the neoplastic chondrogenesis of two rare cartilaginous tumours
Salvatore, R.
Citation
Salvatore, R. (2010, June 22). Chondroblastoma and chondromyxoid fibroma:
disentangling the neoplastic chondrogenesis of two rare cartilaginous tumours.
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Benign cartilaginous tumours of bone: from Morphology to somatic and germ-line genetics
Chapter 2
1
Salvatore Romeo, MD,
2Pancras CW Hogendoorn MD, PhD and
1Angelo Paolo Dei Tos MD
1 Treviso Regional Hospital, Department of Pathology, Treviso, Italy and 2 Leiden University Medical Center, Department of Pathology, Leiden, The Netherlands. The authors are partners within EuroBoNeT, a European Community granted network of excellence for studying pathology and genetics of bone tumours
Abstract
Benign cartilaginous tumours of bones, intrinsic to their name, are tumours forming cartilaginous matrix with a clinically benign behaviour. In this group we recognize:
osteochondromas, (en) chondromas, chondroblastomas and chondromyxoid fibromas. This group includes common tumours, i.e. osteochondroma and (en)chondroma and rare tumour such as chondroblastoma and chondromyxoid fibroma. Several benign and malignant tumours may mimic benign cartilaginous tumours of bones. We reviewed the main morphological features and the differential diagnosis is discussed. The genetics of these tumours is intriguing ranging from single gene event (i.e. EXT mutation in multiple osteochondromas) to heterogeneous rearrangements with no recurrent involved chromosomal regions such as in chondroblastoma. The main genetics findings are hereby reviewed.
Intrinsic to their name, cartilaginous tumours resemble normal cartilage in terms of cellular morphology and quality of the produced extracellular matrix (ECM). The 2002 classification of World Health Organization defined cartilaginous tumours by the presence of chondroid matrix, at least in foci.1 Such definition stresses the importance of a specific ECM produced by the neoplastic cells. Cartilage matrix is composed by: water for 72-75%, proteoglycans 10%, Collagens 16%, other glycoproteins 1.6% and minerals 0.5%. Collagen type II is the major dry weight component of cartilaginous tissue. Other types of collagen mainly found in cartilage are collagen type IX, X and XI. Proteoglycans are made up of a core protein to which glycosaminoglycan (GAG) chains are attached. GAGs in cartilage consist of chondroitin sulphate, heparan sulphate, dermatan sulphate and hyaluronic acid.
The most represented proteoglycan in cartilage is aggrecan. GAGs distribution is not uniform, their highest concentration is around the lacunae, so-called territorial matrix, and less-so in the inter-territorial matrix, the matrix far from the cells.2 Within the wide range of cartilaginous tumours, in agreement with their clinical behaviour, we can recognize benign and malignant entities. Here we focus on benign cartilaginous tumours of bones, which in general are much more frequent and pose differential diagnostically more challenging questions then their malignant counterparts.3-5 As listed in the WHO 2002 classification we recognize, in order of frequency: osteochondroma,(en)chondroma, chondroblastoma and chondromyxoid fibroma (Tab 1). Synovial chondromatosis is not included as it is not originating from bone. The same is true for soft tissue chondroma. Peripheral chondroma will be only briefly mentioned. An accurate estimation of incidence of benign bone cartilaginous tumors is difficult because most of the lesions are asymptomatic and therefore they will not draw the attention of the patient or clinician. Furthermore nation-wide epidemiological studies for non-surgically treated patients are missing.
An exception to this is the dutch national survey of tumours and tumour like lesions in children recently reported.6 In this survey it is clear that osteochondroma are by far the most frequent bone tumours at childhood which are surgically
Table 1 Clinical features of benign cartilaginous tumours of bone
removed outnumbering all other types of bone tumours, benign and malignant ones together.6
Morphology of benign cartilaginous tumours of bones and their differential diagnosis
Bone pathology, more than other pathology subspecialties, requires integration of clinical and radiographic information before final diagnosis can be made.7 This is also true for benign bone cartilaginous tumours, in which each lesion has a specific site of preferential involvement within the skeleton with specific features helping proper classification in a new clinical case (Table1). Therefore radiological examination before histology is a prerequisite. Some important information can be obtained and are relevant for the diagnostic process3:(1) establishing if multi- ple lesions or a solitary lesion is occurring,(2) identifying which bone and which location within the bone is affected,(3) measuring the size of the lesion,(4) pattern of growth within the bone (i.e. permeative or with sclerotic rim), (5)evaluating extension outside the bone in the surrounding soft tissue,(6) characterizing type of matrix,(7) recognizing eventual periosteal reaction and (8) presence of fracture.
Osteochondroma
As defined in WHO 2002: "Osteochondroma is a cartilage capped bony projection arising from the external surface of bone containing a marrow cavity that is continuous with that of the underlying bone"8 (Figure 1 A,B,C). The metaphyseal region of the long bones is the most common site of the involvement, but osteochondromas affect often flat bones, such as ileum and scapula, too. Generally, osteochondromas occur in bones formed by enchondral ossification.
Osteochondroma is mostly recognized either as an incidental finding or due to secondary events such as aesthetic or mechanical problems. More often the patient is a young adult, no gender predilection is reported,8 affected either by a solitary lesion (solitary osteochondroma) or by multiple osteochondromas (previously known as hereditary multiple exostosis). Approximately 15% of patients with osteochondromas have multiple lesions. Solitary and multiple osteochondromas are histologically indistinguishable.9
In the pediatric population the occurrence is 35,2 per million inhabitants per year.6 Osteochondroma has three components, namely perichondrium, cartilage cap and bony stalk. Remarkably only the cartilage cap is neoplastic as shown by the fact that in solitary osteochondroma homozygous deletion of EXT1 gene is only occurring in chondrocytes of the cartilaginous cap and neither in the cells of perichondrium nor in the cells from the bony stalk.10 The histology of the cartilage cap has a striking resemblance to the growth plate in terms of cell morphology and organization (Figure 1B and C). Growth plates, needed for the development/
elongation of long bone, are arranged in columns of chondrocytes that are gradually replaced by the newly deposited bone (enchondral ossification). The cartilage cap of osteochondroma often shows foci of columnar cell organization and gradually merges into the underlying spongiosa. Medullary spaces in the stalk of osteochondroma are filled with haemopietic tissue and/or adipose tissue.
Osteochondroma cells show minimal atypia with rare binucleate cells. The cartilage cap is usually less than 2 cm thick. Interestingly, similarly to the growth plate in pubertal spurt , the cartilage cap usually decreases in thickness and undergoes calcification after the onset of puberty.9
The differential diagnosis of osteochondroma includes: 1 benign lesions simulating osteochondroma, 2 malignant lesions simulating osteochondroma.
Benign lesions morphologically similar to osteochondromas are radiation induced osteochondromas. They occur in 6-31,7 % of patients who underwent bone irradiation in childhood, with a variable time of development.11-13 The exact mechanism driving these tumours is poorly understood. Benign lesions macroscopically similar to osteochondroma also occur in Dysplasia Epiphysealis Hemimelica (Osteochondroma of the Epiphysis, Trevor's Disease or Tarsoepiphyseal Aclasis) and in metachondromatosis.14 Dysplasia epiphysealis hemimelica (DEH) is a skeletal developmental disorder, usually manifested in early childhood, in which there is unilateral irregular enlargement of a medial epiphysis of the lower femur or upper tibia, distal tibia, and talus. Epiphyseal regions are most affected and multiple lesions may occur. Microscopically clumping of chondrocytes within a fibrillary chondroid matrix is present.15 Metachondromatosis mimis osteochondromas and DEH. This autosomal dominant inherited condition is characterized by synchronous occurrence enchondromas and osteochondroma.
These latter are microscopically identical to solitary and multiple osteochondromas.
However some important differences may help the differential diagnosis. First of all, osteochondromas in metachondromatosis occur in the hands and feet.
Furthermore osteochondromas of metachondromatosis point toward the epiphysis, while solitary and multiple osteochondromas occur mainly in long or flat bones and point away from the epiphysis. Finally, osteochondromas in metachondromatosis, but not in multiple osteochondromas, may regress.
The pathogenesis of Trevor's disease and metachondromatosis is still unknown, although it most likely different from the one in osteochondroma.15
Periosteal chondroma, subungueal exostosis and bizarre parosteal osteochondromatous proliferation (Nora's lesion) are benign periosteal cartilage forming lesions which may simulate osteochondromas. In case of these tumours, the differential diagnosis is based on the recognition of the typical growth pattern of osteochondroma: i.e. cartilaginous cap with a growth plate-like architecture covering a bony stalk made up from flaring of the cortex. In other words, the periosteal cartilaginous tumours we mentioned (periosteal chondroma, subungueal exostosis and Nora's lesion) are just attached to the bone and not originating from the cortex. Furthermore they miss the growth plate-like organization of the cartilaginous matrix.
Malignant lesions simulating osteochondroma are periosteal, osteosarcoma paraosteal osteosarcoma, periosteal chondrosarcoma and peripheral chondrosarcoma. Paraosteal osteosarcoma is a low-grade fibro-osseous lesion, while periosteal osteosarcoma is a chondroblastic osteosarcoma, predominantly composed of lobules of low-grade to intermediate-grade hyaline cartilage. Periosteal chondrosarcoma is producing mainly cartilage, soft tissue invasion is often observed and medullary involvement is rarely found. The three sarcomas above mentioned show atypia with nuclear pleomorphism and mitotic activities.
Osteochondroma may undergo malignant transformation towards peripheral chondrosarcoma - 1% of the solitary, 4-5% of the multiple.9 The triad - clinical, radiological and pathological data - is needed to establish the final diagnosis.
Large size of the cartilage cap (especially increase in thickness), growth of the tumour after puberty and pain raise suspicion for malignant transformation.
Histologically, permeation of the bone and formation of nodules of invasive cartilage
within adjacent soft tissues separate from the main tumour, myxoid changes, mitotic activity, atypia and necrosis are favouring a diagnosis of malignancy.
Radiology, especially MRI, might be of help for differential diagnosis with well differentiated GI16 chondrosarcomas.17 In fact upon intravenous administration of gadopentate dimeglumine peripheral enhancement is found in osteochondroma reflecting the vascularized tissue covering the cartilaginous cap.17 In G1 peripheral chondrosarcoma enhancement is central regarding the vascularized septa.17 Furthermore absent staining for BCL2 and PTHLH favours a diagnosis of osteochondroma.18,19 Other type of sarcomatous transformation are also reported in osteochondroma, mainly osteosarcoma.20-24
Enchondroma
"Enchondroma is a benign hyaline cartilage neoplasm of medullary bone. Most tumours are solitary, however, they occasionally involve more than one
bone or site in a single bone"25(Figure 1D,E,F).
Multiple enchondromas or enchondromatosis is known as Ollier's disease26 whereas enchondromatosis associated with soft tissue hemangiomas is known as Maffucci's syndrome.27 Both genders and all age groups are equally affected by enchondroma.
Approximately 50% of solitary enchondromas are found in the hands, typically in the middle and distal portions of the metacarpals and in the proximal portions of the phalanges, 10% in the feet and 20% in the proximal and distal parts of the femur and the proximal part of the humerus.
Microscopically, enchondroma is defined by its sharply demarcated lobules of mature, hypocellular hyaline cartilage (Figure 1E) with few double-nucleated cells without cytological atypia, however cellularity of the tumour may vary. The cells are arranged in small clusters and show minimal variation in size and shape. The matrix does not show any myxoid change. Calcification and ossification are common, especially at the periphery of cartilage lobules. This characteristic pattern is called bone encasement (Figure 1F). Extension of the enchondroma into soft tissues or permeation of medullary bone must be identified before a diagnosis of chondrosarcoma is made. The chondromas in Ollier disease and Maffucci syndrome may demonstrate a greater degree of cellularity and cytological atypia, and may be difficult to distinguish from low-grade chondrosarcoma.
Diagnosis of enchondroma and its differential diagnosis, which includes mainly central low-grade chondrosarcomas, are helped by radiological and clinical evaluation. A small percentage of enchondromas undergoes malignant transformation, usually through a slow process, occurring over decades.3,25 Those transformations are more common in long bones and only rarely found in short bones.28 Remarkably enchondromas of the hands and feet often show cytologic features suggestive of malignancy but their biologic behavior is usually benign.
3,25,28 Pain, together with large size of tumour, scalloping of the cortex and extension in the surrounding soft tissue indicate possibility of malignant changes that can be confirmed or ruled out by histological findings of malignancy such as infiltrative pattern with bone erosion and marrow permeation, and cytological atypia.16 Remarkably, especially in the differential diagnosis of enchondroma versus central chondrosarcoma GI radiological evaluation, including also MRI, may suggest malignancy but has limited power to differentiate the two entities, therefore in dubious cases histological examination is required.29 Fast contrast-enhanced MR imaging may increase sensitivity.30
Chondroblastoma
Chondroblastoma is a rare benign bone neoplasm that typically involves the epiphyses of long bones in skeletally immature individuals, i.e. before puberty. It accounts for less than 1% of all bone tumours, with male sex predominance (2:
1), incidence in patients below 18 years old is 1,18 per million inhabitants per year.6,31
Clinically, patients usually have pain with impaired function. Radiographically, the classic chondroblastoma is a well-circumscribed, ovoid lytic lesion with a thin, partially sclerotic margin. The lytic region may show lobulation and contain radiodensities centrally, reflecting the chondroid matrix calcification occurring in the lesion (Figure 2A).
Microscopically, chondroblastoma is a cellular lesion. The lesion is composed of round-to-polygonal immature cartilage cells (chondroblasts) set within a distinctive and heterogeneous matrix. The latter can be osteoid, fibrous or so-called 'chondroid' (Figure 2B), or even, but more focally and rarely, as clearly identifiable mature cartilage. The cells have well-defined cytoplasmic boarders, clear to slightly basophilic cytoplasm and a round-to-ovoid nucleus (Figure 2C). Although nucleoli may be present, the nuclei of the cells are bland and may contain grooves similar Figure 1. Osteochondroma's feature: A, A bony projection covered by a cartilaginous cap occurs at the metaphyseal region of a young individual (growth plate is still recognizable) and points away from the metaphysis (plain radiography frontal and lateral view).B, Histologically, a bony stalk covered by a cartilaginous layer (HE staining, original magnification 40X). C, A focal columnar arrangement and cells resembling growth plate chondrocytes are recognized (HE stainings, original magnification 200X). Enchondroma's feature: D, A lytic lobulated lesions occurs at the base of the middle phalanx of the fifth finger (arrow head, plain radiography).
E, A specimen from curettage is made up from lobules of cartilage (HE staining, original magnification 40X). F, Atypical features are absent and bone encasement is present at the periphery of the lobule (HE stainings, original magnification 200X). HE indicates hematoxylin and eosin.
to those of the Langerhans cells of Langerhans cells histiocytosis. Osteoclast-like giant cells are often present and most likely reactive.32 Mitoses are scarce but present. Very characteristic for chondroblastoma is, so called "chicken wire calcification", the linear punctuate pericellular calcification that envelopes and links individual chondroblasts. Nonetheless, chondroblastomas show only limited differentiation of chondrocytes: chondroblast-like cells are positive for immunostains for S100 protein, vimentin, neuron-specific enolase and to cytokeratins31 and ECM is negative for collagen type II.33 A secondary aneurysmal bone cyst may be encountered in as many as 33 percent of cases.31
The main differential diagnosis of chondroblastoma includes mainly giant cell tumour of bone, clear cell chondrosarcoma and chondromyxoid fibroma. The former affects the same epiphyseal location however it occurs at different time points in life. In the absence of typical chondroid matrix an immunostain for S-100, positive in chondroblastoma and negative in giant cell tumour of bone, is helpful. Clear cell chondrosarcoma also affects epiphysis of long bones. However clear cell chondrosarcoma shows a higher degree of calcification at plain radiology and histologically a more calcified matrix and the presence of cartilage matrix positive for collagen type II immunostaining.34 Chondromyxoid fibroma affects different Figure2. Chondroblastoma's feature: A, An eccentric epiphyseal lytic lesion is affecting the tibia (x-ray on the right and T2-weighted MRI on the left) (courtesy of Dr C. Van Rijswijk). B, Chondroid matrix is found in chondroblastoma but not clear-cut hyaline cartilage matrix (HE staining, original magnification 40X). C, Chondroblast-like cells and multinucleated giant cells are found in the more cellular areas (HE stainings, original magnification 400X).
Chondromyxoid's fibroma's feature: D, A lytic lesion with sclerotic lesion affecting metadiaphyseal region of the tibia with extension in the surrounding soft tissue (x-ray on the right and T2-weighted MRI on the left), (courtesy of Dr C. Van Rijswijk). E, Lobules of myxochondroid matrix are found in chondromyxoid fibroma (HE staining, original magnification 40X). F, Spindled and stellated cells are present at the periphery of lobules of chondromyxoid fibroma (HE stainings, original magnification 400X). HE indicates hematoxylin and eosin;
MRI, magnetic resonance imaging
location, i.e. metadyaphysis of long bones, however in short bones and in little biopsy differential diagnosis may be difficult. Furthermore chondroblastomas are positive for cytokeratin immunostains, namely CK8, CK18 and CK19, while chondromyxoid fibromas are negative for these immunostains.35
Chondromyxoid fibroma
Chondromyxoid fibroma (CMF) is a benign cartilaginous bone tumor with a polymorphous microscopic appearance as implicated by its name, ranging from a chondroid to a myxoid and even fibrous phenotype (Figure 2 D,E,F).36 It can affect almost every osseous site, however it is more frequently found in long (mainly proximal tibia) and flat bones - the iliac bone being the most frequent (~ 25%).36-
38 Metadiaphyseal region is more often affected in long bones, however less frequently, periosteal occurrence has been reported, too. Males in the second decades of their lives are more frequently affected however wide age range of occurrence is encountered. Incidence in young population is 0,48 per million inhabitants per year.6
The distinct histological features of CMF include lobules of spindle -, or stellate- shaped cells with abundant myxoid and chondroid extracellular matrix (Figure 2 E,F). The cellular elements might show rare mitosis and bland atypia. The histological spectrum of CMF closely resembles different steps of in vitro chondrogenesis because of the presence of round cells similar to mature chondrocytes and less differentiated spindle-cell precursors with myofibroblastic transdifferentiation, with positivity for immunostain for smooth muscle actin.39,40 Differences in extracellular matrix appearance correspond to variation in proteoglycans and collagen composition and in morphology of constituting cells. 41 The matrix-rich areas classified as either myxoid or chondroid depending on 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,41 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.41
The immature cartilage phenotype and eventual mitotic activity makes the pathological differential diagnosis with high-grade central chondrosarcoma, especially when dealing with small biopsies challenging. However, immunohistochemical assessment of high expression of p16-INK4, CCND1, and ALCAM favours a diagnosis of chondromyxoid fibroma.42
The main radiological and pathological features useful for differential diagnosis are summarized in Table 2.
Genetics of benign cartilaginous tumours
Specific molecular alterations have been identified in specific subtypes of mesenchymal tumours.43-46 The genetics findings includes three gross subclasses:
1) tumours harbouring a complex karyotype 2) tumours harbouring chromosomal translocation 3) tumours harboring a specific gene mutation. Two mechanisms are likely to drive tumour formation in benign cartilaginous tumours:1) a chromosomal translocation, 2) a specific gene mutation.
Upon translocation juxtaposed genomic sequence may result in a fusion protein
including COOH sequence from one gene and NH2 sequence from another gene (i.e. EWSR1-FLI1 in Ewing Sarcoma), such protein has usually strong transcription factor-like activity with subsequent dysregulation of the expression pattern.
Alternatively coupling of a strong promoter to a lowly expressed gene (i.e. USP6 coupled to COL1A1 promoter in Aneurysmal Bone Cyst) leads to its over-expression therefore acting as an oncogene. As a further alternative event disruption of the gene function (i.e. PAX3-FOXO1A in ARMS is resulting in disruption of FOXO1A) may occur with reduced expression and selective advantage for neoplastic cells survival and proliferation, therefore acting as a tumour suppressor gene.
Several translocations have been reported to occur in cartilaginous tumours, some of them appear to recurrently involve specific chromosomal regions (i.e. Nora lesion, CMF, etc.). However, their possible role in tumour formation is poorly understood. Specific knowledge of occurring breakpoints and of the consequences of their rearrangement needs to be refined.
Table 2. Main radiological/pathological feature useful for differential diagnosis
Osteochondroma and multiple osteochondromas
Regarding single gene mutation, the unique well recognized example in cartilaginous tumours is the mutation of EXT genes in multiple osteochondromas. Two genes, EXT1 and EXT2, respectively located at 8q24 and 11p11-p12, have been identified to cause multiple osteochondromas, an autosomal dominant disorder defined by the presence of at least two osteochondromas in the juxta-epiphyseal region of long bones.47-51 80% of the mutations are resulting in truncated (non-functional) EXT proteins.52-56 Structural changes in 8q22-24.1, where the EXT1 gene is located, have been reported in ten out of 30 sporadic and in 1 out of 13 hereditary osteochondromas.57,58 LOH detected by microsatellite analysis using DNA isolated
from the cartilaginous cap was found almost exclusively at the EXT1 locus in 3 of 8 sporadic and 2 of six hereditary osteochondromas.59 Fluorescence in situ hybridization revealed loss of the 8q24.1 locus in 27 of 34 (79%) osteochondromas.
60 Finally in seven out of eight sporadic osteochondromas, homozygous deletion of EXT1 was found.10 Remarkably EXT2 was found affected only in multiple osteochondromas and not in sporadic osteochondromas. All these findings suggest a model for osteochondroma in which both copies of EXT gene need to be inactivated for tumour to occur. The gene products, exostosin-1 (EXT1) and exostosin-2 (EXT2) form a Golgi-localised hetero-oligomeric complex that catalyzes heparan sulphate proteoglycans polymerization.61-65 Impairment of EXT genes lead to altered heparan sulphate proteoglycan long chain elongation, which in turn affects diffusion and efficient receptor binding of several signaling molecules such as Indian Hedgehog and fibroblast growth factor.66,67 These latter two are important for regulating cartilage proliferation and differentiation.
Enchondroma and enchondromatosis
The exact cause of enchondromatosis is unknown. Most cases of enchondromatosis are sporadic, but families with multiple affected members have been reported, possibly suggesting autosomal dominant inheritance with reduced penetrance.68 Alternatively a random spontaneous mutation is hypothesized. This might occur in early development, in mesoderm, therefore generating a mosaicism.68 This will explain the propensity of multiple enchondromatosis to affect predominantly one side of the body, in a similar way to what happens in GNAS mutation in McCune/
Albright syndrome.69 A mutation (p.R150C) in PTHR1 (3p22-p21.1) was reported in two out of six patients70 and in 3 out of 14 Ollier patients three additional heterozygous missense mutations (p.G121E; p.A122T and p.R255H) were identified in PTHR1. Both cells from an enchondroma as well as from leukocytes were habouring a R255H mutation.71 The p.G121E and p.A122T mutations were found only in one allele of enchondroma cells from the Ollier patient.71 These mutations were shown to decrease the function of the PTHR1 receptor.71 Despite these findings an elaborative study on 31 patients failed to detect any mutations in PTHR1.72 Furthermore PTHLH signaling has been shown to be active in Ollier disease.73,74 Thus, we speculate that a heterozygous PTHR1 mutation is likely to contribute to Ollier disease in a small subset of patients.
Rearrangements of chromosome 6 and the long arm of chromosome 12 (particularly q13q15) appear to be recurrent in chondromas, including also soft tissue chondromas.75-78 Transcription of HMGA2, in 12q15, has been shown to occur in 2 out of 2 enchondromas.79
Array CGH data of four Ollier samples (2 phalangeal enchondromas and 2 grade II chondrosarcomas) showed highly variable genetic abnormalities.80 One phalangeal enchondroma revealed no alteration while another sample showed complete loss of chromosome 6.80 The two grade II chondrosarcoma showed gains and losses of several chromosomes.80 One of the grade II chondrosarcomas showed gain of almost the entire chromosomes 2,5,8,15,19,20,21 and 22 and gain of parts of chromosomes 1,5,7,9,16,17 and 18.80 The other Ollier disease related chondrosarcoma grade II revealed losses on chromosomes 1,3,4,6,9,10,13,15,16,22 as well as amplifications on chromosomes 6,7,12,14,15,16,17,18,19.80 More over a del(1)(p11q31.2) has been described in a low grade chondrosarcoma of the scapula in an Ollier patient.81
Other syndromes with multiple enchondromas include both autosomal recessive disorders such as spondyloenchondromatosis82 as well as autosomal dominant disorders such as genochondromatosis83 and the previously mentioned metachondromatosis. For these rare syndromes the responsible genes are so far unknown.
Remarkably an association of central cartilaginous tumours (enchondromas and central chondrosarcomas) and breast carcinoma has been described.84,85 Breast tumours in this context occur at a relatively early age and show higher mitotic count, contained less lymphocyte infiltrate and less nuclear pleomorphism.85
Chondroblastoma
DNA flow cytometry studies show chondroblastoma mainly to be a low proliferative diploid neoplasm, however aneuploid near-diploid populations have been reported.
86 Thirteen abnormal karyotypes have been reported: no recurrent chromosomal changes have been described in chondroblastoma.77,87-90 Remarkably both unbalanced as well as balanced rearrangements are described, with no apparent recurring one. Some chromosomes seem to be more often involved: 5 cases each with involvement of chromosome 5 and 17 and 4 each for chromosome 8 and 2 .77,87-90 So far neither the breakpoints have been cloned, nor the consequences of these rearrangements been unraveled.
Chondromyxoid fibroma
Genetic mechanisms driving the pathogenesis of chondromyxoid fibroma are yet unknown. Sixteen abnormal karyotypes have been reported, describing both balanced as well as unbalanced rearrangements.91-93 Involvements of several regions of chromosome 6 e.g. 6p25, 6q13, 6q15, 6q23 and 6q25, have been described in 13 cases with an apparently identical inv(6)(p25q13) as the sole abnormality in 2 cases.89,94 This latter was proposed as potentially diagnostically useful to recognize chondromy xoid fibroma from high grade central chondrosarcomas. However the majority of chondromyxoid fibromas exhibit com- plex unbalanced rearrangements of chromosome 6.
A part from the "successful story" of osteochondroma and the "partial success" in enchondromatosis, no major achievement has been reached in understanding the genetics of benign cartilaginous tumours. The complexity of the identified rearrangements (i.e. chondroblastoma and chondromyxoid fibroma) and the rarity of these lesions have so far precluded the understanding of the genetic mechanisms.
Several lesions show similar morphology but the genetic mechanisms behind them are different and only partially elucidated. Vice versa different tumours may be related at the genetic level, at least concerning the reported structural chromosomal changes. The mechanisms regulating malignant transformation of multiple osteochondromas and enchondromatosis are poorly understood, too. It would be important to identify in advance those cases which will progress to sarcomas.
Answering these unsolved questions can broaden our understanding of neoplastic chondrogenesis. This may be well used for diagnostic purposes (i.e. diagnostic tools for differential diagnosis) as well as for therapeutic purposes (i.e. identifying alternative molecular targets). Finally we believe understanding the mechanisms operating in neoplastic chondrogenesis might help comprehension of non-neoplastic chondrogenesis.
Reference List
1. WHO: Cartilage tumours. World health organization classification of tumours.
Pathology and genetics. Tumours of soft tissue and bone. Edited by Fletcher C.D.M., Unni KK, and Mertens F. 2002: 234-257
2. Porter GA, Gurley MA, and Roth SI: Bone. Histology for Pathologists. Edited by Stern berg SS. Philadelphia, Lippincott-Raven, 1997: 85-105
3. Bovée, JVMG. and Hogendoorn, PCW. Cartilage-forming tumours of bone and soft tissue and their differential diagnosis. Curr.Diagn.Pathol 2001; 7, 223-234
4. Bell WC, Klein MJ, Pitt MJ, Siegal GP: Molecular pathology of chondroid neoplasms:
part 2, malignant lesions. Skeletal Radiol 2006, 35: 887-894
5. Bell WC, Klein MJ, Pitt MJ, Siegal GP: Molecular pathology of chondroid neoplasms:
part 1, benign lesions. Skeletal Radiol 2006, 35: 805-813
6. van den Berg H, Kroon HM, Slaar A, Hogendoorn PCW: Incidence of biopsy-proven bone tumors in children: a report based on the Dutch pathology registration "PALGA".
J Pediatr Orthop 2008, 28: 29-35
7. Jaffe, H. L. Osteogenic sarcoma. Tumours and tumourous conditions of the bones and joints , 256-278. 1958. Lea & Febriger, Philadelphia.
8. Khurana J, Abdul-Karim F, and Bovée JVMG: Osteochondroma. World Health
Organization classification of tumours. Pathology and genetics of tumours of soft tissue and bone. Edited by Fletcher CDM, Unni KK, and Mertens F. Lyon, IARC Press, 2002:
234-236
9. Hameetman L, Bovée JVMG, Taminiau AHM, Kroon HM, Hogendoorn PCW: Multiple Osteochondromas: Clinicopathological and Genetic Spectrum and Suggestions for Clinical Management. Hereditary Cancer in Clinical Practice 2004, 2: 161-173
10. Hameetman L, Szuhai K, Yavas A, Knijnenburg J, van Duin M, Van Dekken H, Taminiau AHM, Cleton-Jansen AM, Bovée JVMG, Hogendoorn PCW: The Role of EXT1 in non hereditary osteochondroma:identification of homozygous deletions. J Natl Cancer Inst 2007, 99: 396-406
11. Jaffe N, Ried HL, Cohen M, McNeese MD, Sullivan MP: Radiation induced
osteochondroma in long-term survivors of childhood cancer. Int J Radiat Oncol Biol Phys 1983, 9: 665-670
12. Bordigoni P, Turello R, Clement L, Lascombes P, Leheup B, Galloy MA, Plenat F:
Osteochondroma after pediatric hematopoietic stem cell transplantation: report of eight cases. Bone Marrow Transplant 2002, 29: 611-614
13. Taitz J, Cohn RJ, White L, Russell SJ, Vowels MR: Osteochondroma after total body irradiation: an age-related complication. Pediatr Blood Cancer 2004, 42: 225-229 14. Trevor D: Tarso-epiphysial aclasis; a congenital error of epiphysial development. J
Bone Joint Surg Br 1950, 32-B: 204-213
15. Bovée JVMG, Hameetman L, Kroon HM, Aigner T, Hogendoorn PCW: EXT-related pathways are not involved in pathogenesis of Dysplasia Epiphysealis Hemimelica and Metachondromatosis. J Pathol 2006, 209: 411-419
16. Eefting D, Schrage YM, Geirnaerdt MJ, Le CS, Taminiau AH, Bovee JV, Hogendoorn PC:
Assessment of interobserver variability and histologic parameters to improve reliability in classification and grading of central cartilaginous tumors. Am J Surg Pathol 2009, 33: 50-57
17. Geirnaerdt MJ, Bloem JL, Eulderink F, Hogendoorn PCW, Taminiau AHM: Cartilaginous tumors: correlation of gadolinium-enhanced MR imaging and histopathologic findings.
Radiology 1993, 186: 813-817
18. Hameetman L, Kok P, Eilers PHC, Cleton-Jansen AM, Hogendoorn PCW, Bovée JVMG:
The use of Bcl-2 and PTHLH immunohistochemistry in the diagnosis of peripheral chondrosarcoma in a clinicopathological setting. Virchows Arch 2005, 446: 430-437 Acknowledgment
The authors like to thank Carlos Eduardo De Andrea, MD and Malgorzata Wiweger, PhD for critically reviewing the manucript and Fabio Canal, MD for helping the pictures editing.
19. Bovée JVMG, Van den Broek LJCM, Cleton-Jansen AM, Hogendoorn PCW: Up-regulation of PTHrP and Bcl-2 expression characterizes the progression of osteochondroma towards peripheral chondrosarcoma and is a late event in central chondrosarcoma. Lab Invest 2000, 80: 1925-1933
20. Matsuno T, Ichioka Y, Yagi T, Ishii S: Spindle-cell sarcoma in patients who have osteochondromatosis. A report of two cases. J Bone Joint Surg [Am] 1988, 70: 137141 21. Tsuchiya H, Morikawa S, Tomita K: Osteosarcoma arising from a multiple exostoses
lesion: case report. Jpn J Clin Oncol 1990, 20: 296-298
22. van Lerberghe E, Van Damme B, van Holsbeeck M, Burssens A, Hoogmartens M: Case report 626: Osteosarcoma arising in a solitary osteochondroma of the femur. Skeletal Radiol 1990, 19: 594-597
23. Nojima T, Yamashiro K, Fujita M, Isu K, Ubayama Y, Yamawaki S: A case of
osteosarcoma arising in a solitary osteochondroma. Acta Orthop Scand 1991, 62: 290- 292
24. Bovée JVMG, Sakkers RJ, Geirnaerdt MJ, Taminiau AH, Hogendoorn PCW: Intermediate grade osteosarcoma and chondrosarcoma arising in an osteochondroma. A case report of a patient with hereditary multiple exostoses. J Clin Pathol 2002, 55: 226-229 25. Lucas DR and Bridge JA: Chondromas: enchondroma,periosteal chondroma,and
enchondromatosis. World Health Organization classification of tumours. Pathology and genetics of tumours of soft tissue and bone. Edited by Fletcher CDM, Unni KK, and Mertens F. Lyon, IARC Press, 2002: 237-240
26. Ollier M: De la dyschondroplasia. Bull Soc Chir Lyon 1899, 3: 22-23
27. Maffucci A: Di un caso encondroma ed angioma multiplo. Movimento medico- chirurgico, Napoli 1881, 3: 399-412; 565-575
28. Bovée JVMG, Van der Heul RO, Taminiau AHM, Hogendoorn PCW: Chondrosarcoma of the Phalanx: a locally aggressive lesion with minimal metastatic potential. A report of 35 cases and a review of the literature. Cancer 1999, 86: 1724-1732
29. Geirnaerdt MJA, Hermans J, Bloem JL, Kroon HM, Pope TL, Taminiau AHM, Hogendoorn PCW: Usefullness of radiography in differentiating enchondroma from central grade I chondrosarcoma. A J R 1997, 169: 1097-1104
30. Geirnaerdt MJ, Hogendoorn PCW, Bloem JL, Taminiau AHM, Van der Woude HJ:
Cartilaginous tumors: fast contrast-enhanced MR imaging. Radiology 2000, 214: 539- 546
31. Kilpatrick SE, Parisien M, and Bridge JA: Chondroblastoma. World Health Organization classification of tumours. Pathology and genetics of tumours of soft tissue and bone.
Edited by Fletcher C.D.M., Unni KK, and Mertens F. Lyon, IARC Press, 2002: 241-242 32. Huang L, Cheng YY, Chow LT, Zheng MH, Kumta SM: Receptor activator of NF-kappaB
ligand (RANKL) is expressed in chondroblastoma: possible involvement in osteoclastic giant cell recruitment. Mol Pathol 2003, 56: 116-120
33. Aigner T, Loos S, Inwards C, Perris R, Perissinotto D, Unni KK, Kirchner T:
Chondroblastoma is an osteoid-forming, but not cartilage-forming neoplasm. J Pathol 1999, 189: 463-469
34. Soder S, Oliveira AM, Inwards CY, Muller S, Aigner T: Type II collagen, but not aggrecan expression, distinguishes clear cell chondrosarcoma and chondroblastoma.
Pathology 2006, 38: 35-38
35. Bousdras K, O'Donnell P, Vujovic S, Henderson S, Boshoff C, Flanagan AM:
Chondroblastomas but not chondromyxoid fibromas express cytokeratins: an unusual presentation of a chondroblastoma in the metaphyseal cortex of the tibia.
Histopathology 2007, 51: 414-416
36. Ostrowski ML, Spjut HJ, and Bridge JA: Chondromyxoid fibroma. World Health
Organization classification of tumours. Pathology and genetics of tumours of soft tissue and bone. Edited by Fletcher CDM, Unni KK, and Mertens F. Lyon, IARC Press,
2002:243-245
37. Gherlinzoni F, Rock M, Picci P: Chondromyxoid fibroma. The experience at the Istituto Ortopedico Rizzoli. J Bone Joint Surg [Am] 1983, 65: 198-204
38. Wu CT, Inwards CY, O'Laughlin S, Rock MG, Beabout JW, Unni KK: Chondromyxoid fibroma of bone: a clinicopathologic review of 278 cases. Hum Pathol 1998, 29: 438- 446
39. Romeo S, Bovée JVMG, Grogan S, Taminiau AHM, Eilers PHC, Cleton-Jansen AM, Mainil-Varlet P, Hogendoorn PCW: Chondromyxoid fibroma resembles in vitro chondrogenesis, though differs in expression of signalling molecules. J Pathol 2005, 206: 135-142
40. Romeo S, Eyden B, Prins FA, Briaire-de Bruijn IH, Taminiau AHM, Hogendoorn PCW:
TGF-beta1 drives partial myofibroblastic differentiation in chondromyxoid fibroma of bone. J Pathol 2006, 208: 26-34
41. Soder S, Inwards C, Muller S, Kirchner T, Aigner T: Cell biology and matrix biochemistry of chondromyxoid fibroma. Am J Clin Pathol 2001, 116: 271-277 42. Romeo S, Oosting J, Rozeman LB, Hameetman L, Taminiau AH, Cleton-Jansen AM,
Bovée JVMG, Hogendoorn PCW: The role of noncartilage-specific molecules in differentiation of cartilaginous tumors: lessons from chondroblastoma and chondromyxoid fibroma. Cancer 2007, 110: 385-394
43. Mitelman F, Johansson B, Mertens F: The impact of translocations and gene fusions on cancer causation. Nat Rev Cancer 2007, 7: 233-245
44. Helman LJ, Meltzer P: Mechanisms of sarcoma development. Nat Rev Cancer 2003, 3:
685-694
45. Suva ML, Cironi L, Riggi N, Stamenkovic I: Sarcomas: genetics, signalling, and cellular origins. Part 2: TET-independent fusion proteins and receptor tyrosine kinase
mutations. J Pathol 2007, 213: 117-130
46. Riggi N, Cironi L, Suva ML, Stamenkovic I: Sarcomas: genetics, signalling, and cellular origins. Part 1: The fellowship of TET. J Pathol 2007, 213: 4-20
47. Bovee JV: Multiple osteochondromas. Orphanet J Rare Dis 2008, 3: 3
48. Stickens D, Clines G, Burbee D, Ramos P, Thomas S, Hogue D, Hecht JT, Lovett M, Evans GA: The EXT2 multiple exostoses gene defines a family of putative tumour suppressor genes. Nature Genet 1996, 14: 25-32
49. Wuyts W, Van Hul W, Wauters J, Nemtsova M, Reyniers E, Van Hul E, De Boulle K, De Vries BBA, Hendrickx J, Herrygers I, Bossuyt P, Balemans W, Fransen E, Vits L, Coucke P, Nowak NJ, Shows TB, Mallet L, Van den Ouweland AMW, McGaughran J, Halley DJJ, Willems P: Positional cloning of a gene involved in hereditary multiple exostoses. Hum Mol Genet 1996, 5: 1547-1557
50. Ahn J, Ludecke H-J, Lindow S, Horton WA, Lee B, Wagner MJ, Horsthemke B, Wells DE:
Cloning of the putative tumour suppressor gene for hereditary multiple exostoses (EXT1). Nature Genet 1995, 11: 137-143
51. Cook A, Raskind W, Blanton SH, Pauli RM, Gregg RG, Francomano CA, Puffenberger E, Conrad EU, Schmale G, Schellenberg G, Wijsman E, Hecht JT, Wells D, Wagner MJ:
Genetic heterogeneity in families with hereditary multiple exostoses. Am J Hum Genet 1993, 53: 71-79
52. Raskind WH, Conrad EU, III, Matsushita M, Wijsman EM, Wells DE, Chapman N, Sandell LJ, Wagner M, Houck J: Evaluation of locus heterogeneity and EXT1 mutations in 34 families with hereditary multiple exostoses. Hum Mutat 1998, 11: 231-239 53. Seki H, Kubota T, Ikegawa S, Haga N, Fujioka F, Ohzeki S, Wakui K, Yoshikawa H,
Takaoka K, Fukushima Y: Mutation frequencies of EXT1 and EXT2 in 43 Japanese families with hereditary multiple exostoses. Am J Med Genet 2001, 99: 59-62 54. Xu L, Xia J, Jiang H, Zhou J, Li H, Wang D, Pan Q, Long Z, Fan C, Deng H-X: Mutation
analysis of hereditary multiple exostoses in the Chinese. Hum Genet 1999, 105: 45-50 55. Park KJ, Shin K-H, Ku J-L, Cho T-J, Lee SH, Choi IH, Phillipe C, Monaco AP, Porter DE,
Park J-G: Germline mutations in the EXT1 and EXT2 genes in Korean patients with hereditary multiple exostoses. J Hum Genet 1999, 44: 230-234
56. Wuyts W, Van Hul W, De Boulle K, Hendrickx J, Bakker E, Vanhoenacker F, Mollica F, Ludecke H-J, Sitki Sayli B, Pazzaglia UE, Mortier G, Hamel B, Conrad EU, Matsushita M, Raskind WH, Willems PJ: Mutations in the EXT1 and EXT2 genes in hereditary multiple exostoses. Am J Hum Genet 1998, 62: 346-354
57. Bridge JA, Nelson M, Orndal C, Bhatia P, Neff JR: Clonal karyotypic abnormalities of the hereditary multiple exostoses chromosomal loci 8q24.1 (EXT1) and 11p11-12 (EXT2) in patients with sporadic and hereditary osteochondromas. Cancer 1998, 82:
1657-1663
58. Mertens F, Rydholm A, Kreicbergs A, Willen H, Jonsson K, Heim S, Mitelman F, Mandahl N: Loss of chromosome band 8q24 in sporadic osteocartilaginous exostoses. Genes Chromosomes Cancer 1994, 9: 8-12
59. Bovée JVMG, Cleton-Jansen AM, Wuyts W, Caethoven G, Taminiau AHM, Bakker E, Van Hul W, Cornelisse CJ, Hogendoorn PCW: EXT-mutation analysis and loss of
heterozygosity in sporadic and hereditary osteochondromas and secondary chondrosarcomas. Am J Hum Genet 1999, 65: 689-698
60. Feely MG, Boehm AK, Bridge RS, Krallman PM, Neff JR, Nelson M, Bridge JA:
Cytogenetic and molecular cytogenetic evidence of recurrent 8q24.1 loss in osteochondroma. Cancer Genet Cytogenet 2002, 137: 102-107
61. McCormick C, Duncan G, Goutsos KT, Tufaro F: The putative tumor suppressors EXT1 and EXT2 form a stable complex that accumulates in the golgi apparatus and catalyzes the synthesis of heparan sulfate. Proc Natl Acad Sci USA 2000, 97: 668-673
62. Senay C, Lind T, Muguruma K, Tone Y, Kitagawa H, Sugahara K, Lidholt K, Lindahl U, Kusche-Gullberg M: The EXT1/EXT2 tumor suppressors: catalytic activities and role in heparan sulfate biosynthesis. EMBO Rep 2000, 1: 282-286
63. Simmons AD, Musy MM, Lopes CS, Hwang L-Y, Yang Y-P, Lovett M: A direct interaction between EXT proteins and glycosyltransferases is defective in hereditary multiple exostoses. Hum Mol Genet 1999, 8: 2155-2164
64. McCormick C, Duncan G, Tufaro F: New perspectives on the molecular basis of hereditary bone tumours. Mol Med Today 1999, 5: 481-486
65. Lind T, Tufaro F, McCormick C, Lindahl U, Lidholt K: The putative tumor suppressors EXT1 and EXT2 are glycosyltransferases required for the biosynthesis of heparan sulfate. J Biol Chem 1998, 273: 26265-26268
66. Bovée JVMG, Cleton-Jansen AM, Taminiau AHM, Hogendoorn PCW: Emerging pathways in the development of chondrosarcoma of bone and implications for targeted
treatment. Lancet Oncology 2005, 6: 599-607
67. Hameetman L, David G, Yavas A, White SJ, Taminiau AH, Cleton-Jansen AM, Hogendoorn PCW, Bovee JVMG: Decreased EXT expression and intracellular accumulation of heparan sulphate proteoglycan in osteochondromas and peripheral chondrosarcomas. J Pathol 2007, 211: 399-409
68. Mertens F and Unni KK: Enchondromatosis: Ollier disease and Maffucci syndrome.
World Health Organization Classification of Tumours. Pathology and genetics of tumours of soft tissue and bone. Edited by Fletcher CDM, Unni KK, and Mertens F.
Lyon, IARC Press, 2002: 356-357
69. Cohen MM, Jr. and Siegal GP: McCune-Albright syndrome. World Health Organization Classification of Tumours. Pathology & Genetics. Tumours of Soft Tissue and Bone.
Edited by Fletcher C.D.M, Unni KK, and Mertens F. Lyon, IARC Press, 2002, pp. 357- 359
70. Hopyan S, Gokgoz N, Poon R, Gensure RC, Yu C, Cole WG, Bell RS, Juppner H, Andrulis IL, Wunder JS, Alman BA: A mutant PTH/PTHrP type I receptor in enchondromatosis. Nat Genet 2002, 30: 306-310
71. Couvineau A, Wouters V, Bertrand G, Rouyer C, Gerard B, Boon LM, Grandchamp B, Vikkula M, Silve C: PTHR1 mutations associated with Ollier disease result in receptor loss of function. Hum Mol Genet 2008, 17: 2766-2775
72. Rozeman LB, Sangiorgi L, Bruijn IH, Mainil-Varlet P, Bertoni F, Cleton-Jansen AM, Hogendoorn PCW, Bovée JVMG: Enchondromatosis (Ollier disease, Maffucci syndrome) is not caused by the PTHR1 mutation p.R150C. Hum Mutat 2004, 24: 466-473 73. Rozeman LB, Hameetman L, Cleton-Jansen AM, Taminiau AHM, Hogendoorn PCW,
Bovée JVMG: Absence of IHH and retention of PTHrP signalling in enchondromas and central chondrosarcomas. J Pathol 2005, 205: 476-482
74. Rozeman LB, Hameetman L, van Wezel T, Taminiau AHM, Cleton-Jansen AM, Hogen doorn PCW, Bovée JVMG: cDNA expression profiling of central chondrosarcomas: Ollier disease resembles solitary tumors and alteration in genes coding for energy
metabolism with increasing grade. J Pathol 2005, 207: 61-71
75. Buddingh EP, Naumann S, Nelson M, Neffa JR, Birch N, Bridge JA: Cytogenetic findings in benign cartilaginous neoplasms. Cancer Genet Cytogenet 2003, 141: 164-168 76. Bridge JA, Persons DL, Neff JR, Bhatia P: Clonal karyotypic aberrations in
enchondromas. Cancer Detect Prev 1992, 16: 215-219
77. Bridge JA, Bhatia PS, Anderson JR, Neff JR: Biologic and clinical significance of cytogenetic and molecular cytogenetic abnormalities in benign and malignant cartilaginous lesions. Cancer Genet Cytogenet 1993, 69: 79-90
78. Mandahl N, Willen H, Rydholm A, Heim S, Mitelman F: Rearrangement of band q13 on both chromosomes 12 in a periosteal chondroma. Genes Chromosomes Cancer 1993, 6: 121-123
79. Dahlen A, Mertens F, Rydholm A, Brosjo O, Wejde J, Mandahl N, Panagopoulos I:
Fusion, disruption, and expression of HMGA2 in bone and soft tissue chondromas. Mod Pathol 2003, 16: 1132-1140
80. Rozeman LB, Szuhai K, Schrage YM, Rosenberg C, Tanke HJ, Taminiau AHM, Cleton- Jansen AM, Bovée JVMG, Hogendoorn PCW: Array-comparative genomic hybridization of central chondrosarcoma - Identification of ribosomal protein S6 and cyclin-depend ent kinase 4 as candidate target genes for genomic aberrations. Cancer 2006, 107:
380-388
81. Ozisik YY, Meloni AM, Spanier SS, Bush CH, Kingsley KL, Sandberg AA: Deletion 1p in a low-grade chondrosarcoma in a patient with Ollier disease. Cancer Genet Cytogenet 1998, 105: 128-133
82. Zack P, Beighton P: Spondyloenchondromatosis: syndromic identity and evolution of the phenotype. Am J Med Genet 1995, 55: 478-482
83. Le Merrer M, Fressinger P, Maroteaux P: Genochondromatosis. J Med Genet 1991, 28:
485-489
84. Odink AE, van Asperen CJ, Vandenbroucke JP, Cleton-Jansen AM, Hogendoorn PCW: An association between cartilaginous tumours and breast cancer in the national pathology registration in The Netherlands points towards a possible genetic trait. J Pathol 2001, 193: 190-192
85. Cleton-Jansen AM, Timmerman MC, Van de Vijver MJ, van Asperen CJ, Kroon HM, Eilers PH, Hogendoorn PCW: A distinct phenotype characterizes tumors from a putative genetic trait involving chondrosarcoma and breast cancer occurring in the same patient. Lab Invest 2004, 84: 191-202
86. Cuvelier C, Roels HJ: Cytophotometric studies of the nuclear DNA content in cartilaginous tumors. Cancer 1979, 44: 1363-1374
87. Swarts SJ, Neff JR, Johansson SL, Nelson M, Bridge JA: Significance of abnormalities of chromosomes 5 and 8 in chondroblastoma. Clin Orthop 1998, 189-193
88. Mark J, Wedell B, Dahlenfors R, Grepp C, Burian P: Human benign chondroblastoma with a pseudodiploid stemline characterized by a complex and balanced translocation.
Cancer Genet Cytogenet 1992, 58: 14-17
89. Sjogren H, Orndal C, Tingby O, Meis-Kindblom JM, Kindblom LG, Stenman G:
Cytogenetic and spectral karyotype analyses of benign and malignant cartilage tumours. Int J Oncol 2004, 24: 1385-1391
90. Van Zelderen-Bhola SL, Bovée JVMG, Wessels JW, Mollevangers P, Nijhuis JV, Taminiau AHM, Hogendoorn PCW: Ring chromosome 4 as sole anomaly in a chondroblastoma. A case report and review of the literature. Cancer Genet Cytogenet 1998, 105: 109-112 91. Mitelman, F., Johansson, B., and Mertens, F. Mitelman Database of Chromosme
Aberrations in Cancer. http://cgap.nci.nih.gov/Chromosomes/. 2009.
92. Armah HB, McGough RL, Goodman MA, Gollin SM, Surti U, Parwani AV, Rao UN:
Chondromyxoid fibroma of rib with a novel chromosomal translocation: a report of four additional cases at unusual sites. Diagn Pathol 2007, 2: 44
93. Smith CA, Magenis RE, Himoe E, Smith C, Mansoor A: Chondromyxoid fibroma of the nasal cavity with an interstitial insertion between chromosomes 6 and 19. Cancer Genet Cytogenet 2006, 171: 97-100
94. Granter SR, Renshaw AA, Kozakewich HP, Fletcher JA: The pericentromeric inversion, inv (6)(p25q13), is a novel diagnostic marker in chondromyxoid fibroma. Mod Pathol 1998, 11: 1071-1074
