Chondromyxoid fibroma (CMF) is a rare, slow-growing, benign bone tumor of chondroblastic derivation.[1, 2, 3, 4] Jaffe and Lichtenstein first described the condition in 1943.[5] They differentiated this benign lesion from chondrosarcoma, a much more common, but malignant, tumor. Before 1943, CMF would have been considered a giant-cell variant or a benign cartilaginous tumor. A myxoid element is the defining characteristic.
Grossly, CMFs are firm, grayish-white masses that are sharply demarcated; they are lobulated or pseudolobulated. Their appearance can mimic that of fibrous tissue or hyaline cartilage. The lesions can rarely destroy trabecular bone and often thin the cortex. Rarely, CMFs may have areas of hemorrhagic and cystic degeneration and mimic aneurysmal bone cysts.
Many chondromyxoid fibromas display morphologic features that resemble different stages of chondrogenesis.[6, 7] The most important diagnostic pathologic characteristic is the myxoid element. Without the finding of the myxoid element, the diagnosis cannot be made. Giant cells are frequently present, especially toward the periphery of the lesion. A study by Romeo et al examined the DNA microarray of chondromyxoid fibroma and demonstrated that CMFs could be differentiated from other cartilaginous tumors.[8]
As is the case with most bone tumors, no specific cause is known for CMF.
Some authors noted an association with certain chromosomal abnormalities. In a study of four patients with CMF, Granter et al found that all of the subjects had a clonal rearrangement of chromosome 6,[9] which had not been associated with other bone tumors. This finding may be useful as a cytogenetic marker to distinguish CMF from other histologically similar tumors. The authors suggest that oncogene activation resulting from this clonal rearrangement is likely to be involved in the genesis of CMF.[10, 11]
Nord et al subjected a series of CMFs to whole-genome mate-pair sequencing and RNA sequencing.[12] They found that the glutamate receptor gene GRM1 recombines with several partner genes through promoter swapping and gene fusion. The GRM1 coding region remained intact, and 18 of 20 CMFs (90%) showed pronounced (100- to 1400-fold) increases in GRM1 expression levels compared with control tissues. These findings demonstrate that direct targeting of GRM1 is a necessary and highly specific driver event for the development of CMF.
CMFs account for fewer than 1% of primary bone tumors in the United States. CMFs are becoming less frequently diagnosed, and thus, the current frequency is much lower than 1%.
Approximately 500 cases of CMF had been described in the world literature.[13] The frequency of diagnosis seems to be decreasing.
CMF primarily affects young adults in their second and third decades of life. Eighty percent of patients are younger than 36 years. According to most reports, males and females are affected equally, although a few series have reported a slight male predominance.[14] No racial predilection has been reported.
Patients are generally cured with en-bloc excision. After resection both with and without bone grafting, CMFs may recur locally, especially after a marginal excision. The recurrence rate is approximately 25% with the usual treatment of curettage.
In a study of 22 consecutive cases of CMF treated with intralesional curettage,[15] Bhamra et al documented local recurrence in two patients (9%) within the first 2 years after the index procedure. This was treated by recurettage of only the residual defect. Two postoperative complications occurred: a superficial wound infection in one patient, and a transient deep peroneal nerve neurapraxia in the other. The mean postoperative score on the Musculoskeletal Tumour Society scoring system was 96.7%.
In most cases, radiation therapy should be avoided because of its causative relation to postradiation sarcoma.
Occasional CMFs may behave locally in an aggressive fashion after resection, especially when they are located in the axial skeleton.
Malignant conversion is extremely rare and is difficult to distinguish from a misdiagnosed de-novo chondrosarcoma. Consequently, mortality from true CMF is essentially nonexistent.
Approximately 70% of patients with chondromyxoid fibromas (CMFs) have symptoms at the time of diagnosis; the remaining lesions are discovered incidentally. Pain is the most common symptom and may be present for years.[16] Although the pain is typically mild, it may become severe with time, and night symptoms may be present. Patients may also report swelling and stiffness. These symptoms may be especially common around the knee and may cause a reduction in physical activity.
Pathologic fractures have been rarely reported, probably as a consequence of the slow growth of this tumor; the symptom of pain may be due to pending fracture through the lesion.
Approximately 90% of CMFs involve the lower extremity. The proximal tibia metaphysis is the most common location, followed by the distal femoral metaphysis.[17] Long bones are involved much more frequently than are other bones, especially in younger patients. After the long bones, the pelvis is one of the more common sites.[18] Flat bone involvement may rarely be seen in older patients.
Patients may have localized tenderness or swelling over a CMF lesion, and in rare cases, they may incur a pathologic fracture.
On radiographs,[23, 24] chondromyxoid fibromas (CMFs) are well-defined, eccentric, elongated, radiolucent lesions. Like many bone tumors, CMFs occur most frequently in the metaphysis of the proximal tibia and the distal femur. Epiphyseal occurance has not been reported. Other reported locations are the pelvis and the first metacarpal.
A common appearance is a bubbly, expansile, eccentric, elongated, metaphyseal, lytic lesion. A rare diagnostic feature is a eccentric, nearly hemispherical "bite" from the cortical margin without periosteal reaction (see the image below). The greatest dimension of a CMF is less than 10 cm. The margins are usually sclerotic with scalloped borders and may demonstrate mild cortical expansion. The lesions can extend into the diaphysis but do not cross the physeal plate.
View Image
Radiograph showing the "bite" out of the metaphyseal cortex that is a diagnostic feature of chondromyxoid fibroma.
Trabeculations within the tumor, which reflect bony ridges formed around a lobulated tumor may be visible on radiographs. Matrix calcifications are unusual.[25]
When CMF involves the vertebrae (quite rare) radiographs may show a more aggressive appearance.[26] CMFs of the small bones of the hands or feet (rare) are more central and expansile. CMFs may have associated or secondary aneurysmal bone cysts (ABCs).
Computed tomography
On computed tomography (CT), mild cortical expansion may be observed, and the lesions have a density greater than fluid throughout. CT scans also exhibit characteristic lack of mineralization within CMFs. CT may be superior to conventional radiography for analysing the expansion of the lesion, cortical breakthrough, and internal mineralization.[27]
Magnetic resonance imaging
Chondroid and myxoid tissues, as well as any normal hyaline cartilage within the lesion, have an intermediate-to-high signal on proton-density and T2-weighted magnetic resonance imaging (MRI) and a low signal on T1-weighted images (see the image below).[28, 29, 27] Fibrous tissue components have a variable appearance, depending on their vascularity. Because of their diverse tissue components, CMFs have a heterogeneous appearance. They are typically solid but can have cystic areas. Secondary ABCs have typical septations and fluid-fluid levels.
View Image
Magnetic resonance imaging (MRI) scan of chondromyxoid fibroma (T1 image).
Bone scanning
CMFs usually have increased activity on bone scintigraphy.
Biopsy is used for histologic examination.[30] A generous tissue sample is required for an accurate diagnosis, because small biopsies may not be representative.
Microscopically, CMFs are lobulated or pseudolobulated, with peripheral condensation of more cellular tissue within the lobules. Composed of myxoid or chondroid tissue, the center of each lobule is hypocellular. The surrounding stroma is denser, with spindle-shaped cells, blood vessels, and occasional multinucleate giant cells.
Tumor nuclei may be hyperchromatic, are of moderate size, and may lie in chondroid lacunae. Nuclear atypia can be observed, but mitoses are rare or absent. Microcalcification is present in 15-20% of cases, with an increased incidence in older patients. (See the image below.)
View Image
Close-up of a lobule of a chondromyxoid fibroma.
Scattered areas of hyalinization, xanthomatous changes, cholesterol clefts, and cystic degeneration may be noted, including secondary ABCs. The tumors have a heterogeneous immunohistochemical staining pattern, with the central chondroid areas staining positively for S-100 protein and the peripheral, hypercellular tissue staining diffusely for muscle and smooth muscle actin.[31, 32] None of the cells express desmin.
Local staging typically includes plain radiography and MRI or CT. Because CMF does not metastasize, there is no need for routine chest radiographs or other systemic staging studies. A total skeletal bone scan is generally advisable during the initial evaluation to assess local activity and to confirm the solitary nature of the tumor.
No medical care is usually necessary in the treatment of chondromyxoid fibromas (CMFs). Nonsteroidal anti-inflammatory drugs (NSAIDs) or analgesics may be beneficial for pain control.
CMFs are treated with intralesional curettage or en-bloc excision.[33] Jaffe and Lichtenstein noted in their original description of CMF that "even with incomplete removal, spontaneous regression of the remnants followed."[5] Subsequent reports noted recurrence rates of approximately 25% with curettage and bone grafting, though this rate may be higher in young children (first or second decade of life) and in patients with tumors that are predominantly composed of myxoid areas.
Wide en-bloc excision may lower the recurrence rate, but it usually adds unnecessary morbidity. Local adjunct treatment agents, such as phenol, methylmethacrylate, and liquid nitrogen, have not been shown to decrease the recurrence rate.
Radiotherapy may be used in tumors that are considered unresectable.[34]
Arrest of growth may occur after aggressive curettage of tumors adjacent to the physis. Malignant transformation has been noted as a possible complication, even in the absence of preceding radiation therapy. However, many authors believe that cases of CMF that have been reported as malignant transformation have not been sufficiently documented and more likely represent a misdiagnosis of chondrosarcoma.
Activity need not be restricted unless the lesion is large enough to create a risk of fracture. This is an unusual occurrence, and pain with weightbearing should alert one to the possibility of impending fracture. Some patients may limit their activity to control discomfort.
The average time to recurrence is typically less than 2 years, but it has been reported to be as long as 19 years after the initial tumor presentation.[19, 35, 36, 37] Patients should be monitored with periodic history and physical examinations and with routine radiographs of the affected site for a minimum of 2 years.
Clinical Context:
DOC for patients with mild to moderate pain. Ibuprofen inhibits inflammatory reactions and pain by decreasing prostaglandin synthesis.
Clinical Context:
Used for the relief of mild to moderate pain. Inhibits inflammatory reactions and pain by decreasing the activity of cyclo-oxygenase, which results in decreased prostaglandin synthesis.
Clinical Context:
Used for the relief of mild to moderate pain and inflammation. Small dosages are initially indicated in small and elderly patients and in persons with renal or liver disease. Doses >75 mg do not increase the therapeutic effects. Administer high doses with caution and closely observe the patient for his/her response.
NSAIDs have analgesic, anti-inflammatory, and antipyretic activities. Their mechanism of action is not known, but they may inhibit cyclo-oxygenase activity and prostaglandin synthesis. Other mechanisms may exist as well, such as inhibition of leukotriene synthesis, lysosomal enzyme release, lipoxygenase activity, neutrophil aggregation, and various cell membrane functions.
Clinical Context:
DOC for pain in patients with documented hypersensitivity to aspirin or NSAIDs, with upper GI disease, or who are taking oral anticoagulants.
Pain control is essential to quality patient care. Analgesics ensure patient comfort and have sedating properties, which are beneficial for patients who experience pain.
Michael S Clarke, MD, Clinical Associate Professor, Department of Orthopedic Surgery, University of Missouri-Columbia School of Medicine
Disclosure: Nothing to disclose.
Specialty Editors
Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Received salary from Medscape for employment. for: Medscape.
Chief Editor
Omohodion (Odion) Binitie, MD, Medical Director, Assistant Member, Department of Sarcoma, Section Head, Orthopedics, Adolescent/Young Adult and Pediatric Orthopedic Oncology, Medical Director, Physical Therapy, Speech Therapy, and Rehabilitation Services, Assistant Fellowship Program Director, Musculoskeletal Oncology, Moffitt Cancer Center; Assistant Professor, Department of Oncologic Sciences, Department of Ortho and Sports Medicine, University of South Florida Morsani College of Medicine
Disclosure: Nothing to disclose.
Additional Contributors
Howard A Chansky, MD, Associate Professor, Department of Orthopedics and Sports Medicine, University of Washington Medical Center
Disclosure: Nothing to disclose.
Acknowledgements
Timothy A Damron, MD David G Murray Endowed Professor, Department of Orthopedic Surgery, Professor, Orthopedic Oncology and Adult Reconstruction, Vice Chair, Department of Orthopedics, State University of New York Upstate Medical University at Syracuse
Timothy A Damron, MD is a member of the following medical societies: American Academy of Orthopaedic Surgeons, American College of Surgeons, American Medical Association, Children's Oncology Group, Connective Tissue Oncology Society, Musculoskeletal Tumor Society, Orthopaedic Research Society, and Society for Experimental Biology and Medicine
Disclosure: Lippincott, Williams, and Wilkins Royalty Editing/writing textbook; Genentech Grant/research funds Clinical research; Orthovita Grant/research funds Clinical research; National Institutes of Health Grant/research funds Clinical research; UpToDate Royalty Update Preparation Author; Wright Medical, Inc. Grant/research funds Clinical research
Hannah D Morgan, MD Consulting Staff, Connecticut Orthopaedic Specialists
Hannah D Morgan, MD is a member of the following medical societies: American Academy of Orthopaedic Surgeons and American Medical Association
){kind=link}
){kind=link}
){kind=link}