Lesions Characterized by Cartilage Deposition and Nonaggressive/Intermediate Radiology

Definition and Synonyms

Chondroblastoma is a benign cartilage-forming neoplasm occurring in the epiphyses of immature long bones.

Brief Historical Overview

Chondroblastoma was originally called a “calcifying giant cell tumor” by Ewing and “epiphyseal chondromatous giant-cell tumor” by Codman. In 1942, Jaffe and Lichtenstein recognized this entity as distinct from the so-called giant cell tumor variants under the name “benign chondroblastoma.”

Incidence and Demographics

Chondroblastoma is relatively uncommon; it accounts for less than 1% of all bone tumors and is approximately one fifth as common as a giant cell tumors. The peak incidence is between 10 and 25 years of age. The male-to-female ratio varies depending on the study (1.4 : 1 to 2 : 1).

Cases involving the skull or temporal bone are more common in patients in their 40s and 50s.

Localization and Clinical Manifestations

Typically, chondroblastoma occurs in the epiphyses of the long bones in skeletally immature patients. Although it typically arises at the end of the major tubular bones, chondroblastoma can also originate at a secondary ossification center, such as the greater trochanter. More than 75% of cases develop at the epiphyseal and epimetaphyseal region of the distal and proximal femur, proximal tibia, and proximal humerus. Chondroblastoma can also occur at epiphyseal equivalent sites in flat bone, such as the acetabulum and iliac crest. Rarely, chondroblastoma may arise in the patella, calcaneus, or other tarsal bones. Cases involving the craniofacial bone can be found in the base of the skull and temporal bone.

Occasional cases of multifocal synchronous chondroblastoma have been reported. Chondroblastoma has almost never been found in the spine.

The typical clinical presentation is localized pain that may occur as a single incident or as prolonged episodes lasting several months or years. In addition, patients may also suffer from swelling, gait disturbances, and joint stiffness. Tumors of the knee joint may present with effusion. In the temporal bone, tumoral invasion can cause difficulty hearing, tinnitus, or vertigo.

On physical examination, patients have tenderness in the affected area along with limitation of motion and muscular atrophy.

Radiologic Features and Gross Pathology

Chondroblastoma is usually located in the medullary portion of bone and arises either at the epiphysis or apophysis of long tubular bones. Extension to the metaphysis can be seen at times. Size is usually less than 5 to 6 cm. Conventional radiographs typically demonstrate well-defined, geographic bone destruction with either a spherical or an oval shape ( Fig. 9-1A ). There are amorphous calcific foci within the lesion. In rare cases, extensive calcifications can be seen. The lesion has a marginal sclerotic rim on plain radiography, and it shows expansion of the cortex with a periosteal reaction in cases of extension into the cortex. However, pathologic fracture is uncommon. In a typical case, the contour of the involved bone is not usually changed.

On magnetic resonance imaging (MRI), chondroblastoma shows low signal intensity on T1-weighted images and variable signal intensity on T2-weighted images (see Fig. 9-1B and C ). Sometimes, the lesion shows perilesional high signal intensity on T2-weighted images, indicating inflammatory or edematous changes.

Grossly, chondroblastoma appears as fragments of soft pink to gray tissue with occasional zones of hemorrhage and calcification. Small cystic spaces are common; occasionally, the cystic change is so prominent that aneurysmal bone cyst is suspected. On rare occasions, the boundary of the resected specimen is well delineated and a sclerotic rim is observed.

Histopathology

The predominant cell is the chondroblast, which is a uniform, round to polygonal cell with a well-defined cytoplasmic border. The cytoplasm ranges from pink to focally clear ( Fig. 9-2 ). The nucleus is located in the central portion of the cytoplasm and is oval to round with one to two inconspicuous nucleoli. A longitudinal groove is typical, accounting for the so-called “coffee bean” appearance.

The chondroblasts are usually packed in pseudolobulated sheets with a random distribution of multinucleated giant cells with 5 to 40 nuclei ( Fig. 9-3 ). Another diagnostic clue is immature chondroid matrix that appears as variably sized nodules composed of lightly staining, amorphous, bluish to eosinophilic material surrounded by chondroblasts ( Fig. 9-4 ). Mature hyaline cartilage is very rarely present. Ossification can occur; however, if there is abundant ossification, a diagnosis of osteoblastoma should be considered. Prominent ossification is more commonly observed in talus and calcaneus lesions. Fine networks of pericellular calcification, often called “chicken wire calcification,” are found around the degenerating tumor cells ( Fig. 9-5 ). Mitotic activity is usually minimal, and atypical figures are rare. Frequently, individual chondroblasts can show considerable cytologic atypia such as enlarged, irregular, and hyperchromatic nuclei. This finding is not indicative of aggressive behavior and has no impact on patient prognosis.

Focal spindle cell change can be seen in chondroblastoma and expands the differential diagnosis to include lesions with divergent pathways of differentiation or, more often, chondromyxoid fibroma. Brown to yellow granular pigment that is positive on iron stain is frequently observed in chondroblastoma of the skull and can be very helpful in arriving at the correct diagnosis. Secondary aneurysmal bone cystic change is present in about 15% of chondroblastoma cases. Usually, these cystic changes are appreciated as microscopic cystic changes; however, occasionally, this secondary cystic change is very pronounced and the chondroblastoma itself is only present as a mural nodule.

On electron microscopic examination, chondroblasts show deep indentation of the nuclear membrane, abundant rough endoplasmic reticulum and long cytoplasmic processes. These findings are quite characteristic for fetal chondroblasts.

Differential Diagnosis

The major differential diagnoses are giant cell tumor of bone, chondromyxoid fibroma, clear cell chondrosarcoma, and osteosarcoma.

Although both chondroblastoma and giant cell tumor of bone are epiphyseal lesions, most giant cell tumors develop in skeletally mature patients, in contrast to chondroblastoma. Furthermore, radiographic analysis of chondroblastoma shows a more distinct delineation than giant cell tumor of bone, which typically lacks a reactive sclerotic margin. Histologically, the mononuclear cells in giant cell tumor of bone lack the characteristic nuclear groove seen in chondroblastoma. “Chicken wire calcifications” and chondroid matrix are also lacking in giant cell tumor of bone.

Chondromyxoid fibroma develops in a similar age group as chondroblastoma; however, chondroblastoma occurs mostly at the epiphysis of long bones, whereas chondromyxoid fibroma develops in the metaphysis of long bones. Histologically, the lesional cells in chondromyxoid fibroma tend to have a more spindled to stellate appearance in contrast to the round to polygonal cells of chondroblastoma. The characteristic calcification pattern in chondroblastoma is not observed in chondromyxoid fibroma.

In older patients, clear cell chondrosarcoma enters the radiologic differential diagnosis because it is typically a well-circumscribed lytic lesion with sclerotic margins at the end of a long bone. Histologic evaluation shows obviously malignant chondrocytes and large cells with clear cytoplasm often in a background of ossified bone.

On very rare occasions, osteosarcoma can mimic chondroblastoma and such examples have been called “chondroblastoma-like osteosarcoma.” However, in these cases, there is marked diffuse cytologic atypia, areas of osteoid and, often, focal permeation of the atypical cells through the surrounding trabecular bone.

Ancillary Diagnostic Studies

Immunohistochemically, the mononuclear cells of chondroblastoma express S-100 protein and vimentin. In addition, there are a few reports of them expressing cytokeratin.

The chondroblasts generally express SOX-9 and cellular areas of chondroblastoma express DOG1. Osteoprotegerin is highly expressed in the stromal cells of chondroblastoma.

Genetics

According to flow cytometry studies, most chondroblastomas are diploid with low proliferative fractions. However, there are some lesions reported with near diploid “aneuploid cells.” Clonal abnormalities have been described in several benign and one aggressive chondroblastoma. Chromosomal structural abnormalities involving chromosomes 5 and 8 have also been reported.

The CORS-26 (collagenous repeat containing sequence of the 26-kDa protein) gene has been localized to the short arm of chromosome 5. CORS-26 mRNA is strongly expressed in chondroblastoma, and this gene may play a significant role in the pathogenesis of chondroblastoma. Romeo et al. reported higher levels of the cartilage growth plate signaling molecules PTHHR1, BCL2, and FGFR-3 in chondroblastoma. These findings suggest that chondroblastoma is a neoplasm that originated from a mesenchymal cell committed toward chondrogenesis via active growth plate signaling pathways. Chondroblastoma associated with joint inflammation shows considerably increased cyclooxygenase-2 expression. Superoxide dismutase 1, acid phosphatase, and 5-tartrate resistant cathepsin K, which are expressed in osteoclastic giant cells, are more highly expressed in chondroblastoma. In addition, versican and perlecan expression has been shown to be significantly down-regulated in chondroblastoma. However, the clinical significance of these changes is subject to further investigation. P.Lys36Met alterations predominantly encoded in H3F3B , which is one of the two genes for histone H3.3, were found in 95% of chondroblastoma. The mutations were restricted to the stromal cells and not seen in the giant cells.

Treatment and Prognosis

Most chondroblastomas are appropriately treated by curettage with or without bone graft. Recurrences, which are typically treated by curettage, occur in 6% to 15% of cases. Local recurrence occurs more commonly in flat bones as opposed to long bones; in the temporal bone, approximately 50% of cases recur.

On rare occasions, chondroblastoma grows or recurs so aggressively that the bone is destroyed; in such cases, resection may be indicated. The clinical term “aggressive chondroblastoma” may be used; however, this is not a pathologic term. Cases of histologically benign chondroblastoma with pulmonary metastasis have been reported. However, these metastases are clinically nonprogressive. Only simple surgical excision or simple observation is needed.

There are reports of extremely rare cases of malignant transformation and metastasis in chondroblastoma.

Definition and Synonyms

Chondromyxoid fibroma (CMF) is a benign tumor composed of spindle or stellate cells forming lobules. There is abundant myxoid and/or chondroid intercellular material.

Brief Historical Overview

CMF was first described by Jaffe and Lichtenstein in 1948. Previously, it was considered to be a myxoma or a myxomatous variant of giant cell tumor of bone.

Incidence and Demographics

CMF is extremely rare; it accounts for less than 1% of all bone tumors and represents approximately 2% of benign bone tumors. There is a male predominance. More than 50% of CMF cases develop in the second and third decades of life.

Localization and Clinical Manifestations

Most cases of CMF occur in the metaphysis of tubular bones of the lower extremity. Approximately one third of the cases involve the knee joint; the most common site of involvement is the proximal tibial metaphysis, followed by the distal femoral metaphysis. Rarely, there are reports of cases that involve the cortex or juxtacortical region of bones. Small bones of the feet are among the frequently involved sites. Upper extremity involvement is rare. In the pelvis, the ilium is the most frequent site of involvement. CMF has also been reported in craniofacial bones, ribs, spine, clavicle, calcaneus, and sternum.

Clinically, patients present with pain that can persist for several months to several years and/or local swelling. On very rare occasions, they suffer from rickets, which is reported as an oncogenic osteomalacia.

Radiologic Features and Gross Pathology

CMF appears as a sharply circumscribed, eccentric radiolucent lesion with an elongated shape ( Fig. 9-6A ). Cortical expansion, exuberant endosteal sclerosis, and coarse trabeculation can be seen. Extensive periostitis and pathologic fracture are rare, and calcification is infrequent. Size ranges from 2 to 10 cm; large lesions can be seen as hemispheric osseous defects with destruction of cortex. CMF arising in a flat bone may show irregular contours with osteolysis and bone expansion.

On MRI, CMF shows a multilobulated pattern with low signal intensity on T1-weighted imaging and high signal intensity on T2-weighted images. With contrast enhancement, the central portion of the lesion may show no enhancement due to the myxoid component (see Fig. 9-6B–D ).

Curettage specimens are composed of blue-gray or white tissue that rarely shows necrosis, cystic change, or liquefaction. Typical hyaline cartilage is not present. When the surrounding bone is available for evaluation, the multilobulated appearance and sharp delineation from bone can be appreciated.

Histopathology

CMF has a distinct microscopic appearance characterized by variably sized lobules that are sharply demarcated from the surrounding bone. The lobules tend to be hypocellular centrally with greater cellularity at the periphery ( Fig. 9-7 ), and they are separated by fibrous bands that contain blood vessels and giant cells ( Fig. 9-8 ).

The lesional cells are spindled to stellate and are distributed in an abundant extracellular chondroid matrix ( Fig. 9-9 ). Frequently, there is abundant pink cytoplasm, producing an epithelioid appearance. Approximately 50% of CMF cases have scattered benign giant cells.

Large, bizarre hyperchromatic nuclei can be seen in 20% to 30% of cases, but they are usually focal and associated with large amounts of cytoplasm, sometimes with smudgy or degenerative features. Because of these cytologic features, chondrosarcoma may be considered as a differential diagnosis.

Mitoses are extremely rare in CMF, and atypical mitoses have not been noted. Microscopic cystic or liquefactive change is uncommon and is usually focal when present. Well-formed hyaline cartilage is present in less than 20% of cases. Calcification is present in about one-third of cases, either as fine granules or dense plaques ( Fig. 9-10 ). Hemosiderin deposition is present at the lobular periphery associated with inflammatory cells and lymphocytes. A secondary aneurysmal bone cyst is rarely seen.

Differential Diagnosis

Chondrosarcoma enters the differential diagnosis, particularly in tumors involving the pelvic bones. Correlation with the radiologic features is essential: chondrosarcomas are usually poorly circumscribed and contain calcification. Histologically, high-grade chondrosarcoma can be differentiated from CMF by (1) brisk mitotic activity; (2) permeation of marrow spaces by tumor cells; and (3) the appearance of the myxoid stroma, which stains more uniformly in CMF. Another important distinguishing feature is the presence of multinucleated giant cells, which are common in CMF but extremely rare in chondrosarcomas.

Extragnathic myxomas may be distinguished from CMF by their lack of a lobular growth pattern and the absence of pleomorphism or atypia in the stellate or spindle cells. Furthermore, from a practical point of view, extragnathic myxoma is very rare.

Ancillary Diagnostic Studies

Immunohistochemically, S-100 protein has been reported in CMF, especially within the areas that exhibit more mature chondroblastic differentiation. In the loose myxoid areas, S-100 protein may show only focal positivity. At the periphery of the lobules, smooth muscle actin and CD34 have been noted. Ultrastructurally, the stellate cells have irregular cell processes, scalloped cell membranes, and cytoplasmic fibrils and glycogen, features of both chondroblastic and fibroblastic differentiation.

Genetics

Only limited cytogenetic studies have been done on CMF. Clonal abnormalities of chromosome 6 appear to be nonrandom. In particular, rearrangements of the long arm of chromosome 6 at bands q13 and q25 are recurrent. Pronounced expression of hydrated proteoglycans (a major constituent of the myxoid matrix) and focal expression of collagen type II (a marker of chondrocytic cell differentiation) as well as collagen types I, III, and VI are characteristic of matrix composition and gene expression patterns in CMF. In CMF, N-cadherin, PTHLH, and PTHR1 are expressed at a significantly lower level than in articular chondrocytes but, conversely, significantly higher expression of cyclin D1, p16, and BCL2 has been reported. There is a single report that tumor growth factor β1 is derived from partial myofibroblastic differentiation in CMF. There are higher expression levels of CD166, cyclin D1, and p16INK4A in CMF, in contradistinction to low levels present in high-grade chondrosarcoma.