Definitions of Osteosarcoma, Chondrosarcorna, and Fibrosarcoma of Bone N. G. SANERKIN, MD* The current definition of osteosarcoma, based on the presence of tumor osteoid, is unsatisfactory because it fails to identify wme examples of chondroblastic, fibroblastic, and anaplastic osteosarcoma having no demonstrable tumor osteoid. The tumor cells in osteosarcoma, whether osteoblastic, chondroblastic, fibroblastic, or anaplastic, contain abundant alkaline phosphatase, whereas this enzyme is scanty or absent in condrosarcoma and fibrosarcoma. It is therefore proposed that these bone sarcomas are best defined according to the origin of the constituent tumor cells and their alkaline phosphatase content: osteosarcoma-a malignant tumor of osteoblasts (alkaline phosphatase positive); chondrosarcomaa malignant tumor of chondroblasts (alkaline phosphatase negative); and fibrosarcoma-a malignant tumor of fibroblasts (alkaline phosphatase negative). Cancer 46:178-185, 1980. HE CURRENT INTERNATIONAL DEFINITIONS Of T osteosarcoma, chondrosarcoma, and fibrosarcoma,2~4~7~10~12 based on the presence or absence of tumor osteoid in histologic sections, provide a major stumbling block to their proper understanding and diagnosis. When tumor osteoid is present, the diagnosis of osteosarcoma is beyond question. However, tumor osteoid may be absent in some examples of osteosarcoma, either in the biopsy sample or throughout the entire tumor. The search for osteoid then becomes a massive and frustrating task and one may finally be forced to call an osteosarcoma by some other name, such as fibrosarcoma, chondrosarcoma, unspecified sarcoma, or anaplastic sarcoma, depending on its precise histomorphologic structure. Cytochemistry or histochemistry for the demonstration of alkaline phosphatase will facilitate the diag- From the Department of Osteo-articular Pathology, Bristol Royal Infirmary, Bristol, United Kingdom. * Consultant in Osteo-articular Pathology and Hon. Secretary, Bristol Bone Tumor Registry, Bristol Royal Infirmary. Address for reprints: Dr. N. G. Sanerkin, Department of Osteoarticular Pathology, Bristol Royal Infirmary, Bristol, United Kingdom. The author thanks the very numerous colleagues who have referred their cases to the Bristol Bone Tumour Registry with clinical, radiologic, and pathologic material, Dr. G. M. Jeffree for helpful criticism, Messrs. M. Findlay and A. Wilson for technical and photographic assistance, and Mrs. J. N. Nutt for secretarial help. Accepted for publication June 27, 1979. nosis of these sarcomas and should form an indispensable part of their pathologic investigation and ultimate definition-alkaline phosphatase is abundantly present in osteosarcoma, and absent or scanty in chondrosarcoma and fibrosarcoma. In this report, our routine investigative approach to the study and diagnosis of these sarcomas is described and new definitions are proposed based on the origin of the constituent tumor cells and their alkaline phosphatase content. Materials and Methods Systematic study of enzyme histochemistry and cytochemistry of bone tumors has been undertaken in this laboratory for about 20 years5 and alkaline phosphatase preparations, either on smears or on cryostat sections, are available from 47 examples of osteosarcoma, 29 of chondrosarcoma, and 18 of fibrosarcoma. Alkaline phosphatase preparations are made by the diazo technique of Burstone on smears or cryostat sections from fresh unfixed tumor tissue. In this laboratory, we have come to prefer the use of smears because these are easy to prepare and are also used for the study of cytomorphologic detail after staining with a variety of routine stains, including hematoxylin and eosin (H & E) and Taylor s blue.13 Paraffin sections are stained routinely with H & E and any other stain necessary, such as Taylor s blue 0008-543X/80/0701/0178 $0.90 0 American Cancer Society 179
No. 1 DEFINITIONS OF BONE SARCOMAS. Sanerkin 179 FIG. 1. Smear from chondroblastic osteosarcoma. Tumor cells contain abundant alkaline phosphatase in their cytoplasm, partly overlying and obscuring the nuclei. There is much background staining due to release of enzyme from ruptured cells during smearing process. With colour photography, enzyme would show as red, nuclei as blue, both appear black in monochrome (alkaline phosphatase preparation, ~960). for the demonstration of metachromatic chondroid or myxoid matrix. Although ultrathin sections have also been prepared in the recent years, it is not felt that electron microscopy has any useful role in the diagnosis and categorization of osteosarcoma, chondrosarcoma, or fibrosarcoma. In this report, the term cytomorphology will refer specifically to the appearance of tumor cells in smeared preparations, not in histologic sections. The term osteosarcoma will refer to conventional examples of that tumor, exclusive of low-grade types such as parosteal osteosarcoma. Cytomorphology Results It is not the intention in this report to describe in detail the cytomorphologic characteristics of these sarcomas; these will be dealt with elsewhere.x It is our experience, however, that bone sarcomas may be cytologically diagnosed with full confidence and reliability. Low-grade and medium-grade chondrosarcomas have a characteristic cytomorphology8~9 which cannot be confused with high-grade chondrosarcoma or chondroblastic osteosarcoma. Low-grade fibrosarcoma shows nonpleomorphic fusiform cells which are larger than those of reactive fibroblastic proliferations or of the fibromatoses, but cannot be confused with those of higher grade fibrosarcomas or fibroblastic osteosarcoma. Osteosarcoma cannot be distinguished on cytomorphologic criteria alone from high-grade chondrosarcoma or fibrosarcoma, with one exception. Osteoblastic osteosarcoma can be so identified because the sarcoma cells still retain their characteristic osteoblastic features. Enzyme Cytochemistry und Histochemistry All osteosarcoma cells, whether morphologically osteoblastic, chondroblastic, fibroblastic, or ana-
180 CANCER July 1 1980 Vol. 46 FIG. 2. Cryostat section from chondroblastic osteosarcoma. Tumor cells all contain abundant alkaline phosphatase, shown black in monochrome, ringing the nuclei. Clear intercellular spaces represent cartilage matrix (alkaline phosphatase preparation, x 240). plastic, contain abundant alkaline phosphatase. By contrast, this enzyme is scanty or absent in chondrosarcoma and fibrosarcoma. For diagnostic purposes, it is immaterial whether alkaline phosphatase is demonstrated in cytologic smears or cryostat sections (Figs. 1-3). Histomorphology Although a confident definitive diagnosis can be made on the basis of cytomorphologic appearance in conjunction with enzyme cytochemistry or histochemistry, paraffin sections remain an essential element in the study of these tumors. Histologic examination reveals the tissue structure and organization, type and extent of matrix formation, and the behaviour of tumor in relation to the host tissues, such as the infiltration or destruction of normal structures and permeation of vascular channels. It thus complements and augments the information gained from cytomorphologic and enzyme studies. Such a complementary cytologic, cytohistochemical, and histomorphologic study provides the following significant information about these sarcomas: Malignant osteoblasts retain their enzyme characteristics, i.e., are alkaline phosphatase positive, although cytomorphologically and functionally they may undergo deviation or metaplasia from the expected line of differentiation. Osteoblastic osteosarcoma cells deviate least, retaining their characteristic morphologic and functional features, i.e., they look like osteoblasts and produce osteoid. Chondroblastic osteosarcoma cells deviate or undergo metaplasia along chondroblastic lines; they look like cartilage cells and lay down matrices which may be chondroid, chondrosteoid, or myxoid. They nevertheless retain their enzymatic character and contain alkaline phosphatase (Figs. 1, 2). Fibroblastic osteosarcoma cells deviate or undergo metaplasia along fibroblastic lines, look like fibroblasts, and lay down matrices which may be collagenous or intermediate between collagen and osteoid (fibroosteoid), without losing their potential for producing alkaline phosphatase (Fig. 3). Anaplastic osteosarcoma cells do not differentiate or undergo metaplasia along the above lines, do not
No. 1 DEFINITIONS OF BONE SARCOMAS. Sanerkin 181 FIG. 3. Cryostat section from fibroblastic osteosarcoma. Tumor cells contain abundant alkaline phosphatase. In monochrome, both nuclei and enzyme appear black, so it is difficult to make out nuclear detail. Staining of enzyme highlights the fusiform shape of the tumor cells (alkaline phosphatase preparation, X 380). produce osteoid, chondroid, or collagenous matrix, but retain their capacity for producing alkaline phosphatase. In any given osteosarcoma, some or all of the above varieties of malignant osteoblast may be found to a greater or lesser degree. The final designation of an osteosarcoma as predominantly osteoblastic, chondroblastic, fibroblastic, or anaplastic will depend on the predominance of a particular cell type. Equally, any of these cell types may be absent in a given osteosarcoma. Absence of osteoblastic osteosarcoma cells will result in absence of tumor osteoid, in which case the osteosarcoma will be exclusively chondroblastic, fibroblastic, anaplastic, or a mixture of these. High-grade chondrosarcomas cannot be distinguished, either cytomorphologically or histologically, from chondroblastic osteosarcoma in which tumor osteoid is absent, but can be identified by the absence or sparsity of alkaline phosphatase (Figs. 4, 5). Fibrosarcoma is a spindle celled or pleomorphic tumor which is distinguished from fibroblastic or anaplastic osteosarcoma by the absence or sparsity of alkaline phosphatase in the tumor cells (Figs. 6, 7). Discussion Review of bone tumors in any large collection will show a fair proportion of bone sarcomas which are almost certainly osteosarcomas but which, in the absence of demonstrable tumor osteoid, have been labeled as chondrosarcoma, fibrosarcoma, spindle cell sarcoma, unspecified or pleomorphic sarcoma, or giant cell sarcoma. Inevitably, most of this material is represented by paraffin sections alone, but over the past 20 years, we have done histochemical and cytochemical studies of representative examples of such cases in which alkaline phosphatase has been demonstrable, indicating their osteosarcomatous character. Chondroblastic osteosarcomas devoid of tumor osteoid are diagnosed as chondrosarcoma or unspecified bone sarcoma, usually with an explanatory remark that the diagnosis of osteosarcoma had been considered and dismissed because of the failure to demonstrate tumor osteoid. Almost without exception, these tumors are in children and adolescents, with all the classic radiologic features of chondroblastic osteosarcoma including rapid clinical progression and
182 CANCER July 1 1980 Vol. 46 FIG. 4. Smear from high-grade chondrosarcoma. Binucleate tumor cell containing no alkaline phosphatase. With colour photography, cytoplasm would show as pale blue, nuclei as blue, (alkaline phosphatase preparation, ~960). dismal prognosis with a very high metastatic risk. I believe that they would all have been proven to be osteosarcomas if enzyme cytochemistry or histochemistry had been performed. Their designation as chondrosarcomas, especially when, as is usually the case, they are not specified as high-grade chondrosarcomas, is most unfortunate and might conceivably lull the surgeon into a false sense of security, resulting in treatment less aggressive than warranted by osteosarcoma. There might be no real harm in calling them high-grade chondrosarcomas provided it is fully appreciated that they will behave just as badly, and necessitate as radical a treatment, as chondroblastic osteosarcoma. It is, nevertheless, far more preferable to establish their true osteosarcomatous nature by enzyme cytochemistry or histochemistry and to avoid a too rigid and misleading reliance on the absence of tumor osteoid. Fibroblastic osteosarcoma labeled as fibrosarcoma or spindle cell sarcoma carries less risk of undertreatment than chondroblastic osteosarcoma labeled chondrosarcoma. But again, it is preferable that a firm diagnosis should be established by enzyme cytochemistry or histochemistry. Special varieties of anaplastic osteosarcoma include one with an overabundance of giant tumor cells with huge or multiple nuclei, one with an overabundance of osteoclasts (osteoclast-rich osteosarcoma) and telangiectatic osteosarcoma. In all these, osteoid is absent or scanty, but alkaline phosphatase is abundant. Nevertheless, telangiectatic osteosarcoma has a characteristic histomorphology and its diagnosis can be established without enzyme tests being undertaken, even in the total absence of tumor osteoid. It should be explained that, in addition to osteosarcoma, liposarcoma and angiosarcoma may contain alkaline phosphatase in the tumor cells. Nevertheless, these two tumors are extremely rare in bone. For all practical purposes, an alkaline-phosphatase-positive sarcoma in bone can be accepted as osteosarcoma until proven to be a liposarcoma or angiosarcoma by histomorphologic examination. Chondrosarcoma is almost exclusively a tumor of adults which, as a generic group, is a more slowly
No. I DEFINITIONS OF BONE SARCOMAS. Sanerkin 183 FIG. 5. Cryostat section from high-grade chondrosarcoma. Tumor cells do not contain alkaline phosphatase, hence the pale staining-nuclei are not rimmed by enzyme staining. Several small blood vessels stand out prominently because endothelial cells contain alkaline phosphatase (alkaline phosphatase preparation, x 240). progressive and less lethal than osteosarcoma, but this is not true of high-grade chondrosarc~ma~~~ which has a metastatic potential as high as osteosarcoma of the adult patient. Likewise, the prognosis of fibrosarcoma (excluding the well differentiated type) does not materially differ from that of osteosarcoma.6 Accordingly, for practical purposes of prognosis and treatment, a simplistic approach might eventually decline to split high-grade sarcomas into subgroups. In the meantime, cytochemical or histochemical examination should be routinely undertaken for the demonstration of alkaline phosphatase in order to facilitate the diagnosis and better understanding of these sarcomas. The surgeon should assist in this by submitting tumor material in the fresh unfixed state, because enzyme studies cannot be undertaken on formalin-fixed material. It is also recommended that these sarcomas be defined according to the origin of the constituent tumor cells and their alkaline phosphatase content: Osteosarcoma: A malignant tumor of osteoblasts, in which the tumor cells contain abundant alkaline phosphatase irrespective of whether tumor osteoid is present or absent. Chondrosarcoma: A malignant tumor of chondroblasts, in which the tumor cells contain scanty or no alkaline phosphatase. Fibrosarcoma: A malignant tumor of jibroblasts, in which the tumor cells contain scanty or no alkaline phosphatase. A final comment must be made about malignant mesenchymoma, the only recognized example of which is one containing osteosarcomatous and liposarcomatous elements.'' Composite tumors might also exist as additional examples of malignant mesenchymoma, with osteosarcomatous, fibrosarcomatous, or chondrosarcomatous elements, but proof of these would be impossible on histomorphologic grounds alone. Unfortunately, our enzyme studies have hitherto been limited to single samples taken at random from a given tumor. Much wider sampling from different areas of the tumor might help to clarify this question.
FIG. 6. Cryostat section from fibrosarcoma. No alkaline phosphatase in tumor cells-nuclei stand out sharply, cytoplasm pale without black granules. One or two positively stained cells are probably endothelial cells cut tangentially (alkaline phosphatase preparation, x 380). FIG. 7. Smear from fibrosarcoma (same case as in Fig. 6). No alkaline phosphatase in fusiform tumor cells. Because enzyme is absent, nuclei stand out sharply, cytoplasm stains pale (alkaline phosphatase preparation, X960).
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