—  SPECIALTY CONFERENCE  —

Bone & Soft Tissue Pathology

Case 4 - Chondromyxoid Fibroma of Bone

Pancras C. W. Hogendoorn
Leiden University Medical Center
Leiden, Netherlands


Click on each slide thumbnail image for an enlarged view
Clinical History
A 29-YOF presents with a history of three months of pain in the lower back, extending into the right leg. There is neither a relation of the pain with coughing nor with position of the vertebral column. Her medical and family history are unremarkable. There were no neurovascular abnormalities. Routine blood laboratory findings were within normal limits. At physical examination, there was no swelling palpable, though there was pain upon deep palpation of the dorsal back at the right sacro-iliac area. A plain X-ray Radiology showed a bubbly ovoid shape a lytic lesion (size: 4 x 3 cm), with a sclerotic rim, in the right ilium. The overlying cortex was focally interrupted. MRI scanning was performed and showed on T1-weighted images a sharply demarcated lesion with intermediate signal intensity comparable to the surrounding muscles in the absence of surrounding oedema. T2-weighted MR image showed homogeneous high signal and subtle expansion.

Bone scans showed a solitary lesion of the right ilium wing with only minimal-mild activity.

Taken together clinical features were favouring a diagnosis of a cartilaginous tumour of benign/low grade malignant nature.


Case 4 - Figure 1 - Plain X ray showing in the cranial right iliac wing a lobulated lytic lesion with sclerotic margins with dimensions of 4 x 3 cm
Case 4 - Figure 2 - Enlarged plain X ray 4 months later showing essentially the same morphology of the lesion
Case 4 - Figure 3 - T1 weighted MR image showing the lesion with intermediate signal intensity comparable to the surrounding muscles. The lesion is sharply demarcated. No surrounding oedema



Case 4 - Figure 4 - T2 weighted MR image showing homogeneous high signal and subtle expansion
Case 4 - Figure 5 - T1 weighted MR image showing the lesion with intermediate signal intensity and sharp margins in another plain
Case 4 - Figure 6 - H&E stained sections of open biopsy specimen showing the morphology of the lesion in different areas and at different magnifications



Case 4 - Figure 7 - H&E stained sections of open biopsy specimen showing the morphology of the lesion in different areas and at different magnifications
Case 4 - Figure 8 - H&E stained sections of open biopsy specimen showing the morphology of the lesion in different areas and at different magnifications
Case 4 - Figure 9 - H&E stained sections of open biopsy specimen showing the morphology of the lesion in different areas and at different magnifications



Case 4 - Figure 10 - H&E stained sections of open biopsy specimen showing the morphology of the lesion in different areas and at different magnifications
Case 4 - Figure 11 - H&E stained sections of open biopsy specimen showing the morphology of the lesion in different areas and at different magnifications
Case 4 - Figure 12 - H&E stained sections of open biopsy specimen showing the morphology of the lesion in different areas and at different magnifications

Pathology
Histologically the lesion showed to be formed by multiple lobules of myxochondroid matrix with moderately pleomorphic chondrocyte-like cells. The lobules are rimmed by spindle cells and scant giant cells. Microscopic cystic changes were evident. Neither bone permeation nor erosion was found. No obvious mitotic activity was seen.

Diagnosis: Chondromyxoid Fibroma of bone

Discussion

Introduction
Chondromyxoid fibroma (CMF) is a benign cartilaginous bone tumour. Since its first definition [1] it appeared as an emblematic entity:

  1. for the challenging differential diagnosis; because of its morphological features has to be distinguished from a high-grade chondrosarcoma
  2. for its possible histogenesis (chondrogenic or non), which is difficult to identify because of the polymorphous microscopic appearance ranging from a chondroid to a myxoid and even fibrous phenotype [2, 3, 4] .

Epidemiology
Chondromyxoid fibroma is a very rare neoplasm accounting for less than 1% of all bone tumours, and less of 2% of all benign bone tumours. Despite 75% of the cases occur in patients younger than 30 years of age, a wide range is reported (4-79 year) Males are slightly more commonly affected [2, 3, 5, 6] .

Clinics
Often a long story of mild pain is reported at the first clinical examination. Bones of the lower extremity are more frequent affected, esp. the metaphyseal region. Radiology shows characteristically an eccentric lytic lesion (wide size range: 1-14 cm), with a sclerotic rim, and ovoid shape (in parallel with the long axis of the bone) with bubbly appearance [3, 4, 5, 6, 7, 8, 9, 10] . Simple curettage sometimes with the application of adjuvant phenolisation or cryosurgery is the standard treatment. The rate of recurrence is about 15%. Some advocate where appropriate and feasible en bloc resection. The prognosis is excellent.

Pathology
Histologically the tumour shows a multilobular pattern. The size of the lobules varies from tumour to tumour as well as from field to field. They are composed of polymorphous fibrous, myxomatous and chondroid areas. However frank hyaline cartilage is less often recognized. The neoplastic cells vary in shape from spindle to stellate, focally atypical nuclei are recognized in 20-30% of the cases. Usually the centre of the lobules is less cellular than the periphery. At the edge of the latter, giant cells can often be recognised. Chunky calcification can be present, especially in older patients [3, 4, 5, 6, 7, 8, 9, 10] . On gross examination the specimens have a white to flesh coloured appearance with a soft texture. Cystic and hemorrhagic areas may be present.

Differential Diagnosis
Chondromyxoid fibroma can be mistaken for central high-grade chondrosarcoma (G2-G3). However, in the latter there is usually more abundant hyaline cartilage. Furthermore high grade chondrosarcomas show higher degree of atypia and mitosis [4] .

The differential diagnosis with central dedifferentiated chondrosarcoma is based on the presence, in the latter, of an abrupt passage from differentiated part to dedifferentiated part and on the clear-cut anaplasia and number of mitosis present in the less differentiated part [4].

Presence of "chondroid" matrix could lead to a misdiagnosis of chondroblastoma. However the latter is characterized by abundant chondroblasts and more diffuse multinucleated giant cells [11].

Presence of cartilaginous islands close to spindle cells lesion could resemble fibrocartilaginous dysplasia. However this is characterized by the presence of nearby typical areas of fibro-osseous lesions. Furthermore the islands of cartilage show peripheral enchondral ossification merging with the surrounding fibro-osseous lesion.

A rare chondromyxoma-like variant of low-grade osteosarcoma has been described [11, 12] This strictly resembles chondromyxoid fibroma and does only shows subtle osteoid deposition. However the neoplastic cells show clear-cut atypia and mitosis are more frequent.

In general the combined careful evaluation of clinical, radiological and histological features is leading to the correct diagnosis.

Cytogenetics
Karyotypes of 12 cases are reported in the literature. Complex cytogenic abnormalities are reported. In ten cases chromosome 6 appears to be involved and non-random clonal abnormalities involving 6p25, 6q13 and 6q23 are reported. Of interest 4 cases with peri-centromeric inversion are described [3 cases inv(6)(p13q25) and 1 case inv(6)(p13q23)] [13, 14, 15, 16, 17, 18] .

Tumour Biology
The name of this tumour focuses on similarities to cartilage, based on histological, histochemical, immunohistochemical and ultrastructural studies and the characteristic spectrum of cell types ranging from rounded chondroblastic cells to spindled, more fibroblastic elements [3] . Given the intratumoural heterogeneity, the amount of chondroid areas is far from being fixed. Hence in cases where this latter is scantly present it is hard to recognize such tumour as a cartilage forming one, furthermore mature hyaline cartilage is rarely recognized. However since the early morphological observation the morphological spectrum of the constituent cells was related to a variation in tissue maturation. In other terms, mainly in the centre of lobules, more chondroid areas are recognized with features of cells and extracellular matrix strictly resembling normal cartilage while myxoid and fibrous areas showed cells and extracellular matrix different form normal cartilage. Such observations where enforced by ultrastructural and immunohistochemical studies showing chondrocytic ultrastructure of the cells in the chondroid areas [19, 20, 21] together with an intense S-100 staining, stronger than in the rest of the tumour [7, 9, 21] . The apparently "biphasic" nature of the tumour may reflect different degree of commitment of neoplastic cells towards cartilaginous differentiation. Of interest in this regards is the experimental demonstration of different biochemical composition of extracellular matrix, in terms of proteoglycans and collagen amount, corresponds to different morphology of the of constituting cells and of the extracellular matrix in which they are embedded [22]. The cellular areas and the matrix rich areas - the latter being classified as either myxoid or chondroid - differ in the amount of type I and II collagen and aggrecan. Generally, in cellular areas populated with predominantly spindle shaped cells collagen type I is found [22], with no evidence of the presence of collagen type II, or aggrecan. Aggrecan production on the other hand is evident in the myxoid areas, where the cells are displaying a stellate morphology. Cells possessing rounded morphology and an extracellular matrix morphology and biochemical make up similar to normal cartilage (presence of aggrecan and collagen type II) characterize the chondroid regions [22].

The different level of commitment towards cartilaginous differentiation was shown to results in a different pattern of expression [30] . In particular a leading role is played by molecules regulating cartilage growth plate, which appear to be significantly upregulated in more chondroid areas versus the rest of the tumours [30] .

According to and complementary with the different level of cartilage differentiation found in this tumour is the description of myofibroblastic features present mainly in the spindle cells and absent in the round cells with cells with intermediate features [24] . There are scattered reports of SMA expression as well as ultrastructural evidence of myofilaments with focal densities in cartilaginous neoplasm's [24, 25, 26] .

It has been shown that articular cartilage cells may show contractile function and smooth-muscle actin (SMA) expression [27, 28, 29] . The latter can be a result of upregulation by TGF-β1 or down regulation by platelet derived growth factor BB (PDGF-BB) [29] .

A recent study has further characterized this features as reflecting partial myofibroblastic differentiation both per immunophenotype as well as ultrastructural and immuno-ultrastructral features. Furthermore an active TGF- b signalling has been demonstrated between neoplastic and non-neoplastic stromal cells probably promoting a different organization of the contractile actin in spindle and round cells, with a continuum spectrum, and in parallel a different production of extracellular matrix [30].

In conclusion chondromyxoid fibroma is a unique clinicopathological entity reflecting different steps of cartilage differentiation as well as commitment towards other lineage ("transdifferentiation" i.e. partial myofibroblastic differentiation). Improving of scientific knowledge on this tumour will be likely of great benefit in further understanding of neoplastic chondrogenesis. The diagnostic caveat is not recognising this benign entity and overcalling the lesion as a chondrosarcoma leading to unnecessary – often mutilating surgery.

References

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