Synoviocytes from pigmented villonodular synovitis are less sensitive to cadmium-induced cell death than synoviocytes from rheumatoid arthritis.

Pigmented villonodular synovitis (PVNS) is a rare inflammatory articular disease sharing common characteristics with rheumatoid arthritis (RA), notably hyperplasia of the synovium due to a hyperproliferation of synoviocytes, and with cancer owing to mutations of the CSF1/M-CCSF gene. Targeting synovium hyperplasia by the local delivery of Cadmium (Cd) has been already tested in vitro and in vivo models of RA and could be applied to PVNS. PVNS and RA synoviocytes were exposed to low doses of Cd. After different culture time points, a qualitative analysis was done by microscopy and quantitative measurements of apoptosis, cell viability and IL-6 production were carried. IL-6 production by PVNS synovial tissue was also quantified after Cd treatment with or without the presence of pro-inflammatory cytokines (IL-17 + TNF). Addition of Cd induced cell death in both PVNS (1 ppm) and RA (0.1 ppm) synoviocytes, which increased with time and Cd concentrations. Cd increased the percentage of apoptotic cells and decreased cell viability and IL-6 production. In all these experiments, PVNS synoviocytes were tenfold less sensitive to Cd than RA synoviocytes. Cd decreased IL-6 production by PVNS synovial tissue and its effect was enhanced with pro-inflammatory cytokines. In summary, PVNS synoviocytes show resistance to Cd-induced cell death and decreased inflammation. Intra-articular use of Cd could represent a potential therapeutic tool in PVNS.

Gene Expression Profiles Analyzed Using Integrating RNA Sequencing, and Microarray Reveals Increased Inflammatory Response, Proliferation, and Osteoclastogenesis in Pigmented Villonodular Synovitis.

Background: Pigmented villonodular synovitis (PVNS) is a rare condition that involves benign proliferation of the synovial tissue and is characterized by severe joint destruction and high recurrence even after surgical resection. However, poor understanding of the pathogenesis limits its effective therapy. Method: In this study, gene expression profiles of six patients with PVNS, 11 patients with osteoarthritis (OA), nine patients with rheumatoid arthritis (RA) (E-MTAB-6141), and three healthy subjects (GSE143514) were analyzed using integrating RNA sequencing (RNA-seq) and microarray to investigate the PVNS transcriptome. Gene ontology, string, and cytoscape were used to determine the gene functional enrichment. Cell functional molecules were detected using flow cytometry or immunohistochemical test to identify the cell subset and function. CD14+ cells were isolated and induced to osteoclast to evaluate the monocyte/macrophage function. Results: The most obvious local manifestations of PVNS were inflammation, including increased immune cells infiltration and cytokine secretion, and tumor phenotypes. High proportion of inflammatory cells, including T cells, natural killer (NK) cells, NKT cells, and B cells were recruited from the blood. Th17 and monocytes, especially classical monocytes but not nonclassical monocytes, increased in PVNS synovium. An obvious increase in osteoclastogenesis and macrophage activation was observed locally. Elevated expression of MMP9, SIGLEC 15, and RANK were observed in myeloid cell of PVNS than OA. When compared with RA, osteoclast differentiation and myeloid cell activation are PVNS-specific characters, whereas T cell activation is shared by PVNS and RA. Conclusion: The transcriptional expression characteristics of PVNS showed increased immune response, cell migration, and osteoclastogenesis. Osteoclast differentiation is only observed in PVNS but not RA, whereas T-cell activation is common in inflammatory arthritis.

cIAP2 expression and clinical significance in pigmented villonodular synovitis.

Pigmented villonodular synovitis (PVNS) is a rare hyperplasia disease of the synovium with a predilection for the knee in either a localized (LPVNS) or a diffuse form (DPVNS). But the exact cause is not clear. The aim of this study was to explore the relationship between the expression of cellular inhibitor of apoptosis 2 (cIAP2) and proliferation, apoptosis, invasive growth and postoperative recurrence in PVNS. Clinical significance of cIAP2 expression in synovium from 63 patients' knee joints with PVNS (40 DPVNS; 23 LPVNS) were investigated with 20 normal subjects acting as controls. The cIAP2 gene was screened by Human Cancer Pathway Finder PCR Array and real-time polymerase chain reaction (RT-PCR). We also used immunohistochemistry to detect cIAP2 and proliferating cell nuclear antigen (PCNA) protein expression and analyzed their relationship with PVNS type, invasive growth, and postoperative recurrence. The expression of cIAP2, PCNA, caspase-8, caspase-9 and caspase-3 protein was tested in Western blot. Screening results of Human Cancer Pathway Finder PCR array and RT-PCR showed significantly more cIAP2 mRNA in DPVNS synovium than in normal or LPVNS synovium (P < 0.05). Immunohistochemistry and western blot showed that the cIAP2 protein expression level in DPVNS was significantly higher than in LPVNS tissue (P < 0.01). As cIAP2 expression increased, the expression of PCNA increased (P < 0.05) and expression of cleaved caspase-3, -8, -9 decreased (P < 0.01). cIAP2 and PCNA overexpression were found to be related to ligament and bone erosion in PVNS and to disease recurrence (P < 0.05). This study suggested that cIAP2 overexpression plays an important role in the anti-apoptotic, proliferative and invasive growth of PVNS, which may account for the recurrence and poor prognosis of DPVNS.

Cytogenetic Single-Institution Analysis: 101 Consecutive Cases of Soft-Tissue Tumors of the Extremities.

We summarize the results and clinical usefulness of cytogenetic analysis that is routinely performed for musculoskeletal tumors. We performed cytogenetic analysis and traditional histologic evaluation on 101 (51 malignant/ 50 benign) consecutive tumors that were surgically excised. The successful culture rate for cytogenetic analysis was 86% (87/101). Fifty-four percent (25/46) of clearly malignant tumors that were successfully cultured demonstrated significant clonal abnormalities. Fifty-one percent (21/41) of benign tumors that were cultured had significant cytogenetic clonal aberrations. Increased cellular ploidy (> 50 chromosomes/cell) was demonstrated in 14/46 malignant and 1/41 benign tumors that were successfully cultured. Hyperploidy was highly correlated with malignancy (p < 0.001); the only "benign" tumor was a multiply recurrent and giant cell, demonstrating histologic changes consistent with early sarcomatous transformation. As expected, cytogenetic abnormalities frequently occurred in malignant tumors. Surprisingly, almost half of the benign tumors had significant clonal cytogenetic aberrations. Consistent findings of extra chromosomes 5 and 7 in samples of pigmented villonodular synovitis strongly favored a neoplastic origin for this condition. Although the presence or absence of cytogenetic aberrations cannot be used to determine malignant potential, increased cellular ploidy is highly indicative of malignancy. Modern molecular genetics have become more popular, but cytogenetic analysis can be useful for classifying the malignant potential of recurrent and difficult to diagnose tumors of the musculoskeletal system.

CSF-1R Inhibitor Development: Current Clinical Status.

PURPOSE OF REVIEW: Colony-stimulating factor 1 receptor (CSF-1R) and its ligands, CSF-1 and interleukin 34 (IL-34), regulate the function and survival of tumor-associated macrophages, which are involved in tumorigenesis and in the suppression of antitumor immunity. Moreover, the CSF-1R/CSF-1 axis has been implicated in the pathogenesis of pigmented villonodular synovitis (PVNS), a benign tumor of the synovium. As advanced or metastatic malignant solid tumors and relapsed/refractory PVNS remain unresolved therapeutic problems, new approaches are needed to improve the outcome of patients with these conditions. RECENT FINDINGS: In solid tumors, targeting CSF-1R via either small molecules or antibodies has shown interesting results in vitro but limited antitumor activity in vivo. Concerning PVNS, clinical trials assessing CSF-1R inhibitors have revealed promising initial outcomes. Blocking CSF-1/CSF-1R signaling represents a promising immunotherapy approach and several new potential combination therapies for future clinical testing.

Expression of colony-stimulating factor 1 is associated with occurrence of osteochondral change in pigmented villonodular synovitis.

Pigmented villonodular synovitis (PVNS) is a benign, translocation-derived neoplasm. Because of its high local recurrence rate after surgery and occurrence of osteochondral destruction, a novel therapeutic target is required. The present study aimed to evaluate the significance of protein expression possibly associated with the pathogenesis during the clinical course of PVNS. In 40 cases of PVNS, positivity of colony-stimulated factor 1 (CSF1), its receptor (CSF1R), and receptor activator of nuclear factor kappa-B ligand (RANKL) were immunohistochemically determined. The relationship between the positivity and clinical outcomes was investigated. High positivity of CSF1 staining intensity was associated with an increased incidence of osteochondral lesions (bone erosion and osteoarthritis) (p = 0.009), but not with the rate of local recurrence. Positivity of CSF1R and RANKL staining was not associated with any clinical variables. The number of giant cells was not correlated with positivity of any of the three proteins, or with the clinical outcome. Focusing on knee cases, CSF1 positivity was also associated with the incidence of osteochondal change (p = 0.02). CSF1R positivity was high in cases which had local recurrence, but not significantly so (p = 0.129). Determination of CSF1 and CSF1R expression may be useful as a prognosticator of the clinical course and/or outcomes of PVNS.

[Molecular biology of sarcoma and therapeutic choices]. / Biologie moléculaire des sarcomes et choix thérapeutiques.

Soft tissue sarcomas (STS) are a set of very heterogeneous tumors with numerous histological categories. The development of the molecular biology allowed identifying recurring molecular anomalies in certain subgroups of sarcomas, being able to represent diagnostic, prognosis and therapeutic tools. The molecular classification of STS includes until today 5 main groups of abnormalities: sarcomas with "simple genomic profile" showing reciprocal (1) chromosomal translocations, (2) activating mutation, (3) inhibitive mutation or (4) simple amplification; (5) sarcomas with "complex genomic profile" can include several tens of molecular abnormalities. The development of new-targeted therapies is based on the identification of a target, specific of a tumors subgroup and involved in carcinogenesis mechanisms and/or tumoral growth. Then, the aim of clinical research is to establish the proof of the concept through clinical trials, demonstrating the benefit brought to the patient and ending in the marketing of the drug. This proof of the concept was clearly established for imatinib, sunitinib and regorafenib in gastrointestinal stromal tumors, for imatinib in dermatofibrosarcoma protuberans and pigmented vilo-nodular synovitis, for denosumab in giant cell tumors of the bone, ending in the authorization to use these new therapies in these indications. It is in progress and promising for anti-IGF-1R in Ewing sarcomas, for crizotinib in myofibroblastic inflammatory tumors, for mTOR inhibitor in PEComas... The role of molecular abnormalities identified in the mechanisms of tumoral progress for sarcomas and their potential therapeutic impact will be detailed.

Translocation and expression of CSF1 in pigmented villonodular synovitis, tenosynovial giant cell tumor, rheumatoid arthritis and other reactive synovitides.

We recently demonstrated that CSF1, the ligand of the tyrosine kinase receptor, CSF1R, can be translocated in pigmented villonodular synovitis (PVNS) and tenosynovial giant cell tumor (TGCT). In this study, we evaluated the staining characteristics of PVNS/TGCT and reactive synovitides for CSF1 and CSF1R by in situ hybridization and immunohistochemistry on tissue microarrays and correlated these findings with the recently described translocation. We collected specimens of TGCT/PVNS from 60 patients and of rheumatoid arthritis and other reactive synovitides from 74 patients. We identify 2 groups of PVNS and TGCT cases by the presence of CSF1 translocation and CSF1 expression. The first group (35 of 57 cases; 61%) had both the CSF1 translocation and high expression of CSF1 RNA, confirming our previous findings. Interestingly, a second group (22 of 57 cases; 39%) was identified that showed high expression of CSF1 RNA or CSF1 protein but did not have the translocation. The rheumatoid arthritis and reactive synovitis specimens showed localization of CSF1 RNA and protein to the synovial lining cells, implying a possible role for CSF1 in the pathogenesis of these lesions. As the CSF1 translocation is postulated to play an important role in the biology of PVNS/TGCT, the consistent presence of CSF1 expression in translocation-negative cases implies that other mechanisms can lead to CSF1 up-regulation. The consistent presence of CSF1 overexpression in all cases of PVNS/TGCT and reactive synovitides suggests both an important role for CSF1 in the spectrum of synovial pathologies and the possibility of targeting the CSF1/CSF1R interaction therapeutically.

Analysis of pigmented villonodular synovitis with genome-wide complementary DNA microarray and tissue array technology reveals insight into potential novel therapeutic approaches.

OBJECTIVE: To characterize the gene expression profile and determine potential diagnostic markers and therapeutic targets in pigmented villonodular synovitis (PVNS). METHODS: Gene expression patterns in 11 patients with PVNS, 18 patients with rheumatoid arthritis (RA), and 19 patients with osteoarthritis (OA) were investigated using genome-wide complementary DNA microarrays. Validation of differentially expressed genes was performed by real-time quantitative polymerase chain reaction and immunohistochemical analysis on tissue arrays (80 patients with PVNS, 51 patients with RA, and 20 patients with OA). RESULTS: The gene expression profile in PVNS was clearly distinct from those in RA and OA. One hundred forty-one up-regulated genes and 47 down-regulated genes were found in PVNS compared with RA, and 153 up-regulated genes and 89 down-regulated genes were found in PVNS compared with OA (fold change > or = 1.5; Q < or = 0.001). Genes differentially expressed in PVNS were involved in apoptosis regulation, matrix degradation, and inflammation (ALOX5AP, ATP6V1B2, CD53, CHI3L1, CTSL, CXCR4, HSPA8, HSPCA, LAPTM5, MMP9, MOAP1, and SPP1). CONCLUSION: The gene expression signature in PVNS is similar to that of activated macrophages and is consistent with the local destructive course of the disease. The gene and protein expression patterns suggest that the ongoing proliferation in PVNS is sustained by apoptosis resistance. This result suggests the possibility of a potential novel therapeutic intervention against PVNS.

A landscape effect in tenosynovial giant-cell tumor from activation of CSF1 expression by a translocation in a minority of tumor cells.

Tenosynovial giant-cell tumor (TGCT) and pigmented villonodular synovitis (PVNS) are related conditions with features of both reactive inflammatory disorders and clonal neoplastic proliferations. Chromosomal translocations involving chromosome 1p13 have been reported in both TGCT and PVNS. We confirm that translocations involving 1p13 are present in a majority of cases of TGCT and PVNS and show that CSF1 is the gene at the chromosome 1p13 breakpoint. In some cases of both TGCT and PVNS, CSF1 is fused to COL6A3 (2q35). The CSF1 translocations result in overexpression of CSF1. In cases of TGCT and PVNS carrying this translocation, it is present in a minority of the intratumoral cells, leading to CSF1 expression only in these cells, whereas the majority of cells express CSF1R but not CSF1, suggesting a tumor-landscaping effect with aberrant CSF1 expression in the neoplastic cells, leading to the abnormal accumulation of nonneoplastic cells that form a tumorous mass.

Rheumatoid arthritis and pigmented villonodular synovitis: comparative analysis of cell polyploidy, cell cycle phases and expression of macrophage and fibroblast markers in proliferating synovial cells.

AIMS: Rheumatoid arthritis (RA) and pigmented villonodular synovitis (PVNS) are aggressive diseases with progressive joint destruction. The present study aims to define cell cycle phases, polyploidy and the immunophenotype of proliferating synovial cells in both diseases. METHODS AND RESULTS: Synovial tissues from patients with proliferative-active RA, localized and diffuse PVNS were analysed by DNA flow cytometry, immunohistochemistry and double immunofluorescence with confocal laser scan microscopy. Expression of macrophage markers (CD68/CD163), fibroblast markers (h4Ph/CD55) and Ki67 antigen was examined. Synovial cells positive for either macrophage or fibroblast markers as well as double-labelled cells were found in both RA and PVNS. In RA, CD68/CD163+ synoviocytes were preferentially located in the vicinity of the synovial lining layer, while they were more randomly distributed in PVNS. Of cases with diffuse PVNS, 20% showed an aneuploid cell pattern. All samples of localized PVNS and RA were diploid. Proliferative activity was significantly higher in aneuploid PVNS. CONCLUSIONS: In spite of their histologically homogeneous appearance, proliferating synovial cells display a heterogeneous immunophenotype in both RA and PVNS, indicating functional properties of both macrophages and fibroblasts. Aneuploidy seems to be a special feature of diffuse PVNS.

Analysis of chromosomal imbalances by comparative genomic hybridisation of pigmented villonodular synovitis.

Using comparative genomic hybridisation, DNA copy number changes were investigated in 15 cases of pigmented villonodular synovitis of the knee joint. Additionally DNA content was analysed by flow cytometry. Screening revealed numerical chromosomal imbalances in five of the examined cases. A total number of 18 gains were detected. The most frequent gains involved subregions of chromosomal arms 22q and 16p and 16q. No losses were found. One of the cases showed an aneuploid DNA-pattern, which actually proved to be the case with the most numerical chromosomal changes.

Cell characterization of mononuclear and giant cells constituting pigmented villonodular synovitis.

The aim of this study was to determine the histologic and cellular characteristics of 2 cell types, mononuclear cells (Mos) and multinuclear giant cells (GCs), that predominantly constitute pigmented villonodular synovitis (PVS). Synovial tissues examined in this study were obtained from 10 patients with PVS. Five methods were used for cell analysis: (1) enzyme-histochemistry for tartrate-resistant acid phosphatase (TRAP); (2) immunohistochemistry using antibodies for CD68, macrophage colony-stimulating factor (M-CSF), MIB-1, p53, p21, p16, and cathepsin-L (cath L); (3) TdT-mediated deoxyuridine triphosphate-biotin terminal end labeling (TUNEL) as a measure of apoptosis; (4) fluorescence-based polymerase chain reaction single-strand conformation polymorphism analyses (FPCR-SSCP) to detect p53 gene mutations; and (5) in situ hybridization using gene-specific oligoprobes for matrix metalloproteinase (MMP)-2, MMP-9, receptor activator of nuclear factor kappaB ligand (RANKL), and calcitonin receptor (CTR). Both Mos and GCs were shown to express the macrophage/histiocyte marker CD68. In GCs, TRAP and CTR, both of which are known as characteristic phenotype markers of osteoclasts, were expressed. M-CSF and RANKL, which are together essential for osteoclast differentiation, were expressed in both Mos and GCs. Mos were shown to express MIB-1, but GCs were not. Although proliferation-suppressor proteins p53, p21, and p16 were expressed in both Mos and GCs, little apoptotic phenomenon of lining Mos was detected by TUNEL. In our study, p53 gene mutations for exons 5, 7, and 8 in PVS synovial tissues were not detected by FPCR-SSCP analysis. Furthermore, both types of cells demonstrated the proteolytic enzymes MMP-2 and MMP-9 mRNA, and cath L protein. These results suggest that PVS has a hyperplastic property consisting of the CD68-positive monocytic cell lineage with differentiation of osteoclastic giant cells from monocyte and probably controlled against proliferation by wild-type p53, p21, and p16.

Analysis of the distribution and frequency of trisomy 7 in vivo in synovia from patients with osteoarthritis and pigmented villonodular synovitis.

Osteoarthritis (OA) and pigmented villonodular synovitis (PVNS) are disorders associated with trisomy 7. The aim of the present study was to determine the frequency and distribution of the cells with +7 in vivo by analyzing sections of paraffin-embedded synovia from patients affected by OA, PVNS, other forms of synovitis [hemorragic synovitis (HS) and chronic synovitis (CS)], and from individuals without joint disease. Fluorescence in situ hybridization (FISH), using a centromeric probe for chromosome 7, showed that the mean frequency of trisomic nuclei in 5-microm sections was highest in PVNS (9.0%), followed by CS (5.9%), OA (5.6%), and HS (4.6%), whereas trisomic nuclei were rare (0.7%) in normal tissue. When 8-microm sections were studied, the frequencies of trisomic cells in OA and control synovia increased to 6.7% and 1.5%, respectively. Trisomic nuclei were found in all cases, including those for which cytogenetic analysis of short-term cultures had not disclosed any trisomic cells. Overall, the trisomic cells were scattered within the tissue. However, small clusters of cells with +7 were found in three cases. By hematoxylin-eosin staining of the slides used for FISH analysis it could be shown that the clustered trisomic cells were proliferating synoviocytes within villous extensions of the synovial membrane.

Analysis of 35 cases of localized and diffuse tenosynovial giant cell tumor: a report from the Chromosomes and Morphology (CHAMP) study group.

The karyotypes of 44 specimens from 35 patients with localized (n = 19) or diffuse (n = 16) tenosynovial giant cell tumors were studied. The majority of cases in both categories (11 of 19 localized; 12 of 16 diffuse) displayed clonal chromosomal aberrations, with a complex karyotype in three cases and a simple chromosomal aberration in the others. No difference in the distribution of karyotypic abnormalities was found between the localized and diffuse form except for trisomies (usually of chromosomes 5 and/or 7), which were more frequent in the diffuse type. The short arm of chromosome 1 (1p11-13) was most frequently rearranged, with 7 of 11 localized and 7 of 12 diffuse lesions affected. These findings indicate that the localized and diffuse forms of tenosynovial giant cell tumor might represent two morphologic manifestations of the same entity. The high frequency of clonal chromosomal abnormalities, with a clustering of structural rearrangements to 1p11-13, suggests that this disease is most likely neoplastic in nature and paves the way to search for gene(s) that might be involved in its development.

Cytokine and matrix metalloproteinase expression in pigmented villonodular synovitis may mediate bone and cartilage destruction.

BACKGROUND: Pigmented villonodular synovitis (PVNS) is characterized by hypervascular proliferative synovium containing multinucleated giant cells, macrophages, and hemosiderin. The destruction of articular cartilage and erosion of periarticular bone is thought to be mediated by matrix metalloproteinases (MMPs). Expression of MMPs in some tumors appears to be stimulated through local production of cytokines, and several specific cytokines (TNF alpha, IL-1, and IL-6) play an important role in the stimulation of osteoclastic bone resorption. The role of cytokine secretion and regulation of MMP production in PVNS has not been investigated. DESIGN: In the present study, ten specimens from eight patients (ages 19 to 80) were evaluated histologically according to a modified Mirra classification and immunohistochemically (IHC) for the expression of MMP-9 (92 kDa gelatinase B), tumor necrosis factor alpha (TNF alpha), interleukin 1-beta (IL-1 beta), and interleukin 6 (IL-6). Localization of IL-6 and TNF alpha production was confirmed by in situ hybridization (ISH) for mRNA. RESULTS: All specimens, regardless of location (six knees, one ankle, one subtalar joint), showed diffuse and intense immunoreactivity for cytokines in the giant cells and synovial cells, and less intense and diffuse staining in the activated macrophages. Staining in the fibroblastic elements was minimal. In situ hybridization for TNF alpha and IL-6 mRNA mirrored the immunohistochemistry results, although the IL-6 staining was weaker than that for TNF alpha. Immunoreactivity for MMP-9 was diffuse and strong in giant cells, diffuse and moderate in synovial cells, and focal and moderate to strong in macrophages. In contrast, normal synovium demonstrated focal, moderate immunoreactivity for IL-1 beta, IL-6, TNF alpha and MMP-9 localized in the synovial lining cells. CONCLUSION: These findings suggest that periarticular bone resorption and cartilage destruction which characterize PVNS may be related to the expression of inflammatory cytokines, which in turn stimulate MMP production.

Expression of regulatory apoptotic proteins in peripheral giant cell granulomas and lesions containing osteoclast-like giant cells.

Peripheral giant cell granuloma consists of mononuclear cells and osteoclast-like giant cells. The proliferative ability of peripheral giant cell granuloma is restricted to the mononuclear cell compartment, whereas multinucleated giant cells lack mitotic activity. Although the proliferative compartment of peripheral giant cell granuloma has been investigated in detail, the expression and distribution of proteins regulating apoptosis is unknown. The present study demonstrates strong expression of bak and bax in the majority of giant cells. In contrast, giant cells show only weak positivity for bcl-2 and moderate positivity for bcl-x. Mononuclear cells were negative to weakly positive for bcl-x. Only scattered mononuclear cells were positive for bak, bax and bcl-2. The frequency of apoptotic nuclei detected by TUNEL-staining compared to regular nuclei was 18 times higher in giant cells than in mononuclear cells. In summary, our findings support the presumption that giant cells of bone and soft tissue tumors are reactive cell forms and not of neoplastic origin.

Short arm of chromosome 1 aberration recurrently found in pigmented villonodular synovitis.

Pigmented villonodular synovitis (PVNS) is a relatively uncommon benign lesion that is characterized by diffuse synovial proliferation, mainly occurring in knee joints. Cytogenetic reports about this lesion are few and they describe the presence of numerical and structural chromosome aberrations. We obtained PVNS tissue from the left knee joint of a 53-year-old female, and performed cytogenetic analysis. Fluorescence in situ hybridization (FISH) was also performed by using the formalin fixed, paraffin embedded PVNS tissue. Two seemingly unrelated clones were found: the first clone had structural abnormalities of chromosome 1, 3, and 18, and the second one had trisomy 7 as a sole numerical abnormality. FISH using a chromosome 7 specific alpha-satellite DNA probe revealed that interphase nuclei possessed two or three signals. We describe the clonal aberrations found in a case of PVNS. The deleted lesion of the chromosome 1 (1p10-1p31.3) includes the locus of coagulation factor III gene (1p22-p21), and the coagulation factor V (1q21-q25) locus includes another breakpoint that is 1q25. In addition, recurrent structural abnormalities at the short arm of chromosome 1 have been reported. These facts might play some role in the hemorrhagic tendency and histogenesis of these lesions.