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Five cases of unusual chondrosarcomas of the soft tissue and of the skeletal cartilage are reported. A retrospective clinical study has been evaluated on ways to improve our knowledge of these rare neoplasms.
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The authors report five cases treated by wide resection. Pathological studies were made of the whole of the lesion. Three tumours were situated at the upper end of the femur, one at the upper end of the humerus and one at the level of the tibial plateau. The specific features were localisation in an epiphysis and histological areas of clear cells whose cytoplasm contained glycogen. From the anatomical and radiological points of view, these tumours were like chondroblastomata but their progress was more like that of chondrosarcomata. The author concludes that they should be distinguished from both types of tumour.
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AIMS: Extraskeletal myxoid chondrosarcoma is a rare low-grade soft-tissue sarcoma with locally aggressive and metastasizing potential. Extraskeletal myxoid chondrosarcoma has distinctive clinical, light microscopic, immunophenotypic, cytogenetic and ultrastructural features. Evidence that extraskeletal myxoid chondrosarcoma often shows neuroendocrine features was first provided by Chhieng et al. on the basis of an immunohistochemical and ultrastructural study of seven cases. Our study aims to further confirm by immunohistochemistry and ultrastructural studies, including immunoelectron microscopy, that extraskeletal myxoid chondrosarcoma indeed may show neuroendocrine differentiation. METHODS AND RESULTS: Fifteen cases of extraskeletal myxoid chondrosarcoma and seven control cases of skeletal chondrosarcomas were studied. Extensive immunohistochemical analysis was performed in all cases and ultrastructural studies were done in 11 extraskeletal myxoid chondrosarcomas and three skeletal chondrosarcomas. Immunoelectron microscopy was performed on one case each of extraskeletal myxoid chondrosarcoma and skeletal chondrosarcoma. Extraskeletal myxoid chondrosarcomas expressed neuron-specific enolase (100%), synaptophysin (87%), S100 (50%), PGP 9.5 (40%), and epithelial membrane antigen (25%). Co-expression of synaptophysin and PGP 9.5 was observed in six tumours. Skeletal chondrosarcomas showed expression of S100 protein, vimentin and neuron-specific enolase in all cases. Synaptophysin, chromogranin and PGP 9.5 were not expressed in any skeletal chondrosarcoma case. Ultrastructurally, extraskeletal myxoid chondrosarcoma was characterized by distinct cords of cells immersed in a glycosaminoglycan-rich matrix. The cells were rich in mitochondria, had well-developed Golgi apparatus and there were numerous smooth vesicles. In three cases there were easily found 140-180 nm diameter membrane-bound dense-core granules in cell bodies and in processes, unrelated to the Golgi, compatible with neurosecretory granules. Fewer such granules were present in the remaining extraskeletal myxoid chondrosarcoma cases, three of which also contained intracisternal tubules typical of extraskeletal myxoid chondrosarcoma. The skeletal chondrosarcomas had scalloped cell surfaces, prominent rough endoplasmic reticulum focally distended with secretory product, and lacked neurosecretory granules. Intermediate filaments were prominent in both extraskeletal myxoid chondrosarcoma and skeletal chondrosarcomas. Immunoelectron microscopy showed synaptophysin expression in the extraskeletal myxoid chondrosarcoma but not in the skeletal chondrosarcoma case. CONCLUSIONS: This study confirms that a substantial proportion of extraskeletal myxoid chondrosarcomas show immunophenotypic and/or ultrastructural evidence of neuroendocrine differentiation, and are unlikely to be related to conventional skeletal chondrosarcomas.
Ninety-four chondrosarcomas of the Hamburg Bone Tumour Registry were reviewed in a retrospective study. The purpose of this study was to examine the morphological characteristics of different types of chondrosarcomas and to describe distinctive features of location, the age distribution and the male to female ratio. Central chondrosarcomas can be divided into classical chondrosarcomas, dedifferentiated chondrosarcomas, mesenchymal chondrosarcomas and clear-cell chondrosarcomas. Five periosteal chondrosarcomas were represented. Classical chondrosarcomas and clear-cell chondrosarcomas show a significant predominance of males; no sex predilection was seen in dedifferentiated and mesenchymal chondrosarcomas. Nearly 60% of classical and mesenchymal chondrosarcomas occur in the trunk. Eighty-five percent of dedifferentiated chondrosarcomas are located in the long bones of the limbs. Clear-cell chondrosarcomas arise in the proximal part of the femur. There is a marked predilection for mesenchymal chondrosarcomas in the second and third decades of life. The average age of patients with classical chondrosarcomas was 54 years, but clear-cell chondrosarcomas occur 10 years earlier and dedifferentiated chondrosarcomas 10 years later. Characteristically, classical chondrosarcomas produce a pure chondroid matrix with variable differentiation of tumour chondrocytes. The most important histological feature of the defifferentiated chondrosarcoma is the close association of two different cellular components. One of these consists of cartilage, which is generally well differentiated. In most of our cases the second component showed features of osteosarcoma (50%). Mesenchymal chondrosarcoma is characterized by concentric infiltration of cartilage islands by small tumour cells. Clear-cell chondrosarcomas show regions of cartilaginous tumour and areas of closely packed, glycogen-rich, large tumour cells with distinct boundaries. Osteoid formation and multinucleated giant cells are present in clear-cell areas. Knowledge of this group of tumours is indispensable for correct histological diagnosis and typing and is important in the design of surgical therapy and the prediction of biological behaviour.
Membrane type 1 matrix metalloproteinase (MT1-MMP) has been identified as an activator of the proenzyme of matrix metalloproteinase 2 (MMP-2: gelatinase A), and has also been shown to play a crucial role in tumor invasion by activating proMMP2 in both lung and gastric carcinoma. The tissue inhibitor of metalloproteinase 2 (TIMP-2) plus the MT1-MMP complex also plays an important role in the activation of proMMP-2. In this study, the expressions of MT1-MMP, MMP-2 and TIMP-2 were evaluated in 10 enchondromas, 34 conventional chondrosarcomas, 5 clear-cell chondrosarcomas, 7 mesenchymal chondrosarcomas and 8 dedifferentiated chondrosarcomas. The expressions were immunohistochemically visualized on paraffin sections and the levels of expression were assessed semiquantitatively. The extent of staining was assessed by the extent score in order to determine the overall level of expression. The extent scores of MT1-MMP, MMP-2 and TIMP-2 in grade 2 chondrosarcoma were significantly higher than those in either enchondroma or grade 1 chondrosarcoma (P < 0.05). In conventional chondrosarcoma, significant correlations were found between the extent scores of MT1-MMP and MMP-2 (P < 0.001), MT1-MMP and TIMP-2 (P < 0.01), and MMP-2 and TIMP-2 (P < 0.01). The undifferentiated small round tumor cells of mesenchymal chondrosarcoma showed lower positive rates and extent scores for MT1-MMP (2/7, 0.7 +/- 0.5) and MMP-2 (3/7, 0.7 +/- 0.4) than for cartilaginous components of mesenchymal chondrosarcoma [MT1-MMP (4/7, 1.3 +/- 0.5) and MMP-2 (7/7, 1.9 +/- 0.3)] or conventional chondrosarcoma. In dedifferentiated chondrosarcoma, the extent scores of MT1-MMP, MMP-2 and TIMP-2 in low-grade cartilaginous components were not significantly different from those in conventional chondrosarcoma; however, the high-grade anaplastic components showed high extent scores for MT1-MMP, MMP-2 and TIMP-2, compared with the low-grade cartilaginous components of dedifferentiated chondrosarcoma or conventional chondrosarcoma. According to our results, the expression of MT1-MMP as well as that of MMP-2 or TIMP-2 demonstrated a significant correlation with the tumor grade in human cartilaginous tumors. Furthermore, the expressions of MT1-MMP, MMP-2 and TIMP-2 were also found to play a crucial role in invasion in the high-grade components of dedifferentiated chondrosarcoma.
PURPOSE OF THE STUDY: This retrospective study concerns six patients in whom chondrosarcoma was suspected to develop in synovial chondromatosis. We discuss for these cases different diagnosis. The authors expose the clinical signs and radiological aspects which suggest malignant transformation. We report the indispensable criteria for established diagnosis of malignant transformation of synovial chondromatosis and appropriated forms of therapeutic management were suggested. MATERIALS AND METHODS: Six patients, 3 males and 3 females from 36 to 58 years of age were included in this study. Three patients presented 6 months, 3 years and 25 years history of synovial chondromatosis of the knee joint. When the malignant transformation appeared, a surgical biopsy was performed and the pathologist diagnosed a chondrosarcoma in all cases. For the other three patients, the chondrosarcoma and synovial chondromatosis were diagnosed at the same time. The localization was shoulder, hip and knee. A surgical biopsy was performed and the pathologist diagnosed chondrosarcoma. Synovial chondromatosis was diagnosed by histologic examination of the resection or amputation specimen. TREATMENT AND RESULTS: Four patients had thigh amputation, one patient had "en bloc resection" of the hip-joint and the last patient had resection of the shoulder joint. In all cases, the histologic examination diagnosed chondrosarcoma and synovial chondromatosis. All patients were free of disease. DISCUSSION: The malignant transformation of synovial chondromatosis is rare but this diagnosis must be established to perform appropriate treatment. Other possible diagnosis are: low grade synovial chondrosarcoma initially diagnosed as a synovial chondromatosis. Bertoni believes that all cases of malignant transformation of synovial chondromatosis are initially low grade chondrosarcoma. We believe that his criteria are too strict for diagnosed chondrosarcoma. coexistence of synovial chondromatosis and synovial chondrosarcoma. These 2 diagnosis are extremely rare and their coexistence are unlikely. secondary synovial chondromatosis developed into chondrosarcoma. We don't have histologic criteria to confirm this diagnosis in all our cases. The symptoms that should suggest a malignant transformation of synovial chondromatosis were: rapid late deterioration of clinical conditions, bone invasion diagnosed by X-ray films and medullar invasion discovered by MRI. According to us, the indispensable criteria to diagnose malignant transformation were: 1.) histologic diagnosis of synovial chondromatosis established before diagnosis of chondrosarcoma, 2.) histologic diagnosis of chondrosarcoma on the same anatomic site as the synovial chondromatosis, 3.) diagnosis of chondrosarcoma and synovial chondromatosis on the same resection specimen. Only the three first cases were in accordance with these criteria. The treatment must be a "en bloc resection" of the joint or an amputation. CONCLUSION: Malignant transformation is rare, but this diagnosis should be established to perform adequate treatment. This diagnosis should be suspected when a rapid deterioration of the clinical status appeared and when bone involvement was detected by MRI. However, the danger still lies in the misinterpretation of the synovial chondromatosis as chondrosarcoma. This diagnosis can be made with clinical, radiological and pathological criteria. The treatment must be a wide resection or an amputation.
It has been shown that transforming growth factor-beta (TGF-beta) has a potent stimulatory effect on the growth of chondrosarcoma cells in vitro. In order to examine the production of this family of growth factors and their receptors in vivo, we studied the expression of TGF-beta isoforms 1, 2, and 3 and of TGF-beta receptor types I and II (TGF-betaRI and TGF-betaRII) in a series of 24 chondrosarcomas of bone using immunohistochemistry and reverse-transcription polymerase chain reaction analysis. For comparison, five enchondromas and five osteochondromas were also analyzed. TGF-beta1 was expressed in 3 benign lesions (30%) and 18 chondrosarcomas (75%), with a significantly higher expression in grade-2 and -3 tumors than in grade-1 tumors ( P=0.002). TGF-beta2 was identified in 8 benign lesions (89%) and 21 chondrosarcomas (87.5%), with increased expression in grade-2 and -3 chondrosarcomas in comparison with grade-1 tumors ( P=0.05). TGF-beta3 was detected in 6 benign lesions (60%) and 17 chondrosarcomas (70.8%), with no significant differences between chondrosarcomas of different histologic grade ( P=0.6). Twenty-three chondrosarcomas (95.8%) expressed both TGF-beta receptor types I and II. Reverse-transcription polymerase chain reaction analysis performed on ten chondrosarcomas confirmed the presence of low or absent levels of TGF-beta1 and -beta2 mRNA in grade-1 chondrosarcomas, while grade-2 chondrosarcomas presented high levels of transcript of both cytokines. High levels of TGF-betaRI and RII mRNA were also detected. Chondrosarcomas with TGF-beta1 and TGF-beta2 overexpression (>20% of tumor cells) had a significantly higher expression of the cell proliferation marker MIB-1 ( P=0.006 and P=0.0003, respectively), while no significant correlation was found between TGF-beta3 expression and proliferative activity ( P=0.5). When TGF-beta isoform and receptor expression were examined with respect to disease-free survival, TGF-beta1 overexpression was significantly associated with a shorter disease-free survival ( P=0.004, log-rank test). Our data indicate that TGF-beta isoforms are produced by neoplastic cells of chondrosarcomas and could have a potential role as autocrine growth stimulators in these neoplasms.
OBJECTIVE: To analyze and compare the radiological and magnetic resonance imaging (MRI) appearances of chondroblastoma and clear cell chondrosarcoma with histopathological correlation. DESIGN AND PATIENTS: Twelve patients with histologically proven chondroblastoma and of another four patients with clear cell chondrosarcoma were investigated by radiographs and MRI (T1-, T2-weighted sequences, intravenous gadolinium application). Additionally, the clinical and radiologic data of seven cases of clear cell chondrosarcoma without available MRI were considered. The localization, calcification of tumor matrix, periosteal reaction, cortical bone and patterns of bone destruction were analyzed according to the Lodwick radiological grading system (LRGS). The signal intensity on T1- and T2-weighted sequences, characteristics of contrast enhancement, associated bone marrow edema, soft tissue reaction and joint involvement were evaluated. Histopathological specimens were available in all cases. RESULTS: The age of patients with chondroblastoma (range 15-59 years, mean 22.3 years) was lower than that of those with clear cell chondrosarcoma (range 19-61 years, mean 36.6 years), and the lesions were smaller in the chondroblastoma group (range 1-4 cm, mean 2.3 cm) than in patients with clear cell chondrosarcoma (range 3-7.5 cm, mean 5.2 cm). The chondroblastomas were more confined to the epiphysis (10/12) than the clear cell chondrosarcomas. All chondroblastomas and clear cell chondrosarcomas except one were classified as grade 1A or 1B according to the LRGS; one clear cell chondrosarcoma was judged as grade 2. Signal intensity of the tumors on MRI was very heterogeneous in both groups. High signal intensity on T2-weighted MR images in chondroblastoma mostly corresponded to areas with aneurysmal bone cyst components and in clear cell chondrosarcoma to islands of hyaline cartilage. Contrast enhancement occurred in all tumors and tended to be more intense with clear cell chondrosarcoma. Chondroblastoma was more frequently associated with bone marrow edema (11/12), periosteal reaction (10/12), soft tissue reaction (7/12) and synovitis (3/12). CONCLUSION: Chondroblastoma occurs in younger patients, is smaller than clear cell chondrosarcoma and is more confined to the epiphysis. The overlap of signal intensity and contrast enhancement patterns does not allow a reliable differentiation of the two tumors by MRI. Chondroblastomas are typically associated with bone marrow edema, periosteal reaction and soft tissue reaction.
Multicentric chondrosarcomas, other than those from mesenchymal chondroma, are rare and difficult to differentiate from metastatic disease. Eight new patients with multicentric chondrosarcomas are reported. Five patients had chondrosarcomas that were monomelic, 3 had disseminated chondrosarcomas, 3 had synchronous involvement, and 5 had metachronous involvement; 1 patient had Ollier's disease. A bimodal age distribution was apparent: 4 patients were between 62 and 76 years old, and the remaining 4 were between 16 and 33 years old. Average duration of followup was 6 years, 4 months. Each of the patients with synchronous chondrosarcomas had single bone lower extremity involvement and presented with symptoms occurring at only 1 of the 2 sites of tumor. Each of the 5 patients with metachronous chondrosarcomas experienced involvement of a different bone when the second tumor presented. Only 1 of these metachronous chondrosarcomas was limited to the lower extremity. The second tumor occurred in all patients after excellent control of the primary tumor by wide excision. The average duration between diagnosis of the 2 tumors was 4 years, 4 months (range, 8 months-12 years, 9 months). Patients who had nonmonomelic malignancies must be viewed with a considerably more guarded prognosis than those who had monomelic chondrosarcoma because each of the 2 deaths resulting from progressive disease occurred among the 3 patients with nonmonomelic chondrosarcoma. The nonmonomelic malignancies may represent metastatic chondrosarcoma with a rare predilection to bony involvement. Monomelic chondrosarcoma simply may represent lesions analogous to the skip lesions observed in osteosarcoma.
In this study, we undertook to prove the usefulness of cytofluorometric DNA ploidy analysis in distinguishing benign cartilaginous tumors from chondrosarcomas. We analyzed the DNA ploidy of 47 cartilaginous tumors using DNA cytofluorometry, which is more sensitive than flow cytometry. All of these tumors were classified into six groups on the basis of clinical, radiologic, and histologic criteria. The 25 tumors in the No. 1 group showed no histologic signs of malignancy regardless of their clinical signs. The four tumors in the No. 2 group showed histologic signs of malignancy, but had benign clinical signs like small bone origin or Ollier's disease. The No. 3 group (13 tumors), No. 4 group (four tumors), and No. 5 group (three tumors) were conventional grade I, II, and III chondrosarcomas, respectively, and the No. 6 group included three dedifferentiated chondrosarcomas. Tumor cells isolated from fresh tumor materials treated with papain and collagenase were smeared on a glass slide and their nuclear DNA was stained with propidium iodide. The DNA content of each cell was measured by a cytofluorometer as fluorescence intensity. The results of this study showed that all of the tumors in the No. 1 group had a diploid pattern with a significantly lower (P<.001) cell proliferative activity than the grade I chondrosarcomas in the No. 3 group, all of which had a diploid pattern. Cytofluorometric analysis also indicated that grade II and III chondrosarcomas in the No. 4 and 5 groups had a higher frequency of hyperdiploid cells (%HDC), including aneuploid and polyploid cells than grade I chondrosarcomas. Importantly, all of the grade I chondrosarcomas showed a %HDC >8%, whereas all of the tumors in the No. 1 and 2 groups showed a %HDC <8%. Therefore, we believe that a %HDC value of 8% is borderline between biologically benign and malignant states in cartilaginous tumors. Four of five patients with aneuploid chondrosarcoma had tumor recurrence and two of these patients died of metastatic disease, although all of the patients except for one with diploid chondrosarcoma were continuously disease free after surgery. Based on these results, we concluded that the data of DNA ploidy analysis, especially cell proliferative activity expressed as %HDC, is more reliable and clinically more useful than the histologic and clinical signs of malignancy in distinguishing benign cartilaginous tumors from chondrosarcomas and even from low grade chondrosarcomas.
PURPOSE OF STUDY: Dedifferentiated chondrosarcoma is a variant of chondrosarcoma of bone consisting in a highly anaplasic sarcoma associated with low grade chondrosarcoma. The histopathology and the poor prognosis characterize these tumors. The clinical, radiographical and histological features are described before proposing a therapeutic approach to improve prognosis. MATERIAL AND METHODS: Thirteen cases of dedifferentiated chondrosarcoma having the histological requirements described by Dahlin and Beabout were identified and treated between 1977 and 1992 at the Cochin Hospital. These tumors represented 10 per cent of all chondrosarcomas registered in the same period. Eleven cases were primary and in two cases the dedifferentiated chondrosarcomas were first found in recurrent tumors. The average of age was 53 years. This was a retrospective study. The clinical reports, radiograms and histological reports were reevaluated. In doubtful cases the histological sections were reviewed. RESULTS: The clinical features were no different from chondrosarcoma except for the high incidence of pathological fractures. The histology was associated in all cases with a grade 1 or 2 chondrosarcoma and a grade 3 or 4 anaplasic component. The anaplasic components were: 5 osteosarcomas, 5 fibrosarcomas, 2 fibrous histiocytomas, 1 rhabdomyosarcoma. All the patients underwent surgical treatment. Only one patient was treated by adjuvant chemotherapy. Among the eleven primary chondrosarcomas: two disarticulations were performed. En bloc resection was performed in nine patients: one wide margin, six marginal and two intralesional. The two secondary dedifferentiated chondrosarcomas were treated by disarticulation. No local recurrences were observed after disarticulation or wide resection. All patients presented pulmonary metastasis leading to death except one patient with only three months follow up. The average survival time was nine months (1 to 36 months). DISCUSSION: Prognosis is uniformly poor. The five years survival rate is 0 per cent in our series and 10.5 per cent in the series published by Unni and Frassica. The physiopathologic hypothesis which prevails is that the two histologic components originate from two different primitive cell clones, one of which differentiates into a low grade chondrosarcoma while the others fails to differentiate and remains a high grade sarcoma expressing different morphologic features. Treatment was not always adequate, because the diagnosis was missed at time of biopsy in five cases. The biopsies showed the two histological components in only six cases. All our patients presented pulmonary metastasis excepted one patient. This feature was also noted in other series (70 to 100 per cent). Those metastasis originate from the anaplasic component. Chemotherapy has not been well evaluated for these tumors but its effectiveness is evident for treatment of osteosarcoma. CONCLUSION: These tumors, which are characterized by their histology and their poor prognosis, are frequently inadequately treated. It is necessary to improve the prognosis: by performing a large biopsy adjusted on the lytic bone. by performing a wide resection or amputation. We believe that it is necessary to associate a chemotherapy to surgical treatment. We have decided to treat our patients with an osteosarcoma protocol.
Chondrosarcomas are frequent malignant bone tumors. Aside from different subtypes, such as dedifferentiated, mesenchymal and clear-cell chondrosarcoma, chondrosarcomas (classical chondrosarcoma) show different grades of differentiation. The borderline between chondroma and classical chondrosarcoma is not clearly defined. The same chondrosarcoma can be graded differently at different institutes. Standardized therapy concepts are currently in preparation. As the Hamburg Bone Tumor Registry is often consulted for chondrogenic tumors, the histological criteria are based on a series of 74 chondrosarcomas recorded there. The emphasis has been laid on a classification which can be used in daily routine and which is reproducible and in agreement with the classifications of other international groups. Grade I chondrosarcomas (50%) can be distinguished only by growth criteria. The nuclei are small and show high chromatin density. Grade II chondrosarcomas (42%) have medium-sized, regular nuclei with loose chromatin structure. The chondrocytes of grade III cases (8%) show polymorphic nuclei. Binucleas forms, the number of mitoses and cellularity all show considerable overlap for all three grades. So far there are no immunohistological and molecular biological methods for reliable differentiation. The therapeutic consequences of the classification into grades are thorough curettage, in the case of grade I tumors, or complete resection, for grade II and III cases. The long-term results, however, need to be confirmed by a larger number of cases. From 1991 to 1995 the method was applied and proved to be easily practicable in daily diagnostic routine. Some 104 cases of classical chondrosarcomas (grade I 53%, grade II 39%, grade III 8%) were analyzed. Two pathologists both assigned the same grade in 90% of cases.