Chondromyxoid fibroma (CMF) is a rare, peculiar, and benign primary bone tumor that show heterogeneous cytomorphology with a spectrum of chondroid, fibroblastic, and myxoid areas. CMF was originally described and distinguished from other aggressive bone tumors by Jaffe and Lichtenstein in 1948 1. It usually presents in the second to third decade, has a male to female ratio of 2 to 1, and is found most often in the metaphysis around the knee in the proximal tibia, proximal fibula or distal femur 23456789. CMF is thought to be one of the least common bone tumors, representing less than 1% of all primary bone neoplasms and less than 2% of benign bone neoplasms 241011. It occurs most frequently in young adults during the second or third decades of life and is more frequent in males than females 23456789. Although CMF may involve any bone of the skeleton, it is most commonly found in the metaphyses of major long tubular bones of the lower extremities, particularly around the knee joint 2478912. CMF has been described as occurring in the apophyses or intracortically 1314151617. Approximately 25% of lesions occur in flat bones, such as the ilium, metatarsals, vertebrae, skull, facial bones, and ribs 2478912. Lesions in the ribs are extremely rare with only nine reported cases in the English language medical literature 71819202122. Clinically, CMF is slow growing and are commonly asymptomatic lesions that are discovered incidentally on radiography 9. When symptomatic, their clinical presentation is usually chronic local pain (85%), swelling (65%), restriction of motion and, more rarely, pathological fracture 811. The previously described typical radiological features of long bone CMF is a well-defined metaphyseal lytic lesion with a sclerotic rim, septation, and no calcification 2324. Cortical expansion and focal destruction may be observed sometimes, but generally the appearances are of a benign lesion. Calcification and intralesional opacities are uncommon and occurs in about 2% of lesions 2324.

The classic histological features of CMF are lobules of spindle-shaped or stellate cells with abundant myxoid or chondroid intercellular material separated by zones of more cellular tissue rich in spindle-shaped or round cells with a varying number of multinucleated giant cells of different sizes 478910. Mitoses are exceptionally rare in CMF 478910. Although it has been suggested that enlarged, pleomorphic nuclei and a prominent mucinous or myxoid component may indicate a higher recurrence rate, histological features are probably not predictive of recurrence 478910. Recurrence may be more frequent in younger patients 48910. The identified predisposing factors accounting for the recurrence of CMF are its friable nature resulting in incomplete removal 724. Despite occasional nuclear atypia and local recurrences, CMF is a benign neoplasm and there have been no reports of metastases. Curettage and concurrent bone grafting with allograft bone or polymethylmethacrylate (PMMA) resulted in a much lower recurrence rate than curettage alone, whereas tumors treated by excision did not recur 47891024. Local recurrence of CMF following surgery is well recognized and occurs in 3–22% of cases 7891025. Malignant transformation of CMF is a rare event and is reported to be 1–2% 825. Two cases of malignant transformation of CMF after irradiation have been reported 89. Adequate surgical ablation is curative.

The precise histogenesis of CMF is uncertain and is a matter of continuing speculation. A cartilaginous origin, originally proposed on morphological grounds, was subsequently supported by ultrastructural studies and the demonstration of S-100 protein by immunohistochemical studies 5262728. Neilsen 27 showed myofibroblastic, myochondroblastic, and chondrocytic differentiation in CMF on the basis of variable immunostaining for smooth muscle actin (SMA) and S-100 protein. Therefore, it has been suggested on the basis of immunohistochemical studies that CMF resembles chondroblastoma, particularly in relation to the finding of S-100 immunoreactivity; however other types of tumors have similar findings 5262728. Additionally, osteocalcin is present in greater than 50% of CMFs, and in other bone and cartilage tumors, especially chondroblastomas 5.

Karyotypes of fifteen cases of CMF are reported in the English language medical literature, with twelve cases reporting non-random clonal abnormalities involving chromosome 6 29303132333435363738. In the present report, we describe the clinical, cytological, histological, immunohistochemical and cytogenetic features of four cases of CMF that arose in the rib, finger and foot.

Sixteen cases of CMF were retrieved from the surgical pathology files of our institution over an 8-year (1999–2006) period. Four of these 16 cases occurred in relatively unusual regions, including one from metatarsal, two from phalanges, and one from the rib. Clinical information including radiological features and follow-up information was obtained and reviewed for these four cases of CMF at unusual sites. Available original histologic and cytologic slides on all four cases were retrieved and reviewed by two of the authors (AVP and UNMR) who concurred on the diagnoses. Immunohistochemical staining for a panel of antibodies (Table 1) was performed on histologic sections of each of the four cases using standard protocols with a 3-step avidin-biotin-streptavidin procedure. A computer tomography (CT)-guided fine needle aspiration (FNA) biopsy of the right anterior second rib mass (case no. 2) was done prior to the subsequent definitive resection, and immunocytochemical staining for S-100 and Ki-67 was performed for this case. For all immunohistochemical and immunocytochemical analyses, appropriate negative and positive controls were included. A fresh unfixed tumor sample of the resected right anterior second rib mass (case no. 2) was submitted to the Pittsburgh Cytogenetics Laboratory in RPMI tissue culture medium for cytogenetic analysis during the intraoperative evaluation for negative resection margins, since a diagnosis of CMF was favored for the prior CT-guided FNA biopsy. The tumor tissue was treated with collagenase to enzymatically dissociate cells, which were then cultured for 7 to 9 days. Metaphase cells were harvested and chromosomes were GTG-banded using standard procedures.

The radiological and clinical presentation of all the four cases of CMF in this study is similar to those in the available literature on CMF 34591011232425. Between 15% and 31% of cases of CMF have been reported to originate in the foot and ankle, and the involvement of the small bones of the feet by CMF has been reported as five times more common than the involvement of the small bones of the hands 2478912. CMF has no specific radiological distinguishing features. Microscopic calcification is found in about 20% of cases 39. However, they rarely show calcification on plain X-rays, and are less likely to be confused radiologically with chondroblastomas, enchondromas, or low-grade chondrosarcomas 2324. Wilson and colleagues observed that the difficulties with the radiological diagnosis of CMF resulted more from the diversity of sites of involvement and its relative rarity rather than from its radiographic features 23.

CMF rarely arises within the ribs 71819202122, with only seven cases described so far. The tumor we describe in the rib is histologically typical CMF, with low proliferative Ki-67 index and almost total absence of mitotic activity, but it is unusual not only because of the location and size, but also because of the novel chromosomal translocation found herein and the additional non-clonal random chromosomal aberrations. The latter might be indicative of genetic instability 40 and may reflect on its large size, though this is speculative. There is the need to identify genetic or molecular markers that can aid in confirming the histological impression. Cytogenetic studies of CMF are limited, with 15 previously reported cases in the English language medical literature 29303132333435363738. In the 15 previously reported cases, the tumor was shown to be diploid, with the most common recurring clonal abnormalities involving chromosome 6. In particular, rearrangement of the long arm of chromosome 6 at bands q13 and q25 was most frequent 29303132333435363738. Bridge and Tarkannen both described cases of CMF with aberrations in chromosomes 2 and 5 2938, and Ozaki 34 described a case with a gain involving 13q and losses involving 1p, 12q, 16p, 17p, 19p, 19q, 20q, and 22q. The remaining 12 reported cases demonstrated abnormalities in chromosome 6 30313233353637. Four of these cases demonstrated a pericentric inversion, inv(6)(p25q13) 323536. One other case demonstrated a different pericentric inversion, inv(6)(p25q23), and the remainder of the cases demonstrated rearrangements in three distinct breakpoint cluster regions, namely 6p23-p25, 6q12-q15, and 6q23-q27 29303132333435363738. The cytogenetic findings in our case of the rib mass (case no. 2) revealed clonal translocation t(1;5)(p13;p13) and represents the first report of this clonal rearrangement as the sole abnormality in CMF. Although structural chromosomal aberrations involving 1p13 414243 and 5p13 3544 have been described in chondrosarcomas, these have not been previously reported in CMF.

The morphologic features of CMF may mimic other cartilage-producing neoplasms, especially when occurring in flat bones. Most importantly, CMF can be misdiagnosed as a malignant tumor because of its variable histology, occasional striking cytologic atypia, occasional soft tissue extension, and recurrences. Because of the rarity of CMF, little is known regarding its histogenesis, genetic and biologic characteristics. Based on its variable immunostaining for smooth muscle actin (SMA) and S-100, some investigators have suggested that they are related to chondroblastoma, but CMF is thought to be far less aggressive and considerably different histologically 57912262728. The chondroid areas of CMF showed S-100 immunoreactivity in greater than 70% of cases, but did not stain for SMA. Conversely, the peripheral regions surrounding the chondroid areas commonly showed SMA immunoreactivity, but did not stain for S-100 5262728.

The purely histological differential diagnosis of CMF may include chondroblastoma, fibrous dysplasia, chondromyxoma-like or chondroblastic variant of low-grade osteosarcoma, and high-grade myxoid chondrosarcoma 478910. The distinction is important due to their different natural history, prognosis and management. The location, age of the patient, and the radiological features are extremely important in the diagnosis of majority of bone neoplasms. Chondroid neoplasms of the small bones of distal extremities are seldom malignant, and conversely cartilagenous tumors occurring in the flat bones (including ribs and pelvic bones) are more often malignant than benign. To decrease the risk of diagnostic error, the pathological diagnosis of CMF must be established on the basis of careful correlation of clinical, radiographic and immunohistochemical findings 526272845. Chondroblastomas are epiphyseal, unlike CMF which are metaphyseal in location. Additionally, the chondroblasts in chondroblastoma have eosinophilic, polygonal cytoplasm (not stellate as in CMF), and calcification is a conspicuous feature of most chondroblastomas, unlike CMF 526272845. Fibrous dysplasia may, at times, show extreme myxoid change; however, the accompanying presence of irregular osteoid seams and the radiological appearance help to make the distinction from CMF 526272845. None of the four cases herein reviewed were misdiagnosed as any of the differential diagnosis of CMF mentioned above. Immunohistochemistry is not helpful in distinguishing chondrosarcoma from CMF because both tumors are known to express vimentin and S-100 protein 526272845. Chondromyxoma-like or chondroblastic variant of low-grade osteosarcoma, which have very large CMF-like areas, are difficult to differentiate from CMF on a small biopsy. However, mitoses and nuclear atypia, which are seen in osteosarcomas, are not the features of CMF. The diagnostic hallmark of osteosarcoma is the presence of osteoid production, which is totally lacking in CMF 526272845.

CMF can and should be distinguished especially from chondromyxoma-like or chondroblastic variant of low-grade osteosarcoma and high-grade myxoid chondrosarcoma, two tumors which are more frequently seen, more aggressive and have the capacity to metastasize. Hence, any lesion labeled as CMF is best confirmed and managed in a specialty bone center, where clinical, radiological and pathological correlation can be optimally achieved. Although often difficult to diagnose, CMFs are relatively easy to treat by curettage with bone grafting or "enbloc" resection, with mininal risk of recurrence. The t(1;5)(p13;p13) is a novel sole clonal cytogenetic abnormality in CMF. Although cytogenetic studies of CMF have not yet yielded a specific causative genetic abnormality, cytogenetic analysis may be of value, and should be performed in all cases of CMF with unusual or borderline clinicopathological features.

The author(s) declare that they have no competing interests.

HBA participated in the histopathological evaluation, performed the literature review, acquired photomicrographs and drafted the manuscript. AVP, RLM, MAG and UNMR conceived and designed the study, and revised the manuscript for important intellectual content. RLM and GAM clinically managed the three cases, and reviewed the clinical and radiological features of the 3 cases.SMG and US reviewed and interpreted the final cytogenetic diagnosis.AVP and UNMR reviewed and gave the final histopathological diagnosis. All authors read and approved the final manuscript.