Case 4 -

Dedifferentiated Chondrosarcoma Antonio G. Nascimento Mayo Clinic Rochester, MN

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Case History This case concerns a 60-year-old woman who was referred in June 1993 to Mayo Clinic for evaluation of pain in her left lower extremity. The pain was present for one year but became progressively worse in the last six months. It involved the whole left lower extremity but was particularly bad in the knee region. Plain x-rays showed a mineralized mass in her left distal femur. The patient was taken to the operating room on June 15, 1993 for open biopsy, frozen section diagnosis, and definitive surgical procedure. Case 4 - Figure 1 - X-rays of lytic lesion involving left distal femur. Note the stippled calcification that characterizes this lesion. Case 4 - Figure 2 - X-rays of lytic lesion involving left distal femur. Note the stippled calcification that characterizes this lesion. Case 4 - Figure 3 - Gross picture of dedifferentiated chondrosarcoma. In the medullary region, the lesion shows the classic glistening quality of well-differentiated chondroid tumor, while the extraosseous component is fleshy gray and firm. Case 4 - Figure 4 - These microscopic pictures show the biphasic quality of this neoplasm. Case 4 - Figure 5 - These microscopic pictures show the biphasic quality of this neoplasm. Case 4 - Figure 6 - These microscopic pictures show the biphasic quality of this neoplasm. Case 4 - Figure 7 - The chondroid component is highly differentiated and at most could be regarded as grade 1 chondrosarcoma. Case 4 - Figure 8 - The high-grade sarcomatous component is clearly associated with formation of brightly eosinophilic, osteoid matrix, characterizing an osteosarcomatous differentiation. Case 4 - Figure 9 - The high-grade sarcomatous component is clearly associated with formation of brightly eosinophilic, osteoid matrix, characterizing an osteosarcomatous differentiation. Case 4 - Figure 10 - The malignant cells in the high-grade sarcomatous component have an epithelioid shape showing round to ovoid nuclei, clumped chromatin, inconspicuous nucleoli and abundant, eosinophilic cytoplasm. The osteoid is laid down directly by the tumor cells. Case 4 - Figure 11 - The malignant cells in the high-grade sarcomatous component have an epithelioid shape showing round to ovoid nuclei, clumped chromatin, inconspicuous nucleoli and abundant, eosinophilic cytoplasm. The osteoid is laid down directly by the tumor cells. Case 4 - Figure 12 - The malignant cells in the high-grade sarcomatous component have an epithelioid shape showing round to ovoid nuclei, clumped chromatin, inconspicuous nucleoli and abundant, eosinophilic cytoplasm. The osteoid is laid down directly by the tumor cells. Clinical Follow-up June 15, 1993 – Left hip disarticulation September 6, 1993 – Patient died of disease (lung and bone metastases) Diagnosis Dedifferentiated Chondrosarcoma Discussion Introduction Dedifferentiated chondrosarcoma is a bimorphic malignant neoplasm of bone in which a well-differentiated chondrosarcoma is juxtaposed to a high-grade spindle cell sarcoma. It was first described in 1971 by Dahlin and Beabout. [1] Subsequent reports have supported the concept that it as a subtype of chondrosarcoma with distinct histologic features and clinical behavior when compared to conventional chondrosarcoma. [2, 3, 4] However, there has been some controversy over the concept of dedifferentiation itself and therefore usage of the term "dedifferentiated" to describe this entity. It has not been clear whether the low-grade chondrosarcomatous component and the high-grade sarcomatous component represent separate genotypic lineages (collision tumor theory} or whether both components are derived from a common precursor mesenchymal stem cell. [5] Cytogenetic and molecular studies of both components of dedifferentiated chondrosarcoma seem to support the theory of a single, common mesenchymal progenitor cell. [6, 7, 8] Not all genetic alterations have been shown to be shared, however, and it has been hypothesized that these alterations arise after the diversion of the two components and are later events in the histogenesis of dedifferentiated chondrosarcoma. [7] Incidence and location In all major series, dedifferentiated chondrosarcoma represents approximately 10% of all chondrosarcomas. Until the end of the year 2000, the Mayo Clinic files included 130 cases of dedifferentiated chondrosarcoma and 1,551 cases of chondrosarcoma of bone. They most commonly arise with central chondrosarcoma, but occasionally they occur as a dedifferentiated peripheral chondrosarcoma. Dedifferentiated chondrosarcoma has been reported as arising in solitary osteochondromas and in patients who have multiple osteochondromatoses. [9, 10, 11, 12, 13] The development of dedifferentiated chondrosarcoma in patients with multiple enchondromas (Ollier's disease} has also been described. [14] Of the 130 dedifferentiated chondrosarcomas in the Mayo files, 123 arose with central chondrosarcoma and 7 arose secondarily to peripheral chondrosarcoma (4 solitary osteochondromas, 1 with multiple osteochondromas, and 2 with periosteal chondrosarcoma). Two patients had Ollier's disease. The majority of patients are older adults, generally a decade older than those with conventional chondrosarcoma. The age range is wide, but approximately 70% are older than 50 years of age. [15] The sites of involvement are similar to those of conventional chondrosarcoma, that is, towards the axial skeleton. The majority of tumors involve the pelvis, the proximal femur, and the proximal humerus. Rare examples of dedifferentiated chondrosarcoma arising in uncommon sites such as the larynx have been reported. [16, 17] Clinical features Patients generally complain of pain and/or swelling that have been present for months or years. Pathologic fracture is a common presenting feature. Radiographic features The radiographic appearance of nearly all dedifferentiated chondrosarcomas suggests a high-grade sarcoma. They tend to be large tumors associated with cortical destruction and a soft tissue mass. [18] Many show features of chondrosarcoma or enchondroma but also have destructive changes and/or a soft tissue mass that suggest the possibility of dedifferentiation. [19] In some cases there are no features to suggest an underlying cartilaginous component. In others the radiographic appearance is simply that of conventional chondrosarcoma or rarely even enchondroma. MRI can be helpful in identifying the high-grade sarcomatous component and therefore aid in directing CT or ultrasound directed biopsies. [20, 21] Pathology The gross appearance of dedifferentiated chondrosarcoma may also be diagnostic. Typically, the central portion of the bone is filled with a characteristic pale blue cartilaginous material. Cystic change and myxoid change of the matrix may be seen. Juxtaposed to it is a fleshy tumor with the appearance of a soft tissue sarcoma. The chondroid area and the fleshy areas do not mingle. Occasionally, the fleshy area predominates and only focal nodules of cartilage are found. Very rarely, the tumor has the gross appearance of a chondrosarcoma and only microscopically will show the high-grade areas. The microscopic appearance of dedifferentiated chondrosarcoma is that of a well-differentiated chondrosarcoma juxtaposed to a high-grade spindle cell sarcoma. Typically there is an abrupt transition between the two components. The cartilage areas may have obvious features of malignancy or occasionally only borderline features of malignancy with an enchondroma-like appearance. However, in most examples the cartilaginous component will be diagnostic of a grade 1 chondrosarcoma and about 15% of tumors contain a grade 2 chondrosarcoma. The high-grade spindle cell sarcoma most frequently exhibits the histologic features of malignant fibrous histiocytoma, fibrosarcoma or osteosarcoma. Occasionally, rhabdomyoblastic, smooth muscle and even epithelial differentiation may be seen. [22, 23, 24, 25] Rarely, the dedifferentiated portion contains a larger number of giant cells, simulating the appearance of giant cell tumor. [26] Immunohistochemical studies demonstrate strong positive reactivity for S-100 protein within the cartilaginous areas. The diverse histologic patterns seen in the spindle cell component have been shown to react variably with several immunostains including actin, desmin, myoglobin, smooth muscle actin, alpha-1-antitrypsin, EMA, and keratin. The histologic differential diagnosis primarily includes chondroblastic osteosarcoma, mesenchymal chondrosarcoma, malignant fibrous histiocytoma, and metastatic sarcomatoid carcinoma. In chondroblastic osteosarcoma the chondroid areas are very malignant appearing and merge into a spindle cell malignancy. In dedifferentiated chondrosarcoma there is a sharp distinction between a reasonably well-differentiated chondrosarcoma and a high-grade spindle cell sarcoma. Moreover, the cartilaginous component in dedifferentiated chondrosarcoma is not as high-grade as what one typically sees in chondroblastic osteosarcoma. Mesenchymal chondrosarcoma also contains islands of cartilage and high-grade malignant tumor. However, in mesenchymal chondrosarcoma, the high-grade malignancy is represented by a small blue cell malignancy rather than the spindle cell sarcoma found in dedifferentiated chondrosarcoma. Small biopsy samples may be misinterpreted as malignant fibrous histiocytoma. In these cases, radiographic correlation may be helpful in identifying a cartilaginous component. The most common malignancy involving bone in the adult patient is metastatic carcinoma. If only the sarcoma portion of a dedifferentiated chondrosarcoma is obtained in a biopsy specimen, it would be possible to misdiagnose it as metastatic sarcomatoid carcinoma. This is particularly true in tumors where the sarcomatous component contains epithelioid areas. Radiographic correlation can help avoid this error. Keratin and EMA immunostains should be used with caution since focal reactivity may be seen in the sarcomatous areas of dedifferentiated chondrosarcoma. However, diffuse strong reactivity would favor metastatic carcinoma. Treatment and prognosis Treatment of dedifferentiated chondrosarcoma is surgical removal with wide margins. [27] The prognosis of these patients is dismal. The majority develops metastatic disease within one year of surgery and the five-year survival rate is less than 10%. These tumors respond very poorly to chemotherapy. The poor response of the high-grade component may reflect a unique biology as compared to other high-grade sarcomas that have responded better to drug regimens. In a recent review of 42 patients with dedifferentiated chondrosarcoma who were treated at the Mayo Clinic, the five-year survival rate was 4.8% with a median survival of 7.5 months. Twenty-seven of these patients received Neoadjuvant therapy. Overall, there was no statistical difference in disease-free survival with respect to the use of Neoadjuvant chemotherapy. [28] References Dahlin DC, Beabout JW. Dedifferentiated of low-grade chondrosarcomas. Cancer. 1971;23:461-6. Capanna R, Bertoni F, Bettelli G, et al. Dedifferentiated chondrosarcoma. J Bone Joint Surg Am. 1988;70-A:60-9. McCarthy EF, Dorfman HD. Chondrosarcoma of bone with dedifferentiation: a study of eighteen cases. Hum Pathol. 1982;13:36-40. Johnson S, Tetu B, Ayala AG, Chawla SP. Chondrosarcoma with additional mesenchymal component (dedifferentiated chondrosarcoma): I. a clinicopathologic study of twenty-six cases. Cancer. 1986;58-278-86. Aigner T, Unni KK. Is dedifferentiated chondrosarcoma a "de-differentiated' chondrosarcoma? J Pathol. 1999;189-445-7. Bovee JV, Cleton-Jansen AM, Rosenberg C, Taminiau AH, Cornelisse CJ, Hogendoorn PC. Molecular genetic characterization of both components of a dedifferentiated chondrosarcoma, with implications of its histogenesis. J Pathol. 1999;189:454-62. Bridge JA, DeBoer J, Travis J, et al. Simultaneous interphase cytogenetic analysis and fluorescence immunophenotyping of dedifferentiated chondrosarcoma: implications for histopathogenesis. Am J Pathol. 1994;144-215-20. Ropke M, Boltze C, Neumann HW, Roessner A, Schneider-Stock R. Genetic and epigenetic alterations in tumor progression in a dedifferentiated chondrosarcoma. Pathol Res Pract. 2003;199(6):437-44. Bertoni F, Present D, Bacchini P, Pignatti G, Gerlinzoni F, Companacci M. Dedifferentiated peripheral chondrosarcomas: a report of seven cases. Cancer. 1989;63:2054-59. Matsuno T, Ichiora Y, Yagi T, Ishii S. Spindle-cell sarcoma in patients who have osteochondromatosis: a report of two cases. J Bone Joint Surg Am. 1988;70:137-41. Kilpatrick SE, Pike EJ, Ward WG, Pope TL. Dedifferentiated chondrosarcoma in patients with multiple osteochondromatosis: a report of a case and review of the literature. Skeletal Radiol. 1997;26:370-74. Mirra JM. Clinical, radiologic and pathologic correlations in: Bone Tumors. Philadelphia PA, Lea & Febiger, 1989, pp 565-69. Scissions HA, Matlen JA, Lewis MM: Dedifferentiated chondrosarcoma. Report of an unusual case. J Bone Joint Surg. 1991;73-A:294-300. Sanerkin NG, Woods CG. Fibrosarcoma and malignant fibrous histiocytoma arising in relation to enchondromata. J Bone Joint Surg Br. 1979;61:366-72. Frassica FJ, Unni KK, Beabout JW, Sim FH. Dedifferentiated chondrosarcoma. A report of the clinicopathological features and treatment of seventy-eight cases. J Bone Joint Surg Am. 1986;68:1197-205. Garcia RE, Gannon FH, Thompson LD. Dedifferentiated chondrosarcomas of the larynx: a report of two cases and review of the literature. Laryngoscope. 2002 Jun;112(6):1015-8. Rinaggio J, Duffey D, McGuff HS. Dedifferentiated chondrosarcoma of the larynx. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2004 Mar;97(3):369-75. de Lange EE, Pope Jr TL, Fechner RE. Dedifferentiated chondrosarcoma: radiographic features. Radiol. 1986;161:489-92. Mercuri M, Picci P, Campanacci L, Rulli E. Dedifferentiated chondrosarcoma. Skeletal Radiol. 1995;24:409-16. MacSweeney F, Darby A, Saifuddin A. Dedifferentiated chondrosarcoma of the appendicular skeleton: MRI-pathological correlation. Skeletal Radiol. 203 Dec;32(12):671-8. Saifuddin A, Mann BS, Mahroof S, Pringle JA, Briggs TW, Cannon SR. Dedifferentiated chondrosarcoma: use of MRI to guide needle biopsy. Clin Radiol. 2004 Mar;59(3):268-72. Tetu B, Ordonez NG, Ayala AG, MacKay B. Chondrosarcoma with additional mesenchymal component (dedifferentiated chondrosarcoma). II. An immunohistochemical and electron microscopic study. Cancer. 1986;58:287-98. Dervan PA, O'Loughlin J, Hurson BJ. Dedifferentiated chondrosarcoma with muscle and cytokeratin differentiation in the anaplastic component. Histopathol. 1988;12:517-26. Wick MR, Siegal GP, Mills SE, Thompson RC, Sawhney D, Fechner RE. Dedifferentiated chondrosarcoma of bone: an immunohistochemical and lectin-histochemical study. Virchows Arch [A]. 1987;411:23-32. Reith JD, Bauer TW, Fischler DF, Joyce MJ, Marks KE. Dedifferentiated chondrosarcoma with rhabdomyosarcomatous differentiation. Am J Surg Pathol. 1996;20:293-8. Estrada EG, Ayala AG, Lewis V, Czerniak B, Valerie L. Dedifferentiated chondrosarcoma with a noncartilaginous component mimicking a conventional giant cell tumor of bone. Ann Diagn Pathol. 2003 Oct;7(5):336. Mitchell AD, Ayoub K, Mangham DC, Grimer RJ, Carter SR, Tillman RM. Experience in the treatment of dedifferentiated chondrosarcoma. J Bone Joint Surg Br. 2000 Jan;82(1):55-61. Dickey I, Rose PS, Fuchs B, Wold LE, Okuno SH, Sim FH, Scully SP. Dedifferentiated chondrosarcoma: The role of chemotherapy with updated outcomes. J Bone Joint Surg Am. 2004;86:2412-18.