Bone & Soft Tissue Pathology
Case 4 -
Antonio G. Nascimento
Click on each slide thumbnail image for an enlarged view
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
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.
June 15, 1993 – Left hip disarticulation
September 6, 1993 – Patient died of disease (lung and bone metastases)
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.  Subsequent reports have supported the concept that it as a
subtype of chondrosarcoma with distinct histologic features and clinical behavior when compared to
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.  Cytogenetic and molecular studies of both
components of dedifferentiated chondrosarcoma seem to support the theory of a single, common mesenchymal
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. 
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.
The development of dedifferentiated chondrosarcoma in
patients with multiple enchondromas (Ollier's disease} has also been described.
 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.  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
Patients generally complain of pain and/or swelling that have been present for months or years.
Pathologic fracture is a common presenting feature.
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. 
Many show features of chondrosarcoma or enchondroma but also have destructive changes and/or a soft
tissue mass that suggest the possibility of dedifferentiation.  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
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
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.
dedifferentiated portion contains a larger number of giant cells, simulating the appearance of giant cell
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
Treatment and prognosis
Treatment of dedifferentiated chondrosarcoma is surgical removal with wide margins.  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. 
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