Case 2 -

Chondromyxoid Fibroma Chondroblastic Osteosarcoma with Focal Chondromyxoid Fibroma-like Features John M. Hicks Texas Children's Hospital and Baylor College of Medicine Houston, TX

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Clinical History A 17-year-old Caucasian male presented to his local primary care physician with a complaint of right thigh pain that had recently increased in intensity. The pain was deep seated and would awaken him from his sleep. He had been using over the counter nonsteroidal anti-inflammatory medications to lessen the pain. He also expressed concern about a tender mass that he had first noticed about 6 months previously. It had recently increased in size. With further questioning by the primary care physician, the adolescent related that the onset of the discomfort began about 2 years ago following a knee sprain during a high school football game. Treatment had not been sought for this injury. Physical examination revealed a deep-seated firm right distal thigh mass that was tender to palpation and was not freely moveable. The soft tissue overlying the mass had increased warmth. The mass was believed to be contiguous with the underlying distal femur. The knee joint had a normal range of motion and was without excessive anterior-posterior or medial-lateral mobility. Diagnostic imaging studies found an eccentric mass arising within the right distal femur that appeared to have its epicenter within the metaphysis and crossed the epiphyseal plate. The mass was predominantly radiolucent with occasional areas of calcification. Sclerotic borders were not seen. The lesion expanded the cortex of the bone and gave the impression of soft tissue extension. The cortex was believed to be intact. The patient underwent a diagnostic biopsy of the mass by a local surgeon. Multiple portions of red-tan to white-blue tissue, that measured 1.6 x 0.9 x 0.6 cm in aggregate, were received by the local pathologist. Upon sectioning the tissue, it was noted that some portions of the tissue had a glistening surface, while others had a gritty texture. Following evaluation by the local pathologist, the case was sent for consultation. The adolescent was referred to an orthopedic surgeon. Based upon the histopathologic findings (Figures 1-3, Glass Slide 2A) and inconsistency with the diagnostic imaging results, additional tissue was obtained from the mass for further evaluation (Figures 4-7, Glass Slide 2B). Case 2 - Figure 1 - First biopsy of right thigh mass. The tumor is organized into a lobular architecture with a more cellular periphery and a less cellular center. The center has relatively abundant myxoid to chondroid matrix without a hyaline cartilage appearance. Case 2 - Figure 2 - First biopsy of the right thigh mass: The tissue within the periphery of a lobule is comprised of spindled cells, rare osteoclast-like giant cells and also contains a vascular network separating the adjacent lobules. Case 2 - Figure 3 - First biopsy of the right thigh mass: The center of a lobule is comprised of spindle to stellate cells with eosinophilic to amphophilic cytoplasm. These cells are embedded in a myxoid matrix. Mitotic activity is rarely seen. Case 2 - Figure 4 - Second biopsy of right thigh mass: Multiple portions of tissue were received and varied from white glistening to red-brown tissue with focal areas with a gritty consistency on cut sections. Case 2 - Figure 5 - Second biopsy of right thigh mass: This biopsy has a markedly different appearance compared with the first biopsy. The tumor is composed of markedly pleomorphic cells with a high nuclear to cytoplasmic ratio. The cells are embedded in a hyaline cartilage matrix and lie within lacunae. Case 2 - Figure 6 - Second biopsy of right thigh mass: There are areas with noncalcified osteoid production by the chondroblastic tumor cells. Case 2 - Figure 7 - Second biopsy of right thigh mass: Mitotic activity is readily seen within cellular areas of the tumor embedded in an eosinophilic myxoid matrix. These areas of the tumor were comprised of spindled to fusiform tumor cells that also formed osteoid matrix (not shown in this image). Final Diagnosis First Biopsy of Thigh Mass: Chondromyxoid Fibroma Second Biopsy of Thigh Mass: Chondroblastic Osteosarcoma with Focal Chondromyxoid Fibroma-like Features Discussion Bone lesions in childhood and adolescence may represent a variety of entities, such as osteoid osteoma, cortical fibrous defect (non-ossifying fibroma), osteochondroma, osteoblastoma, chondroblastoma, chondromyxoid fibroma, aneurysmal bone cyst, giant cell tumor, Langerhans cell histiocytosis and osteosarcoma. Typically, the clinical signs and symptoms, diagnostic imaging studies, clinical impression and the biopsy will provide a definitive diagnosis. The current case presents a very unusual circumstance in that the histopathologic features from the first biopsy of the thigh mass did not correlate well with the clinical presentation, diagnostic imaging and the orthopedic surgeon's impression. The first biopsy of the right distal thigh mass possessed histopathologic features characteristic for chondromyxoid fibroma. Chondromyxoid fibroma (CMF) [1, 2, 3, 4, 5, 6] is the least common bone tumor, representing between 0.5 to 2% of all bone tumors. It occurs in all age groups with an age range from 6 to 87 years, a mean age at presentation of 31 years, and a peak incidence in the second and third decades of life. There is a slight male predilection (1.3M:1.0F). This tumor involves a variety of sites, including long bones (47%), flat bones (30%), bones of the hands and feet (17%) and less frequently skull and facial bones (5%). The most common long bone sites are the proximal tibia (55%) and distal femur (19%). The ileum (45%) is a common flat bone site, and the bones of the foot (83%) are more often involved than those within the hand (17%). Most patients with CMF present with mild pain or gradually increasing localized pain. The pain may have been present for several years. [1, 2, 3, 4, 5, 6] Soft tissue swelling is not typically present, but may be seen more often with foot and hand tumors. Pathologic fractures have been reported in up to 5% of cases. The diagnostic imaging appearance usually shows a well-demarcated lytic expansile fusiform lesion; however, almost 10% of CMFs have poorly defined outlines. [1, 2, 3, 4, 5, 6] The typical CMF is eccentric and arises in the metaphysis with a peripheral rim of sclerotic bone surrounding the lesion. Occasional coarse radiodense trabeculations may be seen within the lesion. A periosteal reaction purportedly occurs only with pathologic fracture (2.6%). In a large study of 278 chondromyxoid fibromas collected over almost 90 years, the metaphysis alone was involved in two-thirds of tumors. [1] Both the metaphysis and epiphysis were involved in 14% of tumors, while 6% involved the diaphysis and metaphysis. The diaphysis alone was involved in 11% and 1% of tumors were epiphyseal only. Cortical thinning was noted in 90% of tumors, with the cortex being expanded in 85%. The cortex was considered to be absent in 50% of tumors. Periosteal new bone formation was noted in 8% of cases and Codman's triangles were seen in 8%. Soft tissue extension of the tumor was reported in almost 35% of cases. The characteristic lobular architecture of CMF [1, 2, 3, 4, 5, 6] provides the initial clue to this diagnosis (Table 1, Figures 1-3). The tumor is composed of lobules that have cellular peripheries and less cellular centers. The peripheries contain spindled cells and infrequent osteoclast-like giant cells. The lobules are separated from each other by fine fibrovascular cores with readily identified vessels. The centers of the lobules contain stellate to spindled cells embedded in a myxoid matrix. Mitotic activity is not prominent and atypical mitotic figures are not seen. Cytogenetics has shed some new insights into the pathogenesis of CMF (Table 2). [7, 8, 9, 10, 11, 12, 13, 14, 15, 16] Chromosome 6 abnormalities occur in a nonrandom fashion with CMF, in particular clonal aberrations involving 6q13 and 6q25. It is felt that these chromosomal changes may provide a novel diagnostic marker for CMF. A unique unbalanced translocation in CMF has been reported in which several bands from chromosome 3 (3p12-14) were lost and several bands from chromosome 6 (6q21-23) were rearranged. [10] Two well-known cartilage-related genes are located in the regions affected by this translocation. Type X collagen gene is located in the 6q21-23 region and the parathyroid hormone/parathyroid hormone-related peptide receptor (PTH/PTHrP) is located at 3p21.1-22. These genes participate in growth and maturation of endochondral bone formation. It is quite likely that dysregulation of this process by an unbalanced translocation could lead to a neoplastic process. 6q may also be the site of tumor suppressor genes and 6q deletion or loss of heterozygosity could result in loss of tumor suppressor gene function. [9] Both LOT-1 (zinc finger gene lost on transformation-1, 6q25) and AIM1 (absent in melanoma-1, 6q21) tumor suppressor genes are located on 6q. The long arm of chromosome 6 (6q) is also noted to be affected in chondromas, and chondrosarcomas (Table 2). [9, 14] It is possible that these genes or even other yet to be discovered genes on the long arm of chromosome 6 that regulate cartilage development and maturation may participate in cartilaginous tumor formation. The second biopsy of the right thigh mass, that was performed due to the inconsistency in the histopathologic diagnosis and clinical impression, demonstrated features of a chondroblastic osteosarcoma with some areas possessing focal chondromyxoid fibroma-like features (Figures 5-7). Although not a well known entity, chondromyxoid fibroma-like osteosarcoma is described as an unusual subtype of conventional osteosarcoma (Table 3). [1, 2, 3, 4, 5, 6, 17, 18] The typical description of a CMF-like osteosarcoma [1, 2, 3, 4, 5, 6, 17, 18] is that of a low-grade malignant tumor with a high degree of cellularity and pleomorphism, while maintaining a myxoid background for the most part. There is malignant osteoid production in association with the tumor cells and a brisk mitotic rate. The tumor, often times, is mistaken for a cellular atypical CMF or resembles a myxoid chondrosarcoma. Despite the designation of CMF-like osteosarcoma as low-grade, deaths and metastatic disease have occurred in about half of the reported cases. [17, 18] On the second biopsy from the present case (Figures 4-7), the tumor possessed features more consistent with a chondroblastic osteosarcoma, but did have a vague lobular pattern with the areas surrounding the ill-defined lobules composed of malignant osteoid formed by tumor cells. There were also regions with proliferating spindled to fusiform tumor cells embedded in an eosinophilic myxoid stroma. There was a high mitotic rate associated with these tumor regions. The spindled cell areas also produced an osteoid matrix. Chondromyxoid fibroma has been reported to undergo malignant transformation to other sarcomas or occur concomitantly with other sarcomas. [1, 2, 5, 6, 17, 18] This occurs in 1 to 2% of cases from CMF series. Of particular interest was the report of a grade 4 malignant fibrous histiocytoma that arose within a CMF lesion 5 months following initial diagnosis. No radiation therapy had been administered. The patient subsequently succumbed to metastatic disease. At autopsy, both characteristic features of CMF and malignant fibrous histiocytoma were present at the primary tumor site. In a separate case of malignant transformation associated with CMF, a high-grade fibrosarcoma developed in the proximal tibia 6 years following partial curettage and radiotherapy of a histopathologically proven CMF lesion. Transformation of CMF to chondrosarcoma has also been reported in the absence of radiotherapy. The relationship between CMF and CMF-like osteosarcoma and other bone tumors may be linked to clonal abnormalities associated with the long arm of chromosome 6. [7, 8, 9, 10, 11, 12, 13, 14, 15, 16] Although osteosarcomas have complex karyotypes with numerous cytogenetics abnormalities, certain chromosomal losses are seen commonly (Table 2). The most common chromosomal losses are 2q, 3p, 6q, 8p, 9, 10p, 13q, 17p and 18q. The long arm of 6q is lost frequently in osteosarcoma and may be important in tumor development, similar to its role in CMF tumorigenesis. A recent cytogenetic and molecular study of conventional osteosarcoma has shown nonrandom and frequent abnormalities in chromosome 6p12-21. [16] Candidate genes in this region include HSP90, CDC5L and VEGF. This region is also in close proximity to the 6p23-25 region that has structural abnormalities in CMF. [9, 14] It will be interesting to determine whether loss of 6q, loss of heterozygosity of 6q or other chromosome 6 abnormalities are more common findings in chondroblastic osteosarcoma compared with other types of osteosarcomas. The unique nature of the current case demonstrates the necessity to perform additional biopsy procedures in order to resolve discrepancies among the clinical signs and symptoms, diagnostic imaging findings, clinical impressions and the histopathologic findings. Although quite rare, chondromyxoid fibroma may transform to or occur concomitantly with other sarcomas. Table 1: Chondromyxoid Fibroma: Histopathologic Features Lobular Pattern   Macrolobular 46% Microlobular 20% Both Macrolobular and Microlobular 23% Absence of Lobular Pattern 13% Hyaline Cartilage 19% Osteoclast-like Giant Cells 57% Nuclear Pleomorphism 18% Mitotic Activity 11% Calcifications 35% Reactive New Bone Formation 15% Soft Tissue Extension 31% Infiltrative Pattern 9% Necrosis 12% Microcystic Liquefaction 39% Foam Cells 2% Chondroblastoma Areas 8% Aneurysmal Bone Cyst Areas 9% Typical Histopathologic Features of CMF Lobularity Myxoid Matrix Low Mitotic Activity Distinct Interface from Surrounding Bone Condensation of Fibrous Tissue at Periphery Variable Histopathologic Features of CMF Microcystic Degeneration Focal Matrix Calcification Osteoclast-like Giant Cells Ancient Changes (degenerative nuclear features) Histopathologic Features Inconsistent with CMF Diagnosis Intermediate to High Mitotic Activity Extensive Hyaline Cartilage Infiltrative (permeative) Growth Atypical or Bizarre Mitotic Figures Extensive Osteoid or Bone Productio Table 2: Cytogenetics in Cartilaginous Bone Tumors Chondromyxoid Fibroma 6q13-21 rearrangement 6q12-15 rearrangement 6q23-27rearrangement 6p23-25 rearrangement Inversion (6)(p25q13) Translocation (3;6)(p12-14,21;q21-24) Chondroma Extra Copies of Chromosome 15 Chromosome 6 structural abnormalities 12q13-15 Rearrangement Osteochondroma 8q22-24.1 (EXT1) 11p11-12 (EXT2) 19p (EXT3) Chondroblastoma Ring Chromosome 4 Chromosome 5 and 8 abnormalities CHUMP (Chondroid Tumor of Undetermined Malignant Potential) Normal Karyotypes Chondrosarcoma Complex Karyotypes Abnormalities:1, 6q, 8q, 9, 12q13-15,15 Extraskeletal Myxoid Chondrosacoma Translocation (9;22)(q22;q12) (EWS-NR4A3) Translocation (9;17)(q22;q11) (RBP56-NR4A3) Translocation (9;15)(q22;q21) (TCF12-NR4A3) Osteoid Osteoma 22q13 Abnormality Deletion 17q Osteoblastoma No Nonrandom Aberrations Conventional Osteosarcoma Complex Karyotypes Loss of 2q, 3p, 6q, 8p, 9, 10p, 13q, 17p, 18q Loss of Heterozygosity: 3q,13q,17p,18q Gains: 3q26,4q12-13, 5p13-14, 7q31-32, 8q21-23,12q12-13, 12q14-15, 17p-11-12 Structural Abnormalities: 1p11-13, 1q11-12, 1q21-22, 6p12-21,11p14-15, 14p11-13, 15p11-13, 17p, 17p11.2, 19q13 Parosteal Osteosarcoma Supernumerary Ring Chromosomes Gain 12q13-15 Table 3 Osteosarcoma: Histopathologic Types Conventional Osteosarcoma Osteoblastic Chondroblastic Fibroblastic Unusual Subtypes of Conventional Osteosarcoma Sclerosing Osteoblastic Osteosarcoma Osteoblastoma-like Osteosarcoma Chondromyxoid Fibroma-like Osteosarcoma Chondroblastoma-like Osteosarcoma Clear Cell Osteosarcoma Malignant Fibrous Histiocytoma-like Osteosarcoma Giant Cell Rich Osteosarcoma Epithelioid Osteosarcoma Telangiectatic Osteosarcoma Small Cell Osteosarcoma Low Grade Central Osteosarcoma Parosteal Osteosarcoma Periosteal Osteosarcoma High Grade Surface Osteosarcoma Secondary Osteosarcoma References Wu, CT, Inwards CY, O'Laughlin S, Rock MG, Beaboat JW, Unni KK: Chondromyxoid Fibroma of Bone: A Clinicopathologic Review of 278 Cases. 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