A t(X; 18) SYT-SSX2 positive synovial sarcoma in the pelvis of a young adult male: a rare case report with review of literature

Synovial sarcoma is uncommonly documented in the pelvis. Rarely, such cases have dealt with molecular analysis. A 19-year-old boy presented with pain and swelling in his left lower limb of two months duration. He developed acute urinary retention four days prior to his hospital admission, wherein radiological examination unraveled a large soft tissue mass, displacing his pelvic muscles, along with a lytic lesion involving his right pubic bone. Biopsy showed a cellular spindle cell sarcoma, exhibiting hemangiopericytoma-like vascular pattern with focal necrosis. Immunohistochemistry (IHC) showed positivity for vimentin, BCL-2, calponin and MIC 2. Cytokeratin (CK) and epithelial membrane antigen (EMA) were negative. MIB 1 count was 70% (high). P53 was positive. Diagnosis of a poorly differentiated synovial sarcoma was offered and confirmed with a positive t(X; 18) SYT-SSX2 translocation. This case highlights the value of molecular analysis in diagnosis of a synovial sarcoma at rare sites, especially when IHC results are equivocal and the biopsy material is limited.     

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

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.     

Combination of t(14;18) and a Burkitt's Type Translocation in B-cell Malignancies

The combination of chromosomal translocations associated with bcl-2 rearrangement [t(14;18)] and c-myc rearrangement [t(8;14), t(8;22), or t(2;8)] has infrequently been detected in lym-phoproliferative disorders. We have recently identified four cases of a B-cell malignancy exhibiting this dual translocation. In addition to t(14;18), one case had t(8;14) and three had the t(8;22). One case presented as de novo acute lymphoblastic leukemia (ALL-L2), two as de novo high grade lymphomas and the fourth evolved to a “blastic” phase from a previously documented follicular lymphoma. Immunophenotyping and molecular analysis was performed on three of the cases: all were negative for terminal deoxynucleotidyl transferase (TdT) but were CD 10 positive. Two of the three cases with t(8;22) were negative for surface immu-noglobulin (SIg) and positive for HLA-DR. Rearrangement of the oncogene bcl-2 was identified in a single case by polymerase chain reaction (PCR) only. Similar to cases reported in the literature, all patients had a poor clinical outcome despite aggressive therapy. Dual trans-location lymphoid malignancy has a relatively characteristic morphology and the diagnosis should be considered when there is a history of an antecedent low grade lymphoma or when there is discordance between the “blastic” morphology and the immunophenotype (TdT -and/or SIg +). Confirmation requires demonstration of the characteristic translocations. Recognition of this entity has significant clinical implications that may require consideration of alternate treatment strategies.     

Nonrandom secondary chromosome-aberrations in synovial sarcomas with t(x-18)

Thirty samples from 19 patients with synovial sarcoma were analyzed cytogenetically after short-term culturing. Thirteen samples were from primary tumors, 11 from local recurrences, and six from distant metastases. All samples showed the characteristic aberration t(X;18)(p11;q11) or variants thereof; 23 samples had additional numerical and/or structural changes. Including the present cases, chromosome aberrations have been reported in 74 synovial sarcomas, 50 of which have had secondary aberrations in addition to t(X;18). No secondary structural aberration was recurrent. The most common numerical changes were +7, +8, +12 (10 cases each), -3, +9, +21 (7 cases each), +2, -14, -17 (6 cases each), +4, -11, +15, and -22 (5 cases each). Unbalanced stuctural aberrations led to loss of 3p and 17p in six cases, each with loss of bands 3p21 and 17p13, respectively, in common. Most monosomies and trisomies seemed to occur at similar frequencies in primary, recurrent, and metastatic tumors. The only exceptions were +2, which was never seen in a primary tumor, and +8, which was never found in any metastatic lesion.     

Translocation t(14;18)/IGH‐BCL2 in gastrointestinal follicular lymphoma

BACKGROUND:

Chromosomal translocation t(14;18)(q32;q21) involving the immunoglobulin heavy chain gene (IGH) and the BCL2 gene (t[14;18][q32;q21]/IGH‐BCL2) is present in 60% to 90% of nodal follicular lymphomas. To the authors' knowledge, the prevalence and clinical significance of this translocation have not been examined previously in gastrointestinal follicular lymphomas.

METHODS:

Clinicopathologic and molecular features were investigated in 48 patients who had gastrointestinal follicular lymphoma. The site of involvement was the duodenum in 54% of patients, the jejunum in 52%, the ileum in 52%, the stomach in 29%, and the colorectum in 15%. The presence of the t(14;18)/IGH‐BCL2 translocation was detected by interphase fluorescence in situ hybridization.

RESULTS:

Treatment modalities included surgical resection (n = 16), rituximab plus chemotherapy (n = 13), rituximab alone (n = 6), antibiotics (n = 5), and watchful waiting (n = 8). Complete remission (CR) of lymphoma was achieved in 31 patients (65%). The overall survival and event‐free survival rates after 5 years were 93% and 68%, respectively. The t(14;18)/IGH‐BCL2 was detected in 39 patients (81%). The involvement of multiple sites (69% vs 0%), manifestation of the lymphomatous polyposis type (72% vs 22%), and histologic grade 1 or 2 tumors (92% vs 56%) were more frequent in the t(14;18)‐positive group than in the negative group. In addition, the CR rate was lower in the t(14;18)‐positive group than in the negative group (56% vs 100%; P = .0179), and a trend was observed toward poorer event‐free survival in the positive group (P = .089).

CONCLUSIONS:

The t(14;18)/IGH‐BCL2 chromosomal translocation occurred frequently in gastrointestinal follicular lymphomas. The current results indicated that this translocation may be a predictor of an adverse clinical course. Cancer 2011. © 2010 American Cancer Society.     

弥漫大B细胞性淋巴瘤中t(14;18)易位及BCL2表达的意义

  目的  探讨弥漫大B细胞性淋巴瘤(DLBCL)中t(14;18)易位及BCL2表达的意义。  方法  用石蜡包埋组织免疫组织化学法检测142例淋巴结、胃肠道和咽淋巴环等不同器官或部位发生的DLBCL中CD10、BCL6、MUM1和BCL2的抗原表达, 按免疫表型将DLBCL分成GCB-DLBCL和非GCB-DLBCL两个亚型; 聚合酶链反应(PCR)扩增75例淋巴结结内DLBCL新鲜组织中由t(14;18)易位所形成的MBR/JH和lnfr/JH重组基因。  结果  142例DLBCL中, 75例(52.8%)表达BCL2。分型为GCB-DLBCL的51例中, 18例(35.3%)表达BCL2;分型为非GCB-DLBCL的91例中, 57例(62.6%)表达BCL2, 两者阳性率比较有显著性差异(P=0.002)。同时, BCL2的表达阳性率按不同器官或部位发生的DLBCL作比较, 结果也存在显著性差异(P=0.01)。18.7%的淋巴结结内DLBCL中有t(14;18)易位, 阳性病例主要见于GCB-DLBCL之中。  结论  t(14;18)易位是GCB—DLBCL亚型的遗传学特征, BCL2表达在不同亚型和不同器官或部位发生的DLBCL中有显著性差异。      

t(2; 18) and t(18;22) Variant Chromosomal Translocations in B Cell Malignancies

Variant translocations (2;18 and 18;22) are described in this review. The chromosomal and molecular findings of these translocations of BCL2 and their effect on possible BCL2 gene activation is discussed. Unanswered questions still remain and these include why this is so rare compared to the 25% incidence recorded for translocations in Burkitt's lymphoma. Further studies are obviously still needed in order to determine the true frequency of these findings and their distribution in the various B-cell disorders.     

TLE1 is a robust diagnostic biomarker for synovial sarcomas and correlates with t(X;18): Analysis of 319 cases

IntroductionGenomewide expression profiling has identified a number of genes expressed at higher levels in synovial sarcoma than in other sarcomas. Our objectives in this study were (1) to test whether the differentially expressed gene, Transducin-Like Enhancer of split (TLE1) belonging to the groucho/TLE family, is also distinct on the protein level; (2) to evaluate this biomarker in a series of well-characterised synovial sarcomas on standard, full-sized tissue sections and (3) to correlate the expression of TLE1 with t(X;18) and other established biomarkers.MethodsThree-hundred and eighty four spindle cell sarcomas from the German consultation and reference centre of soft tissue tumours initially suspected for synovial sarcoma were revisited. Three-hundred and nineteen of these specimens were analysed immunohistochemically using a monoclonal antibody TLE1 and standard, full-sized tissue sections. The nuclear staining was scored semiquantitatively as ?, negative; +, weak; ++, moderate and +++, strong positive. Furthermore, 118 specimens among these were further analysed using FISH and/or PCR to detect t(X;18). We correlated the TLE1 expression with the t(X;18) translocation and other established biomarkers (EMA, PanCK, CK7, CD34 and BCL2).ResultsTLE1 expression was observed in 96% of the synovial sarcomas (score ? +, 249/259) and discriminates them from other soft tissue tumours (p < 0.001). Multivariate analysis showed that positive TLE1 staining was a statistically independent diagnostic marker. Furthermore molecular analysis showed that t(X;18) was clearly correlated with TLE1 protein expression (p < 0.001).ConclusionsExpression of TLE1 is significantly correlated with t(X;18) and may serve as a new robust diagnostic biomarker in synovial sarcomas and potential therapeutic target.     

Sublocalisation of the X breakpoint in the translocation (X; 18)(p11.2; q11.2) primary change in synovial sarcomas

A specific translocation between chromosomes X and 18 was identified in synovial sarcomas. From a girl with synovial sarcoma, we isolated two clones with t(X; 18)(p11.2; q11.2) and which had lost the normal X chromosome. Southern blot analysis of DNA from the tumor, the patient and her parents demonstrated that the normal X chromosome, lost in the tumor, was the paternal one. A somatic hybrid cell line was established by fusing tumor cells (after passages on athymic mice) to an HPRT deficient hamster cell line. By cytogenetic, in situ hybridization and molecular analysis, it was found to contain the derivative (X) chromosome in the absence of the der (18) chromosome. To determine the position of the breakpoint on the X chromosome, Southern blots of DNA from this hybrid were hybridized to [32P]-labelled X chromosome probes. DXS146 and DXS255 were retained in the hybrid cell line whereas GAPDP1, the ARAF1 and TIMP proto-oncogenes were not present, indicating that the breakpoint lies proximal to GAPD1, ARAF1 and TIMP and distal to DXS255 and DXS146. Results obtained from other authors are compared. Further studies will be necessary to determine the extent of variation of the breakpoint in different tumors.     

Translocation t(2;11) is characteristic of collagenous fibroma (desmoplastic fibroblastoma)

Collagenous fibroma (desmoplastic fibroblastoma) is a rare, benign soft-tissue tumor composed of spindled and stellate-shaped cells embedded in a dense collagenous stroma. Recently, a translocation between chromosomes 2 and 11 or a rearrangement involving the chromosome 11q12 breakpoint was reported to be recurrent and unique in collagenous fibroma. Herein, we describe a case of collagenous fibroma arising in the left thigh of a 57-year-old man. Magnetic resonance imaging revealed a 5.5 cm soft-tissue mass deep relative to the vastus medialis with low signal intensity on both T1- and T2-weighted sequences. A marginal excision of the tumor was performed, and histopathologic features were consistent with collagenous fibroma. Cytogenetic analysis exhibited a reciprocal translocation involving the long arms of chromosomes 2 and 11. This finding suggests that the t(2;11) is likely to be of pathogenetic significance in a subset of collagenous fibromas.     

Translocation t(8;10)(q12;p14) in lymphoproliferative disorders

Cytogenetic studies were performed in two patients with a B-cell lymphoproliferative disease in progressive phase characterized by leukocytosis and important splenomegaly.

In both patients an identical chromsome marker derived from a t(8;10)(q12;p14) translocation was found. This chromosome anomaly was associated with other abnormalities characteristic for lymphoid malignancies, i.e. a structural rearrangment of the long arm of chromosome 11 and a 14q+ in both patients. This new t(8;10) translocation may be a marker of accelerated phase in lymphoid disorders.     

Chromosomal translocation t(14;18) in healthy individuals

The t(14;18)-translocation can frequently detected in the peripheral blood and tissue samples from healthy individuals. If the sensitivity of the assay used for the detection is high enough in almost all healthy individuals one or multiple cell clones carrying the t(14;18)-translocation can be found with a frequency of 1-100 rearranged cells in 10(6) normal cells. The frequency of these cells seems to be increased with age and smoking habits measured in pack years. The prevalence in Asian (Japanese) individuals appears to be lower than in Caucasians. It has been postulated that this translocation is a primary event for the subsequent development of a follicular lymphoma.     

The SYT-SSX1 fusion type of synovial sarcoma is associated with increased expression of cyclin A and D1. A link between t(X;18)(p11.2; q11.2) and the cell cycle machinery

A recent large multi-centre study convincingly confirmed previous observations that the SYT-SSX1 fusion type, compared to SYT-SSX2, of synovial sarcoma is associated with a worse clinical outcome. Apart from the clinical impact, this fact also suggests (1) that the SYT-SSX fusion gene may influence molecular mechanisms involved in tumour growth and progression; and (2) that the SYT-SSX1 fusion type has a stronger influence on these mechanisms than SYT-SSX2. The nature of the underlying mechanisms is, however, still unknown. In this study we made use of the SYT-SSX1 vs SYT-SSX2 concept to investigate whether major, tumour relevant, and growth regulatory proteins (e.g. cyclins and cyclin-dependent kinases) may be involved. Using Western blotting analysis on 74 fresh, fusion variant-typed, tumour samples from localized synovial sarcoma, we found a significant correlation between SYT-SSX1 and high expression of cyclin A (P=0.003) and D1 (P=0.025). Our data suggest that SYT-SSX may influence the cell cycle machinery, and that the more aggressive phenotype of the SYT-SSX1 variant is due to an accelerated tumour cell proliferation.     

t(11;22) and other chromosomal rearrangements in Ewing's sarcoma

Abnormal karyotypes from 13 human cases of Ewing's sarcoma are reported in this paper. The t(11;22) was seen in 9 cases, with 2 additional cases containing only a del(22). Other abnormalities included trisomy of 1q, translocations to 19p13, deletions of 3p and 6q, and homogeneously staining regions.     

Translocation t(X;10)(p10;p10): a rare chromosomal abnormality in a new born female with acute myeloid leukemia

Sex chromosomes are infrequently involved in patients with hematologic malignancies. In most instances, the abnormality is either duplication in the q arm or deletion and translocation involving the q13 and q24 regions. We report herein a rare translocation t(X;10)(p10;p10) in a newborn with 2 months and 20 days with acute myeloid leukemia (AML) (FAB, M4). Cytogenetic analysis detected a cell clone with t(X;10)(p10;p10). Thus was confirmed by FISH analysis with whole chromosome painting (WCP) specific for chromosomes X and 10. The patient was treated with chemotherapy, and a complete morphologic and cytogenetic remission was achieved. To our knowledge, our case is the first report of a neonatal AML4 with t(X; 10). The patient had an excellent early response to a salvage AML-type therapy. The prognostic significance of the t(X; 10) in this setting remains unclear. Due to the rarity of this translocation, further cytogenetic and molecular biologic studies are required to elucidate the clinical and molecular significance of this unusual karyotypic finding.