolinska Hospital, SE-171 76 Stockholm, Sweden.
Cancer Res 2002 Jul 1;62(13):3861-7 Abstract quote The SYT-SSX fusion gene has been implicated in the malignant tumor cell growth of synovial sarcoma, but the underlying molecular mechanisms are still poorly understood.
Here we demonstrate that SYT-SSX is critical for the protein level of cyclin D1 in synovial sarcoma cells. Antisense oligonucleotides to SYT-SSX mRNA rapidly and drastically decreased cyclin D1 and subsequently inhibited cell growth. This effect is specific for SYT-SSX, without involving the wild-type genes SYT or SSX. The decrease in cyclin D1 expression, which occurred shortly after inhibition of SYT-SSX expression, was found to be primarily dependent on an increased degradation of the cyclin D1 protein, as assessed by pulse-chase experiments using [(35)S]methionine. Furthermore, transfection of mouse fibroblasts with SYT-SSX cDNA increased the stability of cyclin D1. Because treatment with a proteasome inhibitor restored cyclin D1 expression, it seems like SYT-SSX interferes with ubiquitin-dependent degradation of cyclin D1. However, SYT-SSX-regulated cyclin D1 expression was proven to be independent of the glycogen synthetase kinase-3beta pathway.
Taken together, our study provides evidence that SYT-SSX stabilizes cyclin D1 and is critical for cyclin D1 expression in synovial sarcoma cells. SYT-SSX-dependent expression of cyclin D1 may be an important mechanism in the development and progression of synovial sarcoma and also raises the possibility for targeted therapy.
EGFR MUTATIONS
- Mutations in the tyrosine kinase domain of the EGFR gene are rare in synovial sarcoma.
Bode B, Frigerio S, Behnke S, Senn B, Odermatt B, Zimmermann DR, Moch H.
1Institute of Surgical Pathology, University Hospital Zurich, Zurich, Switzerland.
Mod Pathol. 2006 Apr;19(4):541-7 Abstract quote.
The prognosis of patients with synovial sarcomas is poor. New therapeutic strategies, such as target inhibition of the tyrosine kinase activity of the epidermal growth factor receptor (EGFR) with erlotinib and gefinitib, could be effective, because most synovial sarcomas overexpress this protein. In lung cancer, the responsiveness to gefinitib is strongly related to the presence of mutations in the tyrosine kinase domain of the EGFR gene, while erlotinib sensitivity seems to be partly linked to chromosome 7 polysomy or gene amplification.
To clarify the role of EGFR in synovial sarcoma and to explore the potential for a targeted therapy approach, we have examined 13 of these soft tissue tumors. We have analyzed the EGFR expression by immunohistochemistry, searched for polysomy and gene amplification with fluorescence in situ hybridization (FISH) and screened for EGFR mutations in exons 18-21 using PCR and direct sequencing. All 13 tumors showed strong diffuse or focal EGFR expression. No amplifications of the EGFR gene were found. In contrast, several point mutations were identified in exons 18-21 of two synovial sarcomas. Whereas one of these tumors carried only a synonymous mutation, two missense mutations in exons 19 and 21 of the EGFR gene (P733S and A840 T, respectively) could be demonstrated in the second sample. In conclusion, strong EGFR expression in synovial sarcomas is not related to gene amplification.
The existence of mutations in the tyrosine kinase domain of the EGFR gene in a small subset of synovial sarcomas suggests that only few patients may profit from the tyrosine kinase inhibitor therapy.HER2/NEU
Molecular and immunohistochemical analysis of HER2/neu oncogene in synovial sarcoma.Nuciforo PG, Pellegrini C, Fasani R, Maggioni M, Coggi G, Parafioriti A, Bosari S.
Hum Pathol. 2003 Jul;34(7):639-45. Abstract quote Amplification and/or overexpression of HER2/neu have been documented in many types of epithelial tumor and recently has been reported in sarcomas, particularly in osteosarcomas. But the role of HER2/neu alterations in soft tissue tumors remains poorly understood. Thus the present study investigates the expression of HER2/neu in 13 patients with synovial sarcoma (SS). In this study, HER2/neu mRNA levels were measured in frozen tissue samples using a real-time reverse transcription-polymerase chain reaction assay; protein expression was assessed by immunohistochemistry using an anti-HER2/neu polyclonal antibody.
Six normal skeletal muscle specimens were used to establish basal levels of HER2/neu mRNA. HER2/neu transcripts were detected in all normal tissues and SSs. Four of 13 sarcomas (31%) demonstrated HER2/neu mRNA levels above the mean value, whereas 3 tumors (23%) displayed HER2/neu protein overexpression. Both membranous and cytoplasmic patterns of immunostaining were observed, and a strong correlation was found between protein expression and mRNA level (P = 0.01). Increased HER2/neu mRNA levels were significantly associated with a lower risk of developing recurrences (P = 0.02). Moreover, none of the patients with HER2/neu overexpression developed metastasis. Our data demonstrate that HER2/neu is expressed in SSs and that both membrane and cytoplasmic HER2/neu expression correlate with mRNA levels.
Our results show that the presence of increased levels of HER2/neu in SSs is associated with a more favorable clinical course. Further studies are needed to assess the role of this oncogene in SSs and to evaluate the application of inhibitory humanized monoclonal antibodies in the treatment regimens for this malignancy.
MAGE
MAGE antigen expression in monophasic and biphasic synovial sarcoma.Antonescu CR, Busam KJ, Iversen K, Kolb D, Coplan K, Spagnoli GC, Ladanyi M, Old LJ, Jungbluth AA.
Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY; the Ludwig Institute for Cancer Research, New York Branch at Memorial Sloan-Kettering Cancer Center, New York, NY; and the Departments of Surgery and Research, University of Basel, Basel, Switzerland.
Hum Pathol 2002 Feb;33(2):225-229 Abstract quote Synovial sarcomas are high-grade malignant mesenchymal tumors carrying a pathognomonic cytogenetic alteration t(X;18) involving the SYT gene on chromosome 18 and either SSX1 or SSX2 on chromosome X. Morphologically, biphasic (BSS) and monophasic (MSS) variants can be distinguished. Cancer/testis (CT) antigens are expressed in a variety of malignant tumors, but not in normal tissues except in germ cells, primarily of the testis. Anti-MAGE monoclonal antibody (mAb) 57B previously showed a high incidence and homogenous reactivity pattern in a preliminary analysis of synovial sarcomas.
This study was performed to analyze the expression of MAGE by immunohistochemistry with mAb 57B in 25 synovial sarcomas (12 monophasic, 13 biphasic), which were typed for the t(X;18)-derived fusion transcript by reverse transcriptase polymerase chain reaction (19 SYT-SSX1, 6 SYT-SSX2). 57B immunoreactivity was present in 22 of 25 (88%) cases, and antigen expression was homogeneous in 14 of 22 57B-positive cases. Both morphological variants and both translocation types were immunoreactive; three SYT-SSX1 tumors (one MSS, two BSS) were 57B negative.
Our study demonstrates that MAGE is frequently and homogeneously expressed in synovial sarcomas of both morphological variants and both translocation types, making these tumors an attractive target for MAGE antigen-based immunotherapy.
GROSS APPEARANCE/
CLINICAL VARIANTSCHARACTERIZATION HEART
- Primary synovial sarcoma of the heart: a cytogenetic and molecular genetic analysis combining RT-PCR and COBRA-FISH of a case with a complex karyotype.
Hazelbag HM, Szuhai K, Tanke HJ, Rosenberg C, Hogendoorn PC.
1Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
Mod Pathol. 2004 Nov;17(11):1434-9. Abstract quote
Synovial sarcomas usually occur in the soft tissues of the extremities of adolescents and middle-aged patients, in the vicinity of large joints.
We present a patient with a synovial sarcoma of the left atrium and ventricle, which is an extremely rare location. Diagnosis was confirmed by reverse transcriptase polymerase chain reaction (RT-PCR), showing the t(X;18) fusion transcript. With a multicolor COmbined Binary RAtio labeling Fluorescence In Situ Hybridization (COBRA-FISH) technique, a complex karyotype evolved with identification of derivative chromosomes with multiplex rearrangements.
This underscores the importance of molecular analyis of spindle cell tumors in unusual locations. Moreover, it shows that the presumed diagnostic translocation t(X;18) can be embedded in a sequence of other chromosomal rearrangements of which the function is as yet unknown.KIDNEY
Instituto Nacional de Nutrición y Ciencias Médicas Salvador Zubirán, Mexico City, Mexico.
- Synovial sarcoma is a tumor of the soft tissues with a unique chromosomal translocation t(X;18)(p 11.2;q11.2) that can be detected by polymerase chain reaction in tissue homogenates.
The case of a 32-year-old woman with a primary synovial sarcoma of the kidney is described, the diagnosis was corroborated by the recently developed method of in situ polymerase chain reaction (IS-PCR).
Synovial sarcoma of the kidney may be confused with other spindle cell tumors, for that reason IS-PCR may be useful to confirm the diagnosis in paraffin-embedded material.
Synovial Sarcoma of the Kidney With Rhabdoid Features: Report of Three Cases.
Jun SY, Choi J, Kang GH, Park SH, Ayala AG, Ro JY.
*Department of Pathology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea; Seoul National University College of Medicine, Seoul, Korea; Korea Cancer Center Hospital, Seoul, Korea; and University of Texas M. D. Anderson Cancer Center, Houston, TX.
Am J Surg Pathol. 2004 May;28(5):634-637. Abstract quote
We report 3 cases of synovial sarcoma with rhabdoid features, initially diagnosed as adult rhabdoid tumors. Two women (case nos. 1 and 2, 35 years and 27 years of age, respectively) and one man (case no. 3, 26 years of age) presented to their physicians with right flank pain.
On physical examination, a poorly defined, firm, palpable mass was found in the upper right quadrant of the abdomen in all cases. Sonography and computed tomography revealed solid, cystic masses in the right kidneys that ranged in size from 8.5 to 20.0 cm. Right radical nephrectomies were performed in all patients. One patient died of disease, and the other two patients were alive and disease-free after chemotherapy and radiotherapy.
Microscopic examination revealed that the tumors were composed mostly of rhabdoid cells with eccentrically located nuclei, prominent nucleoli, and eosinophilic cytoplasm. We also found areas of fasciculated spindle cells, sharply separated from or irregularly admixed with areas of rhabdoid cells. There was tumor necrosis, but no epithelial areas were seen. Hemangiopericytic vasculature was at least focally observed in all cases. The tumor cells were positive for CD99 and bcl-2 in all cases and for CD56 in two cases and negative for CD34 and smooth muscle actin in all cases. The cells in case no. 1 were focally positive for cytokeratin.
To verify the possibility of synovial sarcoma with rhabdoid features, reverse transcriptase polymerase chain reaction using RNA extracted from frozen tissue in case no. 1 and formalin-fixed, paraffin-embedded tissue in case nos. 2 and 3 was performed. SYT-SSX2 transcripts were detected in all 3 cases.
These cases indicate that synovial sarcoma of the kidney should be considered in the differential diagnosis of mesenchymal kidney tumors with prominent rhabdoid features. A subset of adult rhabdoid tumors may be a rhabdoid variant of synovial sarcoma, and molecular studies to detect SYT-SSX fusion transcripts are recommended for an accurate diagnosis.Primary Renal Synovial Sarcoma Molecular and Morphologic Delineation of an Entity Previously Included Among Embryonal Sarcomas of the Kidney
Pedram Argani, M.D.; Paulo A. Faria, M.D.; Jonathan I. Epstein, M.D.; Victor E. Reuter, M.D.; Elizabeth J. Perlman, M.D.; J. Bruce Beckwith, M.D.; Marc Ladanyi, M.D.
From The Johns Hopkins Hospital and National Wilms Tumor Study Group Pathology Center, Baltimore, Maryland, U.S.A. (P.A., J.I.E., E.J.P., J.B.B.); Instituto Nacional do Cancer, Rio de Janeiro, Brazil (P.A.F.); Loma Linda University, Loma Linda, California, U.S.A. (J.B.B.); and Memorial Sloan-Kettering Cancer Center, New York, NY, U.S.A. (V.E.R., M.L.).
Am J Surg Pathol 2000;24:1087-1096 Abstract quote
We report 15 primary renal neoplasms with morphologic, immunohistochemical, and molecular features identical to those of synovial sarcoma.
These tumors form a distinct subset of the entity previously designated as embryonal sarcoma of the kidney. Most were diagnosed between the ages of 20 and 50 years. On gross examination, tumors are large, partially necrotic, and usually contain smooth-walled cysts. Microscopically, tumors are characterized by mitotically active, monomorphic plump spindle cells with indistinct cell borders growing in short, intersecting fascicles. Grossly identified cysts are lined by mitotically inactive polygonal eosinophilic cells with apically oriented nuclei (``hobnailed epithelium''). The spindle cells are immunoreactive for vimentin, often immunoreactive for EMA, but typically non-immunoreactive for desmin, actin, S100, or cytokeratins, whereas the cyst epithelium is cytokeratin-positive. These findings are consistent with monophasic, spindled synovial sarcoma encircling dilated native renal collecting ducts. The presence of an SYT-SSX gene fusion resulting from the t(X;18) characteristic of synovial sarcoma was demonstrated by reverse transcriptase polymerase chain reaction in three of three tumors in which adequate RNA could be obtained from paraffin blocks. An additional case demonstrated the characteristic t(X;18) translocation on cytogenetic analysis, but adequate material to perform molecular studies was not available in this case or the remaining 11 cases.
Primary renal synovial sarcoma is a distinctive clinicopathologic entity confirmed by molecular detection of SYT-SSX fusion transcripts.
Primary Synovial Sarcoma of the Kidney
Duck-Hwan Kim, M.D.; Jin H. Sohn, M.D.; Min C. Lee, M.D.; Gilho Lee, M.D.; Ghil-Suk Yoon, M.D.; Hiroshi Hashimoto, M.D.; Hiroshi Sonobe, M.D.; Jae Y. Ro, M.D.
From the Department of Pathology (D.H.K., J.H.S.), Hallym University College of Medicine, Seoul, Korea; the Departments of Pathology (M.C.L.) and Urology (G.L.), Dankook University Hospital, Cheonan, Korea; the Department of Pathology (G.S.Y., J.Y.R.), Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea; the Department of Pathology and Oncology (H.H.), School of Medicine, University of Occupational and Environmental Health, Kitakushu, Japan; and the Department of Pathology (H.S.), Kochi Medical School, Japan.
Am J Surg Pathol 2000;24:1097-1104 Abstract quote
The authors present two cases of primary synovial sarcoma of the kidney.
Both patients had a mass in the upper part of the right kidney without any primary extrarenal neoplastic lesions. Grossly, the tumors were soft to rubbery masses measuring 5.5 cm and 5 cm in diameter, respectively. Histologically, both tumors were poorly differentiated synovial sarcoma. The lesions exhibited a hypercellular solid or lobular growth of round, oval, or short spindle cells in variably solid sheets, in intersecting fascicles, or in a haphazard fashion. Areas of solid aggregation or fascicles of the tumor cells alternating with hypocellular myxoid tissues, together with areas displaying a prominent hemangiopericytoma-like pattern, were found. Immunohistochemically, vimentin was diffusely positive and a few tumor cells were positive for cytokeratin, epithelial membrane antigen, and neurofilament. The tumor cells were negative for S-100 protein, CD34, smooth muscle actin, and desmin, whereas CD56 and CD99 were positive.
In both cases, reverse transcription–polymerase chain reaction using ribonucleic acid extracted from formalin-fixed, paraffin-embedded tissues detected SYT-SSX2 fusion gene transcripts, which are characteristic molecular findings of synovial sarcoma. One patient died 10 months after diagnosis.
These tumors are unique cases of primary synovial sarcoma of the kidney confirmed by molecular study.
LARYNX Synovial sarcoma of the larynx and hypopharynx.
Dei Tos AP, Dal Cin P, Sciot R, Furlanetto A, Da Mosto MC, Giannini C, Rinaldo A, Ferlito A.
Department of Pathology, Regional Hospital, Treviso, Italy.
Ann Otol Rhinol Laryngol 1998 Dec;107(12):1080-5 Abstract quote
Synovial sarcoma represents a mesenchymal malignancy of unknown histogenesis that most often occurs in the lower limbs of young adults. The head and neck region is a relatively rare location, in which the hypopharynx and larynx are, respectively, the most and least often affected anatomic sites.
Histologically, synovial sarcomas are classified into monophasic and biphasic variants. Immunohistochemistry plays a major part in the differential diagnosis, enabling the demonstration of epithelial differentiation. Both monophasic and biphasic synovial sarcomas are characterized cytogenetically by the reciprocal translocation t(X;18)(p11.2;q11.2) between chromosomes X and 18.
Two cases of synovial sarcoma arising in the larynx and in the hypopharynx and in which cytogenetic analysis detected a diagnostic t(X;18) chromosome aberration are reported here.
Synovial sarcoma of the larynx in a child: case report and histological appearances.
Morland B, Cox G, Randall C, Ramsay A, Radford M.
Department of Paediatric Oncology, Birmingham Children's Hospital, United Kingdom.
Med Pediatr Oncol 1994;23(1):64-8 Abstract quote
Synovial sarcoma of the larynx is extremely rare having been reported only six times previously in the literature. We add another case report, which to our knowledge is the first recorded case in a child.
We discuss the alternative approach of combination chemotherapy and radiotherapy which in this case led to a remission lasting about 3 years. The immunohistological and ultrastructural characteristics of the tumour are also presented.
Synovial sarcoma of the larynx.
Miller LH, Santaella-Latimer L, Miller T.
Trans Am Acad Ophthalmol Otolaryngol 1975 Sep-Oct;80(5):448-51 Abstract quote
There have been several reports in the literature2-5 of synovial sarcomas of the head and neck. The consensus of these authors is that the tumor is not as aggressive in this localization as in the extremities, where the recurrence rate is 60% to 70%, and the five-year long-term follow-up of such cases should be made available.
Thereby, a reasonably clear and effective modality of treatment could be recommoneded.
MEDIASTINUM
- Primary Synovial Sarcomas of the Mediastinum: A Clinicopathologic, Immunohistochemical, and Ultrastructural Study of 15 Cases.
Suster S, Moran CA.
From the *Department of Pathology, Division of Anatomic Pathology, Ohio State University, Columbus, OH; and the daggerDepartment of Pathology, M.D. Anderson Cancer Center, Houston, TX.
Am J Surg Pathol. 2005 May;29(5):569-578. Abstract quote
A series of 15 cases of primary mediastinal neoplasms displaying histopathologic, immunohistochemical, and ultrastructural features of synovial sarcoma is presented.
The patients' ages ranged from 3 to 83 years, with a male-to-female ratio of 2:1. Nine cases presented as anterior mediastinal masses with chest pain, shortness of breath, and pleural effusion, and 6 cases were in paravertebral location in the posterior mediastinum and presented with neck or back pain and pleural effusion. The tumors measured from 5 to 20 cm in greatest diameter and showed a tan white, soft to rubbery cut surface with areas of hemorrhage and necrosis and foci of gelatinous material. Four cases showed areas of cystic degeneration. In 7 cases, the tumors were well circumscribed; in 6 cases, the tumors grossly invaded the pleura, pericardium, heart, great vessels, chest wall, rib, and vertebra.
Histologically, 5 cases displayed a biphasic growth pattern, with well-formed glandular elements admixed with a monotonous spindle cell population. Ten cases were exclusively composed of a monotonous atypical spindle cell proliferation. Immunohistochemical studies showed focal positivity of the tumor cells for cytokeratin and/or epithelial membrane antigen, and strong positivity for vimentin and bcl-2 in the spindle cells in all cases studied (10 of 10). Eight cases also showed focal positivity for CD99. Electron microscopic examination in 5 cases showed oval to spindle tumor cells with closely apposed cell membranes, abundant cytoplasmic intermediate filaments and rough endoplasmic reticulum, and immature desmosome-type cell junctions. Ten patients were treated by complete surgical excision and two by partial excision followed by radiation therapy. In 4 patients, the tumors were inoperable and treated with radiation therapy only.
Clinical follow-up was available in 5 patients and showed local recurrence with metastases to lung, lymph nodes, and epidural space from 1 to 3 years in 4 cases and liver metastases and death due to tumor after 6 month in 1 case. Synovial sarcoma should be considered in the differential diagnosis of biphasic and monophasic spindle cell neoplasms of the mediastinum.PLEURA Primary Monophasic Synovial Sarcoma of the Pleura Five Cases Confirmed by the Presence of SYT-SSX Fusion Transcript Marie-
Christine Aubry, etal.
Am J Surg Pathol 2001;25:776-781 Abstract quote
This study reports five cases of primary pleural monophasic synovial sarcomas and assesses the role of the SYT-SSX fusion transcript in the differential diagnosis. Patients had a mean age of 47 years with no gender predilection. Chest pain and pleural-based masses with effusions characterized the clinical presentations. Each patient underwent a complete surgical resection of the mass. The mean follow-up was 9 months, available in four patients. They were all alive, with no evidence of disease.
Histologically, neoplasms were composed of densely packed fusiform cells focally alternating with less cellular areas. No epithelial differentiation was identified at the hematoxylin and eosin level. Keratin and epithelial membrane antigen reactivity was focal and present in four and two tumors, respectively. There was no immunoreactivity for CD34. RT-PCR studies for the presence of a SYT-SSX1 or SYT-SSX2 fusion transcript were positive in every tumor. In comparison, 10 localized fibrous tumors were immunohistochemically negative for keratin and epithelial membrane antigen and positive for CD34. A SYT-SSX fusion transcript was not identified in any of five localized fibrous tumors tested.
Identification of the synovial sarcoma-specific chimeric transcript (SYT-SSX1 or SYT-SSX2), in conjunction with immunoperoxidase studies, can be extremely helpful in identifying cases of pleural monophasic synovial sarcoma.
SALIVARY GLAND Primary synovial sarcoma of the parotid gland.
Barkan GA, El-Naggar AK.
Ann Diagn Pathol. 2004 Aug;8(4):233-6. Abstract quote
Synovial sarcoma typically develops in the deep soft tissues of the extremities in adolescents and young adults. Uncommonly, these tumors may arise (9%) in the head and neck region (9%), especially at the cervical and parapharyngeal sites.
Primary synovial sarcoma of the parotid gland is a rare occurrence that may not uncommonly cause differential diagnostic difficulties. In these cases, an origin from within the gland rather than a secondary involvement by tumor from a surrounding structure must be confirmed.
We report a new case of biphasic synovial sarcoma arising in the parotid gland and review the previously documented cases.SKIN Primary cutaneous synovial sarcoma: a case report.
Flieder DB, Moran CA.
Department of Pulmonary and Mediastinal Pathology, Armed Forces Institute of Pathology, Washington, DC 20306-6000, USA.
Am J Dermatopathol 1998 Oct;20(5):509-12 Abstract quote
We present a case of synovial sarcoma involving the cutaneous tissue of the knee in an 18-year-old woman.
The 2.5 cm tumor was locally excised and recurred six times over the following 24 years. The neoplasm involved the deep dermis with extension into the papillary dermis and superficial subcutis. The tumor was predominantly composed of spindle cells arranged in compact interdigitating fascicles and scattered epithelial nests were seen. Focal myxoid and hemangiopericytoma-like areas as well as numerous mast cells were identified. Spindle cells stained for vimentin, CAM 5.2, and epithelial membrane antigen, whereas epithelial nests only stained for CAM 5.2 and epithelial membrane antigen. Neither component was reactive for antibodies directed against desmin, muscle specific actin, smooth muscle actin, S-100 protein, CD-31, or CD-34.
This newly reported location for this morphologically heterogeneous tumor creates potential diagnostic confusion with other primary neoplasms in these areas
THORACIC
- Primary Intrathoracic Synovial Sarcoma: A Clinicopathologic Study of 40 t(X;18)-Positive Cases From the French Sarcoma Group and the Mesopath Group.
Begueret H, Galateau-Salle F, Guillou L, Chetaille B, Brambilla E, Vignaud JM, Terrier P, Groussard O, Coindre JM.
From the Departments of Pathology, *Hopital Haut-Leveque, Pessac, daggerCentre Hospitalo-Universitaire, Caen, double daggerHopital de la Timone, Marseille, section signHopital Albert Michallon, Grenoble, parallelHopital Central, Nancy, paragraph signInstitut Gustave Roussy, Villejuif, **Hopital Beaujon, Clichy, daggerdaggerInstitut Bergonie, Bordeaux, France; and double daggerdouble daggerInstitut Universitaire de Pathologie, Lausanne, Switzerland.
Am J Surg Pathol. 2005 Mar;29(3):339-346. Abstract quote
Synovial sarcoma (SS), an aggressive neoplasm accounting for up to 14% of soft tissue sarcomas, was recently recognized as a primary tumor in the lung and pleura. SS is characterized by the chromosomal translocation t(X;18)(SYT-SSX) found in more than 95% of the tumors.
We report a cooperative study from the French Sarcoma Group and the Mesopath Group on 40 t(X;18)(SYT-SSX)-positive primary intrathoracic SS. There were 22 males and 18 females, whose age ranged from 16 to 79 years (median, 47 years). Neoplasms were mostly circumscribed and of large size (median, 7.5 cm; range, 2-16 cm). Thirty-nine tumors were monophasic SS, including 24 (60%) monophasic fibrous and 15 (37.5%) poorly differentiated cases, and one lesion was a biphasic SS. A larger proportion of poorly differentiated tumors were observed among intrathoracic SS as compared with soft tissue SS. Immunohistochemically, 90% of the cases reacted with at least one epithelial marker. CD34 was focally expressed in 3 cases. SYT-SSX1 fusion transcripts were detected in 22 cases (56.4%) and SYT-SSX2 fusion transcripts in 17 cases. Median and 5-year disease-specific survival in 33 patients was 50 months and 31.6%. Median and 5-year disease-free survival was 24 months and 20.9%. Patient sex, age, tumor size, histologic subtype, grade, and SYS-SSX fusion type had no significant impact on outcome.
In conclusion, intrathoracic SS are rare but aggressive tumors with poor prognosis. In this unusual location, the detection of SYT-SSX fusion transcripts is a valuable diagnostic adjunct.
SPECIAL STAINS/
IMMUNOPEROXIDASECHARACTERIZATION Special stains Immunoperoxidase GENERAL
Monophasic Fibrous and Poorly Differentiated Synovial Sarcoma: Immunohistochemical Reassessment of 60 t(X;18)(SYT-SSX)-Positive Cases
Manuela Pelmus, M.D.; Louis Guillou, M.D.; Isabelle Hostein, Ph.D.; Ghislaine Sierankowski; Catherine Lussan; Jean-Michel Coindre, M.D.Am J Surg Pathol 2002; 26(11):1434-1440 Abstract quote
Diagnosing monophasic fibrous and poorly differentiated synovial sarcoma (SS) on morphology alone is often a source of problems for pathologists. SS bear the t(X;18)(p11.2,q11.2) translocation, which proved to be specific for this tumor type and is currently considered one of the most reliable diagnostic criteria.To evaluate the sensitivity of immunohistochemical techniques in diagnosing monophasic fibrous SS (MFSS) and poorly differentiated SS (PDSS), we examined 60 t(X;18)(SYT-SSX)-positive cases (47 MFSS and 13 PDSS) for cytokeratin AE1/AE3, cytokeratin KL1, epithelial membrane antigen, E-cadherin, CD34, S-100 protein, a-smooth muscle actin, desmin, h-caldesmon, CD99, bcl2, and C-kit (CD117) antibodies.
Of the four epithelial markers tested, epithelial membrane antigen proved to be the most sensitive, reacting with 100% of MFSS and 92% of PDSS, followed by cytokeratin AE1/AE3 (70% of MFSS, 46% of PDSS), cytokeratin KL1 (49% of MFSS, 38% of PDSS), and E-cadherin (47% of MFSS, 54% of PDSS). A staining for cytokeratin AE1/AE3 and/or E-cadherin was observed in 79% of MFSS and 69% of PDSS, and a staining for cytokeratin KL1 and/or E-cadherin was observed in 74% of MFSS and 62% of PDSS. S-100 protein was positive in 38% of MFSS and 23% of PDSS, and a-smooth muscle actin in 21% of MFSS and 8% of PDSS. Tumor cells were rarely positive for CD34 (6% of MFSS, 0% of PDSS) and desmin (2% of MFSS, 0% of PDSS). Most SS were strongly positive for bcl-2 (91% of MFSS, 92% of PDSS) and CD99 (91% of MFSS, 100% of PDSS). A weak and focal cytoplasmic reactivity for CD117 was observed in 11% of MFSS (only one case had a strong immunoreactivity) and 8% of PDSS. Staining with h-caldesmon was consistently negative.
In conclusion, in keeping with literature data, our results show that reactivity for epithelial membrane antigen, cytokeratin AE1/AE3, and E-cadherin, in combination with CD34 negativity, are the most useful and sensitive markers for diagnosing monophasic fibrous and poorly differentiated t(X;18)-positive SS. They also support the fact that about one third of MFSS and one fourth of PDSS are positive for S-100 protein, a finding of diagnostic relevance when considering their distinction from other spindle to round cell sarcomas, especially malignant peripheral nerve sheath tumors.
CALRETININ Calretinin and Other Mesothelioma Markers in Synovial Sarcoma Analysis of Antigenic Similarities and Differences With Malignant Mesothelioma
Markku Miettinen, etal.
Am J Surg Pathol 2001;25:610-617 Abstract quote
Synovial sarcoma (SS) is a mesenchymal neoplasm that typically shows epithelial differentiation. SS commonly metastasizes to lung and pleura, and has also been reported as the primary in these locations. The histologic distinction of SS from mesothelioma may be difficult because of the combination of epithelioid and spindle cells, potentially shared locations, and antigenic expression.
In this study the authors examined 103 well-documented SSs including 41 biphasic, 44 monophasic, and 18 poorly differentiated SSs in comparison with 23 epithelioid and seven sarcomatous mesotheliomas. Most biphasic SSs (29 of 41, 71%) had fields or foci of calretinin-positive tumor cells. The spindle cell components were more often positive (55%), whereas 14% of tumors had positive epithelial cells.
The monophasic and poorly differentiated SSs commonly had foci of calretinin-positive cells (in 52% and 56% of cases respectively). In comparison, all 23 epithelioid mesotheliomas (EM) were extensively calretinin positive and seven sarcomatoid mesotheliomas were variably calretinin positive. HBME-1 positivity was similarly detected in biphasic SS and EM (100% and 87% respectively). Among the other sarcomas, two of 15 malignant peripheral nerve sheath tumors were focally calretinin positive, whereas 16 epithelioid sarcomas, 20 leiomyosarcomas, 20 gastrointestinal stromal tumors, and 20 angiosarcomas were negative. Biphasic SSs differed from mesotheliomas by their more common BerEp4 positivity (90%) whereas EMs showed focal reactivity in 13% cases. Marked CD15 reactivity was rare in both. Wilms tumor protein-1 (WT1) was not detected in SS, but was present in 12 of 17 EMs. CD141 was rare in SS, limited to spindle cell components, whereas EMs typically showed prominent membrane staining in epithelial cells. Simple epithelial keratins were present in all epithelial cells of biphasic SS and mesothelioma (keratin 7[K7], K19), but were only focal in monophasic and poorly differentiated SS. Biphasic SSs were extensively K14 positive (89% of cases), whereas epithelial and sarcomatoid mesotheliomas typically showed only scattered positive cells.
The potentially shared calretinin patterns in SS and mesothelioma require the use of other markers. The discriminating features include extensive BerEp4 positivity, rarity of CD141, and lack of WT1 in SS. Global expression of K7 and K19 in mesotheliomas versus focal expression in monophasic and poorly differentiated SSs, and differential patterns of K14 expression may also be helpful.
DYSADHERIN
- Izumi T,
- Oda Y,
- Hasegawa T,
- Nakanishi Y,
- Kawai A,
- Sonobe H,
- Takahira T,
- Kobayashi C,
- Yamamoto H,
- Tamiya S,
- Hirohashi S,
- Iwamoto Y,
- Tsuneyoshi M.
*Department of Anatomic Pathology, Pathological Sciences paragraph signDepartment of Orthopaedic Surgery, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan daggerDepartment of Clinical Pathology, Sapporo Medical University School of Medicine, Sapporo double daggerPathology Division, National Cancer Center Research Institute, Tokyo section signDepartment of Orthopaedic Surgery, National Cancer Center Hospital, Tokyo parallelDepartment of Pathology, Fukuyama Medical Center, Hiroshima.
Dysadherin is a cancer-associated cell membrane glycoprotein, which down-regulates E-cadherin and promotes metastasis. Synovial sarcoma is a very rare mesenchymal tumor that exhibits an epithelial profile.
To confirm the diagnosis of synovial sarcoma, we evaluated several immunohistochemical markers, or detected SYT-SSX fusion gene transcript.
We studied the clinicopathologic features in 92 synovial sarcoma patients and also assessed the immunohistochemical expression of dysadherin and E-cadherin to examine their possible association with histologic subtype and biologic behavior. Moreover, among 30 patients, for whom frozen materials were available, dysadherin mRNA expression was examined by reverse transcription-polymerase chain reaction and real-time quantitative reverse transcription-polymerase chain reaction analysis. Dysadherin-positive expression was significantly correlated with E-cadherin-reduced expression (P=0.0004). Dysadherin-positive immunostaining was diffusely observed in the membranes of tumor cells in 30/68 (44%) patients with monophasic fibrous type and in 1/2 (50%) patients with poorly differentiated type. However, in biphasic tumors, dysadherin expression in the fibrous component was not diffusely observed, but often sporadically or focally observed [20/22 (91%) patients]. In addition, dysadherin mRNA expression in monophasic fibrous type was significantly higher than in biphasic type (P=0.0079).
Synovial sarcoma patients with dysadherin expression survived for a significantly shorter time than those without dysadherin expression (P=0.0006). Patients with combined dysadherin-positive expression and E-cadherin-reduced expression had a significantly worse prognosis than those with other combinations of dysadherin and E-cadherin expression (P=0.0007). SYT-SSX fusion gene transcript was detected in 39 patients.
In our series, SYT-SSX fusion type was found to have no correlation with histologic subtype, prognosis, or dysadherin expression. In multivariate analysis, dysadherin immunopositivity (P=0.0411) was an independent adverse prognostic factor, in addition to a high MIB-1 labeling index (>/=10%). We conclude that E-cadherin dysfunction by dysadherin is associated with reduced E-cadherin expression and morphologic change from epithelioid to spindle phenotype.
Dysadherin expression is considered to be one of the determinants of histologic subtype in synovial sarcoma. Moreover, dysadherin expression is an excellent and independent prognostic indicator.MATRIX METALLO-PROTEINASE-2
Matrix metalloproteinase-2 expression correlates with morphological and immunohistochemical epithelial characteristics in synovial sarcoma.Saito T, Oda Y, Sakamoto A, Tamiya S, Iwamoto Y, Tsuneyoshi M.
Department of Anatomic Pathology, Kyushu University, Graduate School of Medical Sciences, Fukuoka, Japan, Department of Orthopaedic Surgery, Kyushu University, Graduate School of Medical Sciences, Fukuoka, Japan.
Histopathology 2002 Mar;40(3):279-85 Abstract quote Matrix metalloproteinase-2 expression correlates with morphological and immunohistochemical epithelial characteristics in synovial sarcoma
Aims: Synovial sarcoma is a unique mesenchymal tumour characterized by the presence of epithelial differentiation, although the mechanism involved in the epithelial morphology is still unclear. The aim of this study was to evaluate the function of matrix metalloproteinase-2 (MMP-2) in synovial sarcoma, in order to assess whether MMP-2 expression plays an important role in epithelial differentiation, or whether it contributes to a poor clinical outcome.
Methods and results: Immunohistochemical stainings for MMP-2, cytokeratins (CKs) 7, 8, 18 and 19, and E-cadherin were performed for 58 (44 monophasic and 14 biphasic) cases of synovial sarcoma, and we compared the expression of these proteins with the histological and clinical findings. MMP-2 and E-cadherin expression was observed in 43 cases (74.1%) and in 18 cases (31.0%), respectively. Expression of these proteins was preferentially observed in the glandular components of biphasic tumours or the epithelioid areas of monophasic tumours. Statistically significant correlations were recognized between MMP-2 expression and E-cadherin expression of biphasic subtype. Moreover, there were statistically significant correlations between monophasic tumours with epithelioid areas and MMP-2 expression or E-cadherin expression. MMP-2 expression was correlated with epithelial differentiation as assessed by CK immunoreactivity. The expression of MMP-2 did not affect the overall survival rate in synovial sarcoma.
Conclusions: MMP-2 expression seemed to have an important role to play in the epithelial differentiation of tumour cells in synovial sarcoma, through remodelling of the extracellular matrix and by changing the cytoskeletal interaction between the extracellular matrix and tumour cells.
TLE1
- Terry J,
- Saito T,
- Subramanian S,
- Ruttan C,
- Antonescu CR,
- Goldblum JR,
- Downs-Kelly E,
- Corless CL,
- Rubin BP,
- van de Rijn M,
- Ladanyi M,
- Nielsen TO.
*Genetic Pathology Evaluation Centre, British Columbia Cancer Agency, 600 West 10th Avenue, Vancouver, British Columbia, Canada V5Z 4E6 daggerDepartment of Pathology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021 double daggerDepartment of Pathology, Stanford University Medical Center, 300 Pasteur Drive, Stanford, CA 94305 section signDepartment of Anatomic Pathology, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195 parallelDepartment of Pathology and OHSU Cancer Institute, Oregon Health and Science University, Portland, OR 97239-3098 paragraph signDepartment of Anatomical Pathology, University of Washington Medical Center, Seattle, WA 98195
Synovial sarcoma is a soft tissue malignancy defined by the SYT-SSX fusion oncogene. Demonstration of the t(X;18) by cytogenetics, fluorescence in situ hybridization or reverse-transcriptase polymerase chain reaction has become the gold standard for diagnosis, but practical considerations limit the availability of these methods.
Gene expression profiling studies performed by several independent groups have consistently identified TLE1 as an excellent discriminator of synovial sarcoma from other sarcomas, including histologically similar tumors such as malignant peripheral nerve sheath tumor. TLE proteins (human homologues of Groucho) are transcriptional corepressors that inhibit Wnt signaling and other cell fate determination signals, and so have an established role in repressing differentiation.
We examined the expression of TLE proteins in synovial sarcoma and in a broad range of mesenchymal tumors using tissue microarrays to assess the value of anti-TLE antibodies in the immunohistochemical confirmation of synovial sarcoma.
We demonstrate that TLE expression is a consistent feature of synovial sarcoma using both a well-characterized monoclonal antibody recognizing the TLE family of proteins and a commercially available polyclonal antibody raised against TLE1. Both antibodies gave intense and/or diffuse nuclear staining in 91/94 molecularly confirmed synovial sarcomas. Moderate staining is occasionally seen in schwannoma and solitary fibrous tumor/hemangiopericytoma. In contrast, TLE staining is detected much less frequently and at lower levels, if at all, in 40 other mesenchymal tumors.
Our findings establish TLE as a robust immunohistochemical marker for synovial sarcoma, and may have implications for understanding the biology of synovial sarcoma and for developing experimental therapies for this cancer.ELECTRON MICROSCOPY
Aberrant expression of tight junction-related proteins ZO-1, claudin-1 and occludin in synovial sarcoma: an immunohistochemical study with ultrastructural correlation.
Billings SD, Walsh SV, Fisher C, Nusrat A, Weiss SW, Folpe AL.
Department of Pathology, Indiana University, Indianapolis, IN, USA.
Mod Pathol. 2004 Feb;17(2):141-9. Abstract quote
Synovial sarcoma demonstrates epithelial differentiation, either by light microscopy (biphasic synovial sarcoma) or by immunohistochemical/ultrastructural methods only (monophasic) and poorly differentiated synovial sarcoma.
Although the glands of synovial sarcoma are known to have tight junction-like structures, far less is known about junction formation in the spindled component of synovial sarcomas. Additionally, it is unknown whether the tight junctions of synovial sarcoma are normally constituted. The tight junction is a multiprotein complex consisting of numerous proteins that include ZO-1, claudin-1 and occludin. A total of 35 cases of synovial sarcoma (13 biphasic, 14 monophasic and eight poorly differentiated) were immunostained for ZO-1, claudin-1 and occludin using commercially available antibodies, heat-induced epitope retrieval and standard avidin-biotin technique.
When available, corresponding electron micrographs were reviewed. For five cases, the presence of either an SYT-SSX1 (three cases) or SYT-SSX2 (two cases) gene fusion was known. Positive cases showed particulate membrane staining. The glands of biphasic synovial sarcomas expressed ZO-1 (13/13), claudin-1 (12/13) and occludin (11/13) in a manner identical to normal glandular epithelia, at the apical portion of the lateral membrane. The spindle cells of biphasic synovial sarcomas showed abnormal circumferential membranous expression of ZO-1 (12/13), claudin-1 (6/13) and occludin (3/13). Monophasic synovial sarcomas expressed ZO-1 in a circumferential pattern (13/14) but less often claudin-1 (4/14) or occludin (3/14). Poorly differentiated synovial sarcomas expressed ZO-1 (8/8) and claudin-1 (6/8) but only rarely occludin (2/8). By electron microscopy, recognizable tight junctions were seen only in glands. No correlation was seen between histologic subtype or fusion type and expression of tight junction proteins.
We conclude that the glands of biphasic synovial sarcomas show well-organized, true epithelial tight junctions. In contrast, the spindled cells of all synovial sarcomas show significant abnormalities in the expression and localization of tight junction proteins, suggesting partial and/or aberrant epithelial differentiation.
Macpherson and Pincus. Clinical Diagnosis and Management by Laboratory Methods. Twentyfirst Edition. WB Saunders. 2006.
Rosai J. Ackerman's Surgical Pathology. Ninth Edition. Mosby 2004.
Sternberg S. Diagnostic Surgical Pathology. Fourth Edition. Lipincott Williams and Wilkins 2004.
Robbins Pathologic Basis of Disease. Seventh Edition. WB Saunders 2005.
DeMay RM. The Art and Science of Cytopathology. Volume 1 and 2. ASCP Press. 1996.
Weedon D. Weedon's Skin Pathology Second Edition. Churchill Livingstone. 2002
Fitzpatrick's Dermatology in General Medicine. 6th Edition. McGraw-Hill. 2003.
Weiss SW and Goldblum JR. Enzinger and Weiss's Soft Tissue Tumors. Fifth Edition. Mosby Elesevier 2008
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