JOURNAL OF PATHOLOGY, VOL.
163: 93-94 (1 99 1)
EDITORIAL NEW DEVELOPMENTS IN THE DIAGNOSIS OF CHONDROSARCOMA Almost half a century has elapsed since chondrosarcoma was clearly distinguished from osteosarcoma by virtue of its different histology and anatomical location, older age distribution, and better prognosis.' Since then, a number of variants of chondrosarcoma have been separated. However, the diagnosis of conventional cartilage tumours remains one of the most difficult areas of bone tumour pathology, where particularly close co-operation between pathologist, radiologist, and orthopaedic surgeon is required.2 The pathologist examining a biopsy of a cartilaginous lesion must answer several questions. Is the lesion reactive or neoplastic? If neoplastic, is it benign or malignant? If malignant, is it likely to metastasize? If highly malignant and in a young patient, is the lesion a chondroblastic osteosarcoma masquerading as a chondrosarcoma? The clinical history and radiograph are usually helpful in answering the first and last questions. The difficulties lie in distinguishing between benign tumours and those of low-grade malignancy, and in predicting the behaviour of chondrosarcoma. There are three major problems. Firstly, the cytological features which allow a diagnosis of malignancy are often present in only a few fields, so there is a danger of underdiagnosis particularly in small biopsies. Secondly, the criteria of malignancy are ill defined even when the lesion is adequately sampled. Application of vague terms such as 'plump nuclei' and 'more than an occasional cell with two plump nuclei' is necessarily subjective. This lack of precision may be justified: it is said that the cytological features of benign and low-grade malignant tumours overlap in a quarter of cases3Lastly, the criteria vary depending on the anatomical site. Appearances which would support a diagnosis of low-grade malignancy in a central tumour of the pelvis can be safely ignored in a lesion of the tubular bones of the hands and feet or in a subperiosteal location. If a cartilage tumour permeates widely between pre-existing medullary trabeculae it can be regarded as malignant. How0022-341 7/91/02009342 $05.00 0 1991 by John Wiley & Sons, Ltd.
ever, this pattern is not present in all chondrosarcomas and is difficult to interpret in severely fragmented biopsies. Mirra et aL4 have described in detail the architectural patterns which aid in the distinction of benign and malignant cartilage tumours. This thoughtful paper should be read by all interested in the problem. The same difficulties of poorly defined criteria and subjective interpretation apply to the grading of chondrosar~oma.~ This is not surprising as chondrosarcoma may be considered to show a continuous spectrum of biological behaviour. Although criteria vary slightly in different grading systems, the histological grade correlates well with survival in large series,"* but the unpredictable nature of the lesions makes the prognosis in an individual patient difficult to determine. Over the past decade, attempts have been made to supplement histological assessment by other methods. An exhaustive study ofmultiple biochemical measurements, including protein, proteoglycan, DNA, and water content, of a series of 69 cartilage tumours failed to reveal any variable of help in predicting prognosis.' Increasing water content and alterations in proteoglycan chains were found with increasing malignancy, in keeping with the myxoid matrix more commonly seen in higher-grade tumours. A decrease in intensity of immunostaining for S- 100 protein in high-grade chondrosarcoma has been described, lo but in the absence of quantification seems unlikely to be of much prognostic value. Perhaps more encouraging is the demonstration of c-erbB-2 proto-oncogene expression in 18 of 23 chondrosarcomas stained with a polyclonal antibody raised to a synthetic peptide derived from the gene sequence." However, only nine benign tumours of hyaline cartilage were examined and one, an osteochondroma, also stained positively. Clearly many more cases need to be studied before the value of this technique in distinguishing benign from malignant tumours is established. Similarly, it will be important to determine whether the behaviour of
94
EDITORIAL
those chondrosarcomas which express this protooncogene differs from those which do not. Apart from the few high-grade tumours, chondrosarcomas are slow growing with scanty mitotic figures. Although there are considerable technical difficulties in dealing with poorly cellular tumours which are often mixed with hard tissues, investigation of cell proliferation in cartilage tumours has yielded interesting data. Cellular DNA content has been measured initially by microspectrophotometry and more recently by flow cytometr of cellular and isolated nuclear preparations.”-” As might be expected, a higher percentage of diploid cells is found in benign than in low-grade malignant tumours, and more aneuploid cells in high-grade than in low-grade chondrosarcoma.13 Unfortunately, these findings d o not allow clear separation of benign from malignant cartilage tumours.13 However, in Kreicbergs’s series the 10-year survival of patients with diploid tumours was better than that of patients with hyperploid tumours.12 This prognostic factor appeared to be independent of the histological grade, anatomical site, and treatment. Assessment of ploidy may therefore by a useful adjunct to conventional histological assessment. Quantification of cell proliferation has been revolutionized by the development of antibodies directed against antigens expressed during the active phases of the cell cycle. The need for fresh frozen tissue from these uncommon tumours has limited the number of cases studied with the monoclonal antibody Ki-67. In general, a higher proliferation index is found in chondrosarcoma, particularly of high grade, than in chondromas.” The recent development of antibodies which recognize proliferationassociated antigens in paraffin-embedded tissue should allow retrospective analysis of the large number of cases in bone tumour registry files. This may well prove to be the most useful new technique. These exciting and potentially valuable new approaches require further work and critical assessment. The results must be evaluated in large series
where details of the clinical stage and adequacy of surgical excision as well as the outcome are known. ROBINREID Scottish Bone Tumour Registry University Department of Pathology Western Infirmary Glasgow G116NT, U.K. REFERENCES 1. Lichtenstein L, Jaffe HL. Chondrosarcoma of bone. Am J Pathol 1943; 1 9 553-589.
2. Barnes R, Catto M. Chondrosarcoma of bone. J Bone Joint Surg ( B r ) 1966; 48:729-764. 3. Mirra JM, Bone Tumors. Philadelphia: Lea & Febiger, 1989: 492. 4. Mirra JM, Gold R, Downs J, Eckardt JJ. A new histologic approach to the differentiation of enchondroma from chondrosarcoma of the hones. A clinico-pathologic analysis of 51 cases. Clin Orthop 1985; 201: 214-237. 5. Meachim G. Histological grading of chondrosarcomata. J Bone Joint Surg ( B r ) 1979;61: 393-394. 6 . Evans HL, Ayala AG, Romsdahl MM. Prognostic factors in chondrosarcoma of bone. A clinicopathologic analysis with emphasis on histological grading. Cancer 1977; 40:818-831. 7. Sanerkin NG, Gallagher P. A review of the behaviour of chondrosarcoma of bone. JBone Joint Surg ( B r ) 1979; 61: 395400. 8. Pritchard DJ, Lunke RJ, Taylor WF, Dahlin DC, Medley BE. Chondrosarcoma: a clinicopathologic and statistical analysis. Cancer 1980;45 149-157. 9. Mankin HJ, Cantley KP, Schiller AL, Lippiello L. The biology of human chondrosarcoma 11. Variation in chemical composition among types and subtypes of benign and malignant cartilage tumors. JBone JointSurg ( A m ) 1980;62: 176188. 10. Okajima K, Honda I, Kitagawa T. Immunohistochemical distribution of S-100 protein in tumors and tumorlike lesions of bone and cartilage. Cancer 1988; 61: 792-799. 1 1 . Wrba F, Gullick WJ, Fertl H, Amann G, Salzer-Kuntschik M. Immunohistochemical detection of the c-erbB-2 proto-oncogene product in normal, benign and malignant cartilage tissues. Histopathology 1989; 1 5 71-76. 12. Kreicbergs A, Boquist L, Borssen B, Larsson S-E. Prognostic factors in chondrosarcoma. A comparative study of cellular DNA content and clinicopathologic features. Cancer 1982; 5 0 577-583. 13. Mankin HJ, Connor JF, Schiller AL, Perlmutter N, Alho A, McGuire M. Gradingofbone tumors by analysis ofnuclear DNAcontent using flow cytometry. J Bone Joint Surg ( A m ) 1985; 67: 4 0 4 4 1 3 . 14. Xiang J, Spanier S S , Benson NA, Braylan RC. Flow cytometric analysis of DNA in bone and soft-tissue tumors using nuclear suspensions. Cancer 1987;5 9 1951-1958. 15. Vollmer E, Roessner A, Wuisman P, Harle A, Grundmann E. The proliferation behavior of bone tumors investigated with the monoclonal antibody Ki-67. In: Roessner A, ed. Current Topics in Pathology: 80: Biological Characterization of Bone Tumors. Heidelberg: Springer-Verlag, 1989; 91-1 14.
163: 93-94 (1 99 1)
EDITORIAL NEW DEVELOPMENTS IN THE DIAGNOSIS OF CHONDROSARCOMA Almost half a century has elapsed since chondrosarcoma was clearly distinguished from osteosarcoma by virtue of its different histology and anatomical location, older age distribution, and better prognosis.' Since then, a number of variants of chondrosarcoma have been separated. However, the diagnosis of conventional cartilage tumours remains one of the most difficult areas of bone tumour pathology, where particularly close co-operation between pathologist, radiologist, and orthopaedic surgeon is required.2 The pathologist examining a biopsy of a cartilaginous lesion must answer several questions. Is the lesion reactive or neoplastic? If neoplastic, is it benign or malignant? If malignant, is it likely to metastasize? If highly malignant and in a young patient, is the lesion a chondroblastic osteosarcoma masquerading as a chondrosarcoma? The clinical history and radiograph are usually helpful in answering the first and last questions. The difficulties lie in distinguishing between benign tumours and those of low-grade malignancy, and in predicting the behaviour of chondrosarcoma. There are three major problems. Firstly, the cytological features which allow a diagnosis of malignancy are often present in only a few fields, so there is a danger of underdiagnosis particularly in small biopsies. Secondly, the criteria of malignancy are ill defined even when the lesion is adequately sampled. Application of vague terms such as 'plump nuclei' and 'more than an occasional cell with two plump nuclei' is necessarily subjective. This lack of precision may be justified: it is said that the cytological features of benign and low-grade malignant tumours overlap in a quarter of cases3Lastly, the criteria vary depending on the anatomical site. Appearances which would support a diagnosis of low-grade malignancy in a central tumour of the pelvis can be safely ignored in a lesion of the tubular bones of the hands and feet or in a subperiosteal location. If a cartilage tumour permeates widely between pre-existing medullary trabeculae it can be regarded as malignant. How0022-341 7/91/02009342 $05.00 0 1991 by John Wiley & Sons, Ltd.
ever, this pattern is not present in all chondrosarcomas and is difficult to interpret in severely fragmented biopsies. Mirra et aL4 have described in detail the architectural patterns which aid in the distinction of benign and malignant cartilage tumours. This thoughtful paper should be read by all interested in the problem. The same difficulties of poorly defined criteria and subjective interpretation apply to the grading of chondrosar~oma.~ This is not surprising as chondrosarcoma may be considered to show a continuous spectrum of biological behaviour. Although criteria vary slightly in different grading systems, the histological grade correlates well with survival in large series,"* but the unpredictable nature of the lesions makes the prognosis in an individual patient difficult to determine. Over the past decade, attempts have been made to supplement histological assessment by other methods. An exhaustive study ofmultiple biochemical measurements, including protein, proteoglycan, DNA, and water content, of a series of 69 cartilage tumours failed to reveal any variable of help in predicting prognosis.' Increasing water content and alterations in proteoglycan chains were found with increasing malignancy, in keeping with the myxoid matrix more commonly seen in higher-grade tumours. A decrease in intensity of immunostaining for S- 100 protein in high-grade chondrosarcoma has been described, lo but in the absence of quantification seems unlikely to be of much prognostic value. Perhaps more encouraging is the demonstration of c-erbB-2 proto-oncogene expression in 18 of 23 chondrosarcomas stained with a polyclonal antibody raised to a synthetic peptide derived from the gene sequence." However, only nine benign tumours of hyaline cartilage were examined and one, an osteochondroma, also stained positively. Clearly many more cases need to be studied before the value of this technique in distinguishing benign from malignant tumours is established. Similarly, it will be important to determine whether the behaviour of
94
EDITORIAL
those chondrosarcomas which express this protooncogene differs from those which do not. Apart from the few high-grade tumours, chondrosarcomas are slow growing with scanty mitotic figures. Although there are considerable technical difficulties in dealing with poorly cellular tumours which are often mixed with hard tissues, investigation of cell proliferation in cartilage tumours has yielded interesting data. Cellular DNA content has been measured initially by microspectrophotometry and more recently by flow cytometr of cellular and isolated nuclear preparations.”-” As might be expected, a higher percentage of diploid cells is found in benign than in low-grade malignant tumours, and more aneuploid cells in high-grade than in low-grade chondrosarcoma.13 Unfortunately, these findings d o not allow clear separation of benign from malignant cartilage tumours.13 However, in Kreicbergs’s series the 10-year survival of patients with diploid tumours was better than that of patients with hyperploid tumours.12 This prognostic factor appeared to be independent of the histological grade, anatomical site, and treatment. Assessment of ploidy may therefore by a useful adjunct to conventional histological assessment. Quantification of cell proliferation has been revolutionized by the development of antibodies directed against antigens expressed during the active phases of the cell cycle. The need for fresh frozen tissue from these uncommon tumours has limited the number of cases studied with the monoclonal antibody Ki-67. In general, a higher proliferation index is found in chondrosarcoma, particularly of high grade, than in chondromas.” The recent development of antibodies which recognize proliferationassociated antigens in paraffin-embedded tissue should allow retrospective analysis of the large number of cases in bone tumour registry files. This may well prove to be the most useful new technique. These exciting and potentially valuable new approaches require further work and critical assessment. The results must be evaluated in large series
where details of the clinical stage and adequacy of surgical excision as well as the outcome are known. ROBINREID Scottish Bone Tumour Registry University Department of Pathology Western Infirmary Glasgow G116NT, U.K. REFERENCES 1. Lichtenstein L, Jaffe HL. Chondrosarcoma of bone. Am J Pathol 1943; 1 9 553-589.
2. Barnes R, Catto M. Chondrosarcoma of bone. J Bone Joint Surg ( B r ) 1966; 48:729-764. 3. Mirra JM, Bone Tumors. Philadelphia: Lea & Febiger, 1989: 492. 4. Mirra JM, Gold R, Downs J, Eckardt JJ. A new histologic approach to the differentiation of enchondroma from chondrosarcoma of the hones. A clinico-pathologic analysis of 51 cases. Clin Orthop 1985; 201: 214-237. 5. Meachim G. Histological grading of chondrosarcomata. J Bone Joint Surg ( B r ) 1979;61: 393-394. 6 . Evans HL, Ayala AG, Romsdahl MM. Prognostic factors in chondrosarcoma of bone. A clinicopathologic analysis with emphasis on histological grading. Cancer 1977; 40:818-831. 7. Sanerkin NG, Gallagher P. A review of the behaviour of chondrosarcoma of bone. JBone Joint Surg ( B r ) 1979; 61: 395400. 8. Pritchard DJ, Lunke RJ, Taylor WF, Dahlin DC, Medley BE. Chondrosarcoma: a clinicopathologic and statistical analysis. Cancer 1980;45 149-157. 9. Mankin HJ, Cantley KP, Schiller AL, Lippiello L. The biology of human chondrosarcoma 11. Variation in chemical composition among types and subtypes of benign and malignant cartilage tumors. JBone JointSurg ( A m ) 1980;62: 176188. 10. Okajima K, Honda I, Kitagawa T. Immunohistochemical distribution of S-100 protein in tumors and tumorlike lesions of bone and cartilage. Cancer 1988; 61: 792-799. 1 1 . Wrba F, Gullick WJ, Fertl H, Amann G, Salzer-Kuntschik M. Immunohistochemical detection of the c-erbB-2 proto-oncogene product in normal, benign and malignant cartilage tissues. Histopathology 1989; 1 5 71-76. 12. Kreicbergs A, Boquist L, Borssen B, Larsson S-E. Prognostic factors in chondrosarcoma. A comparative study of cellular DNA content and clinicopathologic features. Cancer 1982; 5 0 577-583. 13. Mankin HJ, Connor JF, Schiller AL, Perlmutter N, Alho A, McGuire M. Gradingofbone tumors by analysis ofnuclear DNAcontent using flow cytometry. J Bone Joint Surg ( A m ) 1985; 67: 4 0 4 4 1 3 . 14. Xiang J, Spanier S S , Benson NA, Braylan RC. Flow cytometric analysis of DNA in bone and soft-tissue tumors using nuclear suspensions. Cancer 1987;5 9 1951-1958. 15. Vollmer E, Roessner A, Wuisman P, Harle A, Grundmann E. The proliferation behavior of bone tumors investigated with the monoclonal antibody Ki-67. In: Roessner A, ed. Current Topics in Pathology: 80: Biological Characterization of Bone Tumors. Heidelberg: Springer-Verlag, 1989; 91-1 14.
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