Abstract
Secondary chondrosarcoma is a malignant chondroid tumor arising in a benign precursor. Synovial chondromatosis is a benign chondroid lesion that rarely transforms to chondrosarcoma. We present the case of a 54-year-old male with the diagnosis of low-grade secondary peripheral chondrosarcoma developed in the context of synovial chondromatosis. Cytogenetics revealed a novel aberration t(1;14)(q23.1~24;q24.1~3). Multicolor banding (mBAND) analysis described the chromosomal regions involved in this translocation with a higher detail. Diagnosis of such borderline lesions is very difficult and cytogenetics is helpful in characterizing these tumors.
Chondrosarcoma is a malignant tumor with pure hyaline cartilage differentiation, with peak incidence during the fifth to seventh decade of life. The most common skeletal sites are the bones of the pelvis, proximal femur, proximal humerus, distal femur and ribs. Secondary chondrosarcoma is a type of chondrosarcoma arising in a benign precursor (1). Histopathologically, secondary chondrosarcomas are generally low-grade tumors, thus making their diagnosis difficult.
Synovial chondromatosis is a benign nodular cartilaginous proliferation arising in the synovium of joints, bursae or tendon sheaths. The joints involved are mainly the knee and less often the hip, elbow, wrist, ankle, shoulder or temporomandibular joint (2). Histopathologically, it consists of hyaline cartilage nodules and chondrocytes with moderate nuclear pleomorphism. Synovial chondromatosis may recur locally after excision or synovectomy and rarely may transform to chondrosarcoma (3-6).
Cytogenetic analysis has provided a valuable insight into the pathogenesis of many benign and malignant bone and soft tissue tumors. Only in few cases of synovial chondromatosis have clonal chromosomal aberrations been detected, supporting a clonal neoplastic origin of this benign histopathological entity (7-9). There is even less reported evidence in the literature about secondary chondrosarcomas arising in synovial chondromatosis (10, 11).
In this study, we present the case of a secondary chondrosarcoma occurring in the context of synovial chondromatosis, in which a sole anomaly of a t(1;14) was detected with classical cytogenetic analysis. High-resolution multicolor banding (mBAND) was performed in order to characterize the chromosomal regions involved in greater detail.
Case Report
A 54-year-old male presented with a 10-year history of a growing movable mass of the left wrist joint. The patient complained of exercise-induced pain of the referred joint over the preceding six months. Computer tomography (CT) scan revealed a lesion in the left dorsal region of the cubitus of about 4.5 cm in diameter. Cytological analysis after fine needle aspiration (FNA) biopsy did not reveal malignant cells. Bone scanning did not show any secondary lesions. The patient underwent a total resection of the tumor and external fixation.
Histology. The tumor was excised with a portion of bone and measured 6.5 cm in diameter. It consisted of irregularly shaped lobules of cartilage of various sizes which were separated by cleft-like spaces or by narrow fibrous bands containing blood vessels. Chondrocytes were arranged in clusters and located in lacunae. Their nuclei were fairly uniform and small, while in other areas they were moderately enlarged with irregular shape. Binucleated cells were also observed. The matrix was composed of areas with mature hyaline cartilage, myxoid stroma and sites of degenerative changes.
Chromosome banding analysis. A tissue specimen was obtained for cytogenetic analysis. The tissue was mechanically disaggregated using a scapel and enzymatically treated with collagenase type I (Sigma-Aaldrich, St Gallen, Germany), collagenase type II (Sigma-Aaldrich, St Gallen, Germany) and hyaluronidase (Sigma-Aaldrich, St Gallen, Germany) for 6 hours at 37oC, 5% CO2. Subsequently, the cells were cultured in RPMI 1640 GlutaMAX (Gibco, San Diego, California, USA) media supplemented with 20% fetal bovine serum and 1% penicillin/streptomycin-L-glutamine (Gibco, San Diego, California, USA) in plastic flasks (Cellstar, Greiner Bio One, Frickenhausen, Germany) for 5-7 days. Three hours prior to harvest, cells were exposed to colcemid (Karyo Max, Gibco, San Diego, California, USA) and metaphases were G-banded with Wright stain. The description of the karyotype followed the recommendations of the International System of Cytogenetic Nomenclature (ISCN 2009) (12).
Fluoresence in situ hybridization (FISH). mBAND was performed on fresh metaphase spreads prepared from a cell suspension stored in fixative. The XCyte 1 and XCyte 14 probe kits (Metasystems, Altlusheim, Germany) were used in separate hybridization assays, according to the manufacturer's instuctions. Visualization and analysis of the hybridization results were performed in an Axioplan Imaging fluorescence microscope (Zeiss, Oberkochen, Germany) with the appropriate filters and the mBAND software (ISIS; Metasystems).
Results
Histopathological evaluation revealed a well-differentiated chondrosarcoma (chondrosarcoma grade I) arising in synovial chondromatosis (Figures 1 and 2).
Cytogenetic analysis revealed clonal chromosomal aberration in 25 metaphases resulting in the following karyotype: 46,XY,t(1;14)(q24;q31)[25]/46,XY[4] (Figure 3).
mBAND analysis redefined the breakpoints of the chromosomal regions involved. mBAND analysis of chromosome 1 identified the chromosomal regions 1q23.1~24 to be involved at the breakpoint, while the multiple band pattern of chromosome 14 identified chromosomal regions 14q24.1~3 as participating in the aberration. Thus, the karyotype was: 46,XY, t(1;14)(q23.1~24;q24.1~3)[25]/46,XY [4] (Figures 4 and 5).
Discussion
Radiological distinction between synovial chondromatosis and low-grade chondrosarcoma is a dilemma (2, 13). Histopathologically, the differential diagnosis between synovial chondromatosis and low grade chondrosarcoma can also be difficult (10, 13). Cytogenetic analysis has provided a valuable insight into the pathogenesis of many benign and malignant bone and soft tissue tumors and is very useful in the evaluation of chondromatous lesions especially those with unusual or clinicopathologically borderline features, such as synovial chondromatosis and low grade chondrosarcoma (10).
The cytogenetic profile of synovial chondromatosis is not well established. Only in five out of eight cases previously reported did the cytogenetic findings demonstrate abnormalities in chromosome 6, indicating the neoplastic origin of this entity (7). Synovial chondromatosis rarely undergoes malignant transformation to low grade chondrosarcoma (3-6). Chondrosarcomas have a cytogenetic profile that varies from normal to complex karyotypes (14, 15). Several studies support a positive correlation between histological grade and the degree of kayotypic complexity (16, 17). Tallini et al. were the first to report that among primary well-differentiated bone lesions, a diagnosis of grade I chondrosarcoma is consistently associated with chromosomal alterations (10). Karyotypic aberrations reflect a multistep process of genetic alterations required for the malignant transformation and progression of cartilage tumors (10, 18, 19).
In the present case, cytogenetic analysis revealed a novel aberration with the following karyotype: 46,XY,t(1;14) (q23.1~24;q24.1~3)[25]/46,XY[4]. mBAND analysis helped us to narrow down the chromosomal regions involved. The combination of classic banding analysis with molecular cytogenetic techniques, such as multi-band FISH illustrates how they complement each other and contribute to a more detailed description of the data found.
Only one case of secondary chondrosarcoma arising in synovial chondromatosis has been reported with an abnormal karyotype with structural aberrations. In that case, chromosome 1 participated in a der(1;13)(q10;q10) and chromosome 14 was deleted (10).
Chromosomal region 14q24 has been described as participating in a t(4;14)(q12;q24) and a t(12;14)(q13;q24) in two cases of chondrosarcoma (20, 21). Loss of chromosomal region 14q24~qter has been reported by Mandal et al. (22), while comparative genomic hybridization (CGH) studies revealed gains in 14q24~qter region in 24% of the skeletal tumors studied (23). These data indicate that this region contains genes crucial for the development of chondrosarcomas.
On the other hand, 1q23 is the genetic locus of pre-B-cell leukemia homeobox 1 gene (PBX1), which is fused to transcription factor 3 (TCF3) in acute lymphoblastic leukemia resulting in t(1;19)(q23;p13.3)(24). Paired related homeobox 1 gene (PRRX1) is also found in 1q23 and creates a fusion gene with nucleoporin 98kDa gene (NUP98) in therapy related acute myeloid leukemia, as a result of t(1;11)(q23;p15)(25, 26). Of course, participation of PBX1 or PRRX1 in fusion genes in chondrosarcomas is absolutely speculative. Chromosomal region 1q is frequently amplified in sarcoma and in a variety of other solid tumor types. Copy number gains of chromosomal region 1q21.3-q23.1 have been reported in chondrosarcomas by Hallor et al. (27).
Low power cross section showing cartilagenous nodules surrounded by fibrous connective tissue as in synovial chondromatosis. Hematoxylin and eosin, ×20.
Well differentiated chondrosarcoma (chondrosarcoma grade I) with increased cellularity and binucleated or multinucleated chondrocytes lying in lacunae. Hematoxylin and eosin, ×100.
Representative karyogram showing t(1;14).
Multicolor banding (mBAND) analysis with XCyte1 probe. First lane shows pseudocolor profile of normal chromosome 1. Second lane shows pseudocolor profile of derivative chromosome 1 and third lane of derivative chromosome 14.
Multicolor banding (mBAND) analysis with XCyte14 probe. First lane shows pseudocolor profile of normal chromosome 14. Second lane shows pseudocolor profile of derivative chromosome 14 and third lane of derivative chromosome 1.
In summary, we present a case of a rare clinicopathological entity with a novel cytogenetic finding. Cytogenetic analysis is a very helpful approach complementary to the radiological and immunohistochemical ones used in everyday clinical practice. Cytogenetic data can offer important information for the diagnosis and our understanding of the development of secondary chondrosarcoma from primary synovial chondromatosis.
- Received October 26, 2012.
- Revision received November 16, 2012.
- Accepted November 19, 2012.
- Copyright © 2013 The Author(s). Published by the International Institute of Anticancer Research.
