Case 2 -
Chondroblastic Osteosarcoma with Focal Chondromyxoid Fibroma-like Features
John M. Hicks
Texas Children's Hospital and Baylor College of Medicine
Click on each slide thumbnail image for an enlarged view
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).
First Biopsy of Thigh Mass: Chondromyxoid Fibroma
Second Biopsy of Thigh Mass: Chondroblastic Osteosarcoma with Focal
Chondromyxoid Fibroma-like Features
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)
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.
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
The diagnostic imaging appearance usually shows a well-demarcated lytic expansile fusiform lesion;
however, almost 10% of CMFs have poorly defined outlines.
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.  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
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).
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.  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.  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
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
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).
The typical description of a CMF-like
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.
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.
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.
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.  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.
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%|
|Reactive New Bone Formation ||15%|
|Soft Tissue Extension ||31%|
|Infiltrative Pattern || 9%|
|Microcystic Liquefaction ||39%|
|Foam Cells || 2%|
|Chondroblastoma Areas ||8%|
|Aneurysmal Bone Cyst Areas ||9%|
Typical Histopathologic Features of CMF
|Low Mitotic Activity|
|Distinct Interface from Surrounding Bone|
|Condensation of Fibrous Tissue at Periphery|
Variable Histopathologic Features of CMF
|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|
|Chondroma ||Extra Copies of Chromosome 15|
Chromosome 6 structural abnormalities
|Osteochondroma ||8q22-24.1 (EXT1)|
|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 |
|Osteoblastoma ||No Nonrandom Aberrations|
|Conventional Osteosarcoma |
|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
Table 3 Osteosarcoma: Histopathologic Types
Unusual Subtypes of Conventional Osteosarcoma
Sclerosing Osteoblastic Osteosarcoma
Chondromyxoid Fibroma-like Osteosarcoma
Clear Cell Osteosarcoma
Malignant Fibrous Histiocytoma-like Osteosarcoma
Giant Cell Rich Osteosarcoma
Small Cell Osteosarcoma
Low Grade Central Osteosarcoma
High Grade Surface Osteosarcoma
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