Chondroblastoma: An Update.
Chondroblastoma is uncommon, accounting for less than 1% of all primary bone tumors. While the age range is broad (2-83 years), most CBTs are diagnosed in the second to third decade of life, with an average age of 19 to 23 years. (4-6) There is a male predominance of approximately 2:1. Bone pain is the most common presentation, and may be longstanding, but other more site-specific complaints can also arise. For example, when the epiphysis of a long bone is involved, the symptoms may include local swelling, joint stiffness and/or effusion, and the development of a limp. In tumors arising from the skull bones, symptoms such as seizures and progressive hearing loss can also occur. (6)
Physical examination may reveal findings of local tenderness, decreased range of motion in the affected joint, joint effusion, muscular atrophy, and rarely, a palpable mass.
Chondroblastoma tends to be a solitary lesion. In young people, it preferentially occurs in the epiphysis of long tubular bones, with the most common sites being the proximal tibia or femur, distal femur, and proximal humerus. (7) In older individuals, the location is much more variable, and tumors may involve nontubular bones such as the craniofacial skeleton or bones of the hands and feet. (5,6,8) For example, in a study of 495 CBTs, Kurt et al (5) found that the mean age for patients with skull and facial bone lesions was 44.1 years. For those with flat bone lesions, the mean age was 28.4 years; for hand and foot lesions, 20.8 years; and for patients with long bone lesions, 19.1 years.
In terms of location, 50% to 75% of CBTs are located in the long bones, with most of these being in the femur. (5,7,8) Other common sites are the bones of the hands or feet, including the talus, os calcis, phalanges, and metatarsal bones. Flat bones can also harbor this tumor, where it has been described in the pelvis, ribs, patella, sternum, clavicle, and vertebrae. (5) Least commonly, tumors can arise in the skull and facial bones (temporal bone and mandible).
Most CBTs are situated in the medullary cavity. When arising in the long bones, the tumor usually involves only the epiphysis or the epiphysis with metaphyseal extension, although CBTs arising from nonepiphyseal sites have also been reported. (9) Tumors arising from the flat bones and the bones of hands and feet may extend to an apophysis or an articular surface.
The typical radiologic presentation of CBT is a well-demarcated, eccentric, and lytic lesion with a thin rim of sclerotic bone (Figure 1, A and B). It tends to be small to intermediate in size, averaging 3 to 6 cm, although tumors exceeding 10 cm can occur. (10)
Central "fluffy" calcifications are commonly seen as radiodensities, with the severity of mineralization varying from mild to marked. The adjacent cortex usually shows evidence of erosion or thinning, although frank cortical breach with soft tissue invasion is rarely seen. Pathologic fracture occurs in a minority of cases.
Magnetic resonance imaging (MRI) studies of CBT have shown that extensive edema may be present surrounding the lesion. (11) In addition, most cases show variable intensity on T2-weighted images. This is explained by the fact that the signal intensity on T1- and T2-weighted MRI images in CBT is dependent on the amounts of various components within the lesion, such as chondroid matrix, cellularity, calcification, hemosiderin, and aneurysmal bone cyst-like areas. (12)
Grossly, CBT is sharply separated from the adjacent bone and contains a mixture of soft, friable, grey-yellow material and hemorrhage. Small calcifications provide a gritty and chalky cut surface. Occasionally, areas of rubbery blue-grey chondroid matrix are seen. Necrosis and hemorrhagic cystic cavities (secondary aneurysmal bone cyst formation), may also be present, but usually only comprise a small portion of the tumor.
Chondroblastoma is characterized histologically by a sheetlike proliferation of small to intermediate-sized round polygonal cells (Figure 2, A). The cytoplasm is eosinophilic, although focally, clear cell change can be seen. The nucleus is centrally placed and relatively large (15-20 [micro]m), and often a central, longitudinal nuclear groove ("coffee bean" nucleus) can be seen. Nucleoli are small. Cellular atypia with enlarged, irregular, and sometimes hyperchromatic nuclei may be present, especially in tumors located in the skull and facial bones. (5) Mitoses are occasionally found, although they are not numerous, with an average count of 1 to 3 mitotic figures per 10 high-power fields. Atypical mitotic figures should not be seen, and if present, tend to exclude CBT from the differential diagnosis.
In addition to the above, variable numbers of multinucleated giant cells are often present (Figure 2, A), as are foci of hemosiderin deposition (Figure 2, B). The latter occurs more commonly in the tumors located in the skull and facial bones. (5)
In most lesions, islands of mature cartilaginous differentiation can be found, containing foci of eosinophilic chondroid matrix (Figure 3, A). Less frequently, only an eosinophilic matrix is seen. Matrix formation must be seen to confirm a diagnosis of CBT.
Bluish or purple granular calcium deposits are seen in approximately one-third of cases, most commonly in long bone tumors. The calcifications may be seen in the cytoplasm or stroma, where they demonstrate a delicate pericellular lacelike or "chicken-wire" appearance (Figure 3, C).
Secondary aneurysmal bone cyst (ABC) formation is also commonly encountered, especially in the tumors of the hands or feet, where more than half of the cases show this feature. Although it is usually limited to microscopic foci, ABC formation may sometimes be so dramatic that the underlying CBT may be overlooked (Figure 3, B).
Other features such as tumor necrosis, vascular invasion, cortical breakthrough, and soft issue invasion can also be present in a small percentage of cases. The tumor necrosis is usually composed of bland ghost cells without any inflammation (Figure 3, D).
The cytopathologic features of CBT have been described from fine-needle aspiration findings. (13) Smears are cellular and contain chondroblasts with round to oval nuclei with fine, evenly distributed chromatin and longitudinal nuclear grooves. The cytoplasm is pale on Papanicolaou stain, while the chondroid matrix fragments stain magenta on a DiffQuik stain and green/violet with a Papanicolaou stain. Multinucleated osteoclast-like giant cells may also be found.
As in other tumors with cartilaginous differentiation, the cells in CBT are known to be positive for vimentin, neuron-specific enolase, and S100 protein. One study has also shown that the neoplastic cells in this tumor can be positive for cytokeratins (CAM 5.2) and epithelial membrane antigen, (14) although similar results were not found by other groups. (4) A new marker, discovered on gastrointestinal stromal tumor 1 (DOG1), also shows positivity in CBT tumor cells and may serve as a specific marker for differentiating CBT from other giant cell-containing bone tumors. (15) Sox9 is a transcriptional factor known to be involved in chondrogenesis and also shows positivity in CBT and chondromyxoid fibroma in a nuclear distribution. (16)
Systemic molecular characterization of CBT has been limited owing to the low prevalence of the tumor. Cytogenetic abnormalities have been found in a variety of studies (17,18) and include loss, gain, or translocation of chromosome 5 or 17. No consistent or recurrent cytogenetic abnormality, however, has been found in this tumor.
Isocitrate dehydrogenase (IDH)1 and IDH2 mutations characterize cartilaginous tumors such as enchondromas and chondrosarcomas, but are absent in CBT. (19)
Recently, studies by Behjati et al (20) and Presneau et al (21) have identified a K36M mutation in either the H3F3A (encoding histone 3 family 3A protein; on chromosome 1) or H3F3B (encoding histone 3 family 3B protein; on chromosome 17) genes. This alteration is found in 95% of CBTs, with most cases harboring the mutation in the H3F3B gene (chromosome 17). Interestingly, in the same study, it was also found that a separate mutation (G34W) in the same H3F3A gene was present in up to 92% of giant cell tumors (GCTs) of the bone. A similar result was achieved by another group, (22) which showed a G34W mutation in H3F3A in 69% of GCTs, and the K36M mutation (H3F3B) in 70% of CBTs. None of the groups detected the K36M mutation in GCT; similarly, the G34W mutation was never found in CBT. It therefore appears that the K36M mutation has a high sensitivity and specificity for CBT, and this has great potential for being used as a molecular test to differentiate CBT from bone tumor mimics. A monoclonal antibody has recently been developed to detect this mutation. (23) The precise role of the histone 3 mutations in CBT is unknown. It may relate to an increase in histone methylation, with subsequent differential binding in the genome, affecting gene expression. (22)
While straightforward cases with classical features may lead to a quick diagnosis, several mimics of CBT exist that suggest a cautious approach.
Giant cell tumor of bone is the lesion most often confused with CBT, given the overlap in clinical presentation, radiologic features, and the presence of giant cells and hemosiderin on microscopic examination. In general, GCTs occur in a slightly older age range (third to fourth decade of life), and tend to produce larger tumors with less well-defined borders. Giant cells are also more numerous and evenly distributed in GCT, whereas the presence of chondroblasts, cartilaginous matrix, and S100 protein or DOG1 positivity would suggest a CBT. Many cases, however, will still present challenges, particularly if the biopsy material is not abundant, or if limited sampling misses an area of cartilaginous differentiation. In this scenario, screening for the K36M mutation of H3F3A/ H3F3B with immunohistochemistry or polymerase chain reaction might become a useful tool.
Chondromyxoid fibroma is another intermediate type of cartilaginous tumor that may be misinterpreted as a CBT. Chondromyxoid fibroma can mimic CBT in that it can present as a bland cartilaginous proliferation arising in the bone of a younger individual (second to third decade of life). Chondromyxoid fibroma, however, typically arises in a metaphyseal location rather than in the epiphysis. Additionally, hypercellular areas containing spindled or stellate cells in a myxoid stroma are characteristically seen at the periphery of chondromyxoid fibroma, a finding that is not present in CBT.
Aneurysmal bone cyst is not uncommonly seen as a secondary feature in CBT, and therefore if a biopsy includes prominent ABC-like areas, the primary lesion may be overlooked. Careful attention must therefore be paid to clinicoradiologic features to allow distinction between these 2 entities, and specimens should be sampled thoroughly. Findings such as a location in the epiphysis, the presence of calcification, and histologic evidence of solid areas with chondroblastic differentiation should lean one toward a diagnosis of CBT. In challenging cases, immunohistochemistry or even molecular testing may provide clarity.
Clear cell chondrosarcoma is an uncommon variant of chondrosarcoma that classically presents as a lytic lesion in the epiphysis of the proximal humerus or femur. (24) Although the mean age of presentation is slightly older than in CBT (third-fifth decade), the age range overlaps, and the radiologic appearance may not allow reliable distinction between the 2 entities. Careful microscopic examination, however, should provide the answer; clear cell chondrosarcoma demonstrates larger, more atypical cells with clear cytoplasm, whereas CBT is a tumor of small round-polygonal cells with eosinophilic cytoplasm and limited cytologic atypia.
A CBT-like variant of osteosarcoma (CBTOS) has been reported. (25) This rare variant of osteosarcoma can be difficult to distinguish from CBT, as both tumors can present in young patients as a lytic lesion in an epiphyseal location. CBTOS may demonstrate small round-oval cells with eosinophilic cytoplasm and scattered giant cells, and therefore may cause confusion with CBT, especially on a small biopsy specimen. Clues to the appropriate malignant diagnosis include a more aggressive, infiltrative lesion on imaging studies, and the presence of nuclear atypia, atypical mitoses, and/or malignant osteoid production on histologic examination.
Surgery is the primary treatment of choice for CBT and includes complete surgical curettage with or without bone grafting, en bloc resection, or rarely, amputation. Chemical cauterization with phenol or cryosurgery can also be used as adjunctive therapy. Radiation therapy was used previously in conjunction with surgery either preoperatively or postoperatively; however, the current belief is that radiotherapy should be avoided, as it can stimulate malignant progression. Chemotherapy is generally not indicated for treatment of this tumor. For recurrent tumors, resection remains the treatment of choice, although select cases may also receive radiation therapy after repeated curettage fails to cure.
Although generally benign, CBT is placed in the "intermediate, rarely metastasizing" category in the 2013 World Health Organization classification of bone tumors. (26) The tumor is also known to have a relatively high local recurrence rate, in the order of 14% to 18%. (6,8) The local recurrence rate is somewhat dependent on site; tumors in the skull and other bones with limited resectability are understandably more difficult to excise completely. In a study published by Turcotte et al, (6) local recurrence occurred in 29% of the flat bone lesions and 11% of the long bone lesions, with the temporal bone having the highest recurrence rate of all, at 50%. The interval of recurrence in that study ranged from 6 months to 8 years.
Bone grafting and cryotherapy after surgical curettage decrease the risk of recurrence.
Metastasis to the lung, bone, and soft tissue can occur in CBT, although such cases are rare (<2%), and tend to show indolent growth with no significant effect on mortality.
A so-called malignant chondroblastoma has been proposed, but many of these cases have turned out to be postradiation sarcomas rather than de novo transformation of benign disease, (27) or were malignant tumors from the outset that were misdiagnosed. Isolated fatal cases with massive local recurrence have been reported, (28) however, and spontaneous malignant transformation to a high-grade sarcoma with metastases has been described in cases without radiation therapy. (29)
Regrettably, there are no reliable histologic criteria that predict the risk of local recurrence or even that of metastases, including cytologic atypia, mitotic rate, the presence of giant cells, or the finding of lymphvascular invasion. (30)
Chondroblastoma represents a rare but distinctive cartilaginous bone tumor affecting predominantly children and adolescents. Characteristic features include a small, lytic lesion in the epiphysis of long bones, and the finding of chondroblasts, chondroid matrix, and assorted secondary elements on microscopy. While most CBTs demonstrate a classical appearance, other mimics with a different treatment outcome and/or prognosis can enter the differential diagnosis. Recent advances in immunohistochemical staining patterns and molecular features can assist with this distinction.
Please Note: Illustration(s) are not available due to copyright restrictions.
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Wenqian Chen, MD, PhD; Lisa M. DiFrancesco, MD, FRCPC
Accepted for publication September 16, 2016.
From the Department of Pathology, University of Calgary, Calgary, Alberta, Canada.
The authors have no relevant financial interest in the products or companies described in this article.
Reprints: Lisa M. DiFrancesco, MD, FRCPC, Department of Pathology (CLS), The University of Calgary/Calgary Laboratory Services, 7th Floor McCaig Tower, Foothills Medical Centre, 1403 29th St NW, Calgary, AB T2N 2T9, Canada (email: difrance@ ucalgary.ca).
Caption: Figure 1. Classic radiologic appearance of chondroblastoma: a well-demarcated lytic bone lesion in (A) the greater trochanter of the femur and (B) the epiphysis of the distal humerus.
Caption: Figure 2. A, Chondroblastoma is characterized by polyhedral tumor cells with nuclear grooves and eosinophilic cytoplasm mixed with scattered multinucleated giant cells. B, Brown, granular hemosiderin pigmentation may disguise chondroblastoma cells (hematoxylin-eosin, original magnification X40 [A and B]).
Caption: Figure 3. Common features in chondroblastoma. A, Foci of more mature cartilaginous tissue. B, Secondary aneurysmal bone cyst formation. C, Scattered calcifications. D, Bland necrosis without inflammation (hematoxylin-eosin, original magnification X10 [A through D]).
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|Author:||Chen, Wenqian; DiFrancesco, Lisa M.|
|Publication:||Archives of Pathology & Laboratory Medicine|
|Date:||Jun 1, 2017|
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