Behandelrichtlijnen kraakbeentumor

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Introduction

Cartilaginous tumors form the second largest group of primary bone tumors. They all share characteristic production of chondroid  matrix by tumor cells. Cartilage tumors range from completely benign lesions to highly malignant and are subdivided by location in intramedullary or central and surface or peripheral. 
The WHO classification describes several benign cartilaginous bone tumors being: osteochondroma, enchondroma, periosteal chondroma, chondromyxoid chondroma and chondroblastoma. Multiple chondromatosis is described as the only benign cartilaginous joint lesion.[7]
The malignant cartilage bone tumor is called chondrosarcoma. They are known to occur as primary bone tumors (de novo) or as a malignant degeneration of pre-existing benign cartilaginous bone tumor (secondary). Four histological subtypes of chondrosarcoma are described as peripheral-, dedifferentiated-, mesenchymal- and clear cell chondrosarcoma. [7, 13]

The clinical presentation of these tumors differs for site, location, age groups and gender. Clinical features, radiological appreciation, histology and treatment protocols are therefore described separately for both benign and malignant cartilaginous tumors. Epidemiology data are based on the Netherlands Committee of bone tumors database.

Benign Cartilage Tumors

Benign cartilage tumors arise primarily in young age groups, with a peek incidence between the second and third decade. Osteochondroma and enchondroma occur most frequently as single lesions, but can sometimes be found in multiple skeletal locations as part of rare hereditary syndromes such as Multiple osteochondroma MHE, Ollier’s disease, Maffucci syndrome).

Osteochondroma

Osteochondroma (cartilaginous exostosis) is the most frequently found benign bone neoplasm (35%), is located in the metaphysis and is thought to derive from the epi-metaphysis in the long bones. This tumor is seldom diagnosed before the age of ten as the median age diagnosis averages around the second decade of life, They increase in size with time and are often present for a considerable time before causing complaints. Growth will continue during skeletal growth and stops when the epiphysiseal growth plates have fused.
Osteochondroma can occur in any site but are most frequent around the knee, wrist, hip, shoulder for the long bones and pelvis, scapula and ribs for the flat bones. Most osteochondroma will present as single asymptomatic lesions. However size and location may cause functional restrictions, bursitis, tendonitis, pressure on adjacent neurovascular structures and cosmetic discomfort. 15% Of diagnosed osteochondroma exist as part of a syndrome where at least two osteochondroma in one long bone are diagnosed. They often exist as part of an autosomal dominant disorder but can occur de novo. (multiple hereditary osteochondroma (MHE)) In these patients addition skeletal deformities especially around the knee, ankle and wrist joints are frequently found.

Clinical presentation
Osteochondroma can be palpated as a hard mass consisting of bony stalk fixed to the bone that is covered by a cartilaginous cap. They are seldom painful, but can be covered a painful bursa. Malignant transformation for single lesions is very rare (1%), but somewhat more frequent 1-5% in multiple osteochondroma.[1, 4] Flat bones such as the pelvis and scapula) also have a higher risk for malignant degeneration . Growth of an osteochondroma after skeletal maturity suggests malignant transformation so does  pain at rest and can suggest malignancy.

Radiology
The radiographic appearance of osteochondroma using conventional radiography is usually diagnostic. Osteochondroma are metaphyseal lesions projecting away from the adjacent joint. They can be pedunculated or broad-based (sessile) and vary in size. On radiography, there is continuity of the cortex and bone marrow of the underlying bone into the osteochondroma, which helps to differentiate them from other surface bone lesions.
MR imaging features of osteochondroma are characteristic with normal appearing bone marrow and cortex extending into the lesion with a thin overlying cartilage cap demonstrating high signal intensity on T2-weighted MR images.
Bone scintigraphy will show increased activity in the presence of both persistent enchondral ossification and malignant change. However, normal background activity over a symptomatic osteochondroma excludes malignancy. In malignant degeneration, the thickness of the cartilage cap on MR imaging is often more than 1 cm and a typical ring and arcs configuration with this cartilage cap can be appreciated. (Figure 1)

 

Figure 1.Osteochondroma

  1. Radiograph shows an osteochondroma originating from the thoracic surface of the scapula with a regular outer surface.
  2. Axial T2-weighted MR images shows a large neobursa. Other complications that can occur include nerve and vascular compression, pseudoaneurysm formation, fracture of the stalk, growth disturbances and malignant transformation.


Osteochondromatosis:
Radiographs of the pelvis, knee and ankle of a child show multiple osteochondromas in the metaphyses and metadiaphysis of the proximal femur on the left and around the knee and ankle. Due to the osteochondromas normal remodeling of the metaphyses cannot take place giving them a broad plump shape.


Osteochondromatosis:
Radiograph (A) of chest shows multiple osteochondromas. Additional CT (B) is helpful in anatomically complex regions and in anatomically complex osteochondromas to show the extension of the medullary cavity and the cortex of the underlying bone into the osteochondroma, which is the key feature for the differential diagnosis. 


  1. Osteochondroma transversal section showing trabeculated bone covered by a cartilaginous cap of limited size and  a thin layer of periost.
  2. The outer line of perichondrium is covering the cartilaginous cap. The chondrocytes are organized into cords and showa  variable amount of enchondral ossification.

Differential diagnosis
De diagnosis of an osteochondroma is generally not difficult but should be differentiated from surface lesions such as parosteal osteosarcoma.

Histology (macro en micro)
Osteochondroma consists of a bony stalk, usually consisting of mature lamellar bone, covered by a cartilaginous cap. The interface between bone and cartilage strongly resembles the growth plate, in which resting, proliferating and hypertrophic chondrocytes are recognized, although cells are less organized. When the growth plates are still open, the cartilage can be cellular. After closure of the growth plate the cap becomes less cellular. Nuclear atypia and mitoses are absent. 

Genetics EXT1 and EXT2
Within the context of the multiple osteochondromas (MO) syndrome (previously known as multiple hereditary exostoses MHE). MO is autosomal dominantly inherited and caused by germline mutations in the EXT1 or -2 genes Stickens [32]

Treatment
En bloc resection of osteochondroma including the pseudocapsule is curative and results in very low recurrence rate. Reconstruction using either bone or osteosynthesis is seldom necessary as the structural integrity of long bones is not changed much  with resection.
Asymptomatic, osteochondroma without discomfort can be left untreated.
Indications for surgery are functional discomfort, severely cosmetic disabling lesions, joint or bone deformity and growing lesion after growth stop. In young children care should be taken not to damage the growth plate. Lesions left untreated can be followed up using plain radiographs after skeletal maturity and some years thereafter. MO/MHE patients should be screened using either total body MRI or PET- or bone scintigraphy, for undiagnosed osteochondroma located around the pelvis, scapula, ribs and vertebral column. Patients should seek medical consultation if the osteochondroma starts growing again or becomes painful at rest. Adequate resected cases do not need long term follow up.

Enchondroma

Enchondroma is a benign tumor of hyaline cartilage originating from the medulla of bone. The majority of lesions are solitary but they can occur multiple as a manifestation of a congenital syndrome (M. Ollier, Maffucci). The enchondroma make about a 10-25% of all benign bone tumors. The are found in all age groups ranging from 5-80, most frequent in the third to fifth decade of life. The ratio male to female is equal (1/1).
Enchondromas are especially common in small tubular bones of the hand (50%) and feet. Other sites where enchondroma occur more frequent are long tubular bones such as femur, humerus and tibia. Enchondroma occur in ribs but are (rarely) seen in other flat bones such as pelvis.

Clinically enchondroma of the hand can show some swelling  or present with some pain due to small fractures (usually non displaced) and can be appreciated on standard  radiographs.
In long bones enchondromas are mostly asymptomatic and are often a coincidental finding on plain radiographs. 
Malignant transformation of enchondroma towards chondrosarcoma (usually low grade) in the long bones including the metacarpal bones infrequently occurs in less than 1-5 % of cases. In the phalanges malignant transformation is very exceptional.

Radiology
The typical radiographic appearance is a lytic lesion arising in the medulla with a geographic pattern of bone destruction. In the hands and feet, bony expansion with cortical thinning is common and they may be purely lytic. In larger bones, the lesion arises usually centrally within the meta(-dia)physis such that endosteal resorption is only seen in the larger lesions. If the lesions are larger than 5 cm, the possibility of a low-grade chondrosarcoma is questioned. Identification of classic popcorn-like mineralization indicates the cartilaginous matrix.

Differential diagnosis
The differential diagnosis includes bone infarction, chondromyxoid fibroma, giant cell tumor, aneurysmal bone cyst, solitary bone cyst or fibrous dysplasia. The major diagnostic problem is the differentiation between enchondroma and low-grade chondrosarcoma. In sites other than the phalanges, malignant transformation of enchondroma to chondrosarcoma is not uncommon. (Figure 2a and 2b)


Figure 2a. Enchondroma

  1. Anteroposterior radiograph shows dense calcifications in the proximal femur. The lesion is smaller than 5 cm and there is no associated osteolysis or endosteal scalloping of the cortex. The patient is asymptomatic in this region and additional MR imaging is not required.
  2. Hypocellular tumor with abundant hyaline cartilage matrix. No or sparce double nuclei: enchondreoma.

  

Figure 2b

Histology
Histologically enchondroma has an abundant hyaline cartilaginous matrix, sometimes calcified,. The lesions are lowly cellular, unless located in the phalanges or in the context of enchondromatosis  where increased cellularity is tolerated. The distinction between enchondroma and grade I chondrosarcoma is extremely difficult both at radiology [15]and histology[25] resulting in high interobserver variabilit [12]. The presence of entrapment of pre-existing host bone and mucomyxoid matrix changes favor the diagnosis of chondrosarcoma.[12] With the new treatment options using curettage and adjuvant phenol or cryosurgery[34] for enchondroma as well as grade I central chondrosarcoma the distinction is not always essential for clinical decision making.

Treatment
Enchondroma of the phalanges are usually left alone unless repeated fractures or impairment of function or daily activities requires treatment. In these cases simple curettage and if needed bone grafting is the treatment of choice. The recurrence rate is rather low (1-5%). Asymptomatic enchondroma of the long bones are to be followed-up by plain radiography every other year. Symptomatic enchondroma should be carefully investigated to exclude progression towards malignancy using gadolinium enhanced (dynamic) MRI.

Multiple enchondromatosis

Multiple enchondromatosis  (Ollier disease) is an uncommon developmental bone abnormality characterized by multiple enchondromas located in multiple bones without hereditary or familial tendency (unlike hereditary multiple osteochondroma). Malignant degeneration to a central low-grade chondrosarcoma occurs in about 20% of cases.[28] Multiple enchondromas in combination with soft tissue and, rarely visceral, hemangiomas is called Mafucci’s syndrome. Mafucci’s syndrome is also a developmental nonhereditary disorder, however, with higher malignant potential than enchondromatosis alone.[24] Ollier [27] 

Juxtacortical (periosteal) chondroma

Although very uncommon, periosteal chondroma is a benign cartilaginous tumor arising at the periosteal surface of bone. All age groups can be affected and the male female ratio is equal.  This lesion can arise in both long and small tubular bones usually measuring fewer than 6 cm. If it is situated close to a joint it is called juxta-articular chondroma. The mass is palpable and can be painful.

Radiology
The lesion causes a soft tissue mass with cortical pressure erosion. Calcifications can be appreciated in the soft tissue mass in about 50% of cases. Although cortical erosion is frequently apparent, cortical destruction should raise a high suspicion for malignancy.

Differential diagnosis
The major differential diagnoses are periosteal osteosarcoma, periosteal chondrosarcoma and giant cell tumor of the tendon sheath (especially when situated in the hand and feet).

Histology
In periosteal chondroma increased cellularity as compared to enchondroma is seen; distinction from periosteal chondrosarcoma is made based on size (>5 cm) and cortical invasion in case of periosteal chondrosarcoma.

Treatment
Marginal or wide resection of the lesion en-bloc is mandatory resulting in a low recurrence rate (<5%) If intralesional resection is performed the recurrence rate does increase significantly.

Chondromyxoid fibroma

Chondromyxoid fibroma (CMF) is a very rare benign cartilaginous lesion. They most frequently occur in the second and third decades, more frequent in male and have a predilection for the long bones of the lower limb, especially the proximal tibia and distal femur. Although they are usually small, CMF can become tall as well.
Clinical presentation shows mild pain present for some time (years) and swelling when small bones (hand, feet) are involved.

Radiology
The radiographic appearances are those of a well-defined oval or round lytic lesion with often lobulated margins, and usually eccentrically located in the metaphysis. The may cause mild cortical expansion. Matrix calcification is uncommon. MR imaging will reveal a typical lobulated pattern suggestive of a cartilage tumor. (Figure 3)

 


Figure 3. Juxtacortical chondroma

Juxtacortical chondroma
Radiographs (A,B) show a juxtacortical lesion in the distal femur metaphyses. Axial MR images [proton density (C), T2-weighted with fat suppression (D) and T1-weighted after intravenous contrast injection (E)] show the characteristics of a chondroid lesion separated by an intact cortex from the underlying medullary cavity.

Differential diagnosis
The differential diagnosis includes aneurysmal bone cyst and nonossifying fibroma.

Histology
CMF is a lobular tumor in which spindle shaped or stellate cells are seen embedded in an abundant myxoid matrix. Towards the periphery of the lobules the cellularity increases and cells are more rounded. Multinucleated giant cells are present. Nuclear atypia and (non-atypical) mitoses can be found which may lead to an erroneous diagnosis of high grade chondrosarcoma.

Treatment excision or curettage with local adjuvant (cryotherapy or phenol) and bone grafting or cementation depending on the site and extension of the lesion
The recurrence rate is relative high at about 15%, intensive follow up is therefore necessary.

Chondroblastoma
Chondroblastoma is a rare benign cartilaginous tumor found in skeletal immature patients (10-25 years), located almost exclusively in the epiphysis, and less frequently the apophysis,. If however, there is partial closure of the epiphyseal plate, the lesion may extend into the metaphysis. 

The most common site of involvement is the proximal humerus, followed by the proximal femur, distal femur and proximal tibia. They can also occur in pelvis, calcaneus, patella, mid- and hindfoot and in an older age group (40-50) and involvement of the skull has been reported. At clinical presentation localised mild pain (existing sometimes for a long period of time) is a frequent complaint. A minority of patients has some joint effusion. In 15-30% of the chondroblastomas a secondary aneurysmal bone cyst can be found.

Radiology
On radiography the lesion is predominantly lytic with geographic and sclerotic margins.
About 50% of cases demonstrate some amount of chondroid matrix. Most chondroblastoma elicit a thick periosteal reaction along the metaphysis. MR imaging shows a lobulated lesion with isointense signal intensity compared to muscle on T1-weighted MR images and intermediate to high heterogeneous signal intensity on T2-weighted MR images. MR also shows edema in the adjacent bone marrow and soft tissue. (Figure 4.)


Figure 4. Chondroblastoma

  1. Anteroposterior radiograph shows a lytic oval lesion in the proximal epiphyseal humerus with a geographic pattern of destruction. 
  2. Coronal T2-weighted MR images shows bone marrow edema surrounding the lesion.
  3. Axial T1-weighted MR image after intravenous contrast injection shows peripheral septonodular enhancement.
  4. Histology on HE:  pale cytoplasma and  octagonal shape due to abutmant against other tumor cells. Homogenous, oval and  grooved nuclei .clumps of giant cells are found adjacent to areas of spindle cell stroma.

Differential diagnosis
The differential diagnosis in the adolescent include giant cell tumor extending into the epiphysis, articular lesions with large cysts e.g. PVNS and clear cell chondrosarcoma. In children it includes eosinophilic granuloma and epiphyseal osteomyelitis. Needle biopsy is therefore recommended.

Histology
Chondroblastoma consists of cells with a uniform round polygonal nucleus, sometimes with a nuclear groove, and obvious cytoplasm. Osteoclast-type giant cells are always present, and therefore giant cell tumor of bone is the most important histological differential diagnosis. Cartilaginous foci, sometimes with “chicken-wire”-like calcifications are characteristic of chondroblastoma. Mitotic figures are rare. Moreover, the cells in chondroblastoma are most often S100 positive, while giant cell tumor is negative for S100.

Treatment of choice is curettage and bone grafting, often combined with local adjuvant (phenol or cryosurgery) with a reasonable risk for local recurrence (14-18% within 2 years) This is probably due to the combination of difficult epiphysial location and the initial attempt to save the joint or physis. In rare cases metastases to the lung have been reported, which are usually non progressive and often treated successfully by metastasectomy. 

Synovial chondromatosis

Synovial chondromatosis is a synovial metaplasia in which (osteo)cartilaginous nodules arise in synovial joints. The nodules may grow and variably become loose or reattach to the synovium. This proces, osteochondromatosis, can occur in any site covered with synovium (joint capsule, tendon sheet, bursa and periarticular tissue. When the nodules mature they will be released in the synovial space (joint). Patients are often males (>40 years old) presenting with complaint including: pain, decreased function and sometimes locking features. Knee, elbow, hip and wrist are most the frequently involved joints. 
There are three stages of disease progression: stage one: the early phase, no nodules, only synovitis, stage two: the transition phase: active synovitis with nodules and stage three: the late phase with nodules present even without active synovitis. (Figure 5)


Figure 5. Primary synovial chondromatosis
Anteroposterior and lateral radiograph op the hip show multiple intraarticular chondral fragments.

Radiology
Multiple round bodies of similar size and variable in mineralization in the joint can be seen on conventional radiographs. The round bodies can appear trabeculated. MR imaging is usually not required to make the diagnosis but can be diagnostic if the round bodies lack mineralization. (Figure 6.)


Figure 6. Chondromyxoid fibroma

  1. Radiographs show a well-demarcated eccentric lytic lesion in the metatarsal bone without matrix calcification.
  2. Coronal T2-weighted MR images after intravenous contrast injection with fatsuppression show enhancement of the lesion and extensive surrounding bone marrow edema. The differential diagnosis is enchondroma.

 

C.Radiograph of the pelvis shows a lobulated well-demarcated lytic lesion with ridges. The differential diagnosis is aneurysmal bone cyst and fibrous dysplasia.

D. Usually lobulated pattern of stellate and spindleshaped cells in a myxoid background. Osteoclastlike giant cells are present
 

Differential diagnosis
The main differential diagnosis is loose bodies seen in osteoarthritis.

Histology
Histologically multiple rounded cartilaginous nodules are seen, covered by a thin layer of synovial lining. Increased cellularity, nuclear atypia and an occasional mitosis are accepted; malignant synovial chondromatosis is extremely rare.

Treatment of choice is total open synovectomy, with still a recurrence rate of 10-20%. Postoperative stiffness of the involved joint has shifted primary treatment to more conservative measures involving a partial synovectomy and removal of loose bodies using arthroscopy. Total synovectomy using arthroscopy is hard to achieve and has increased the recurrence rate up to 30-40%

Malignant cartilage tumors 

Malignant Chondrosarcoma

Malignant cartilaginous tumours are the second largest group of primary bone tumours. [2] Most of them occur as de novo malignancies in previously normal bone. A small subset appears secondary to a pre-existing benign cartilage tumors (enchondroma, osteochondroma). Highest prevalence is found between the fourth and sixth decade, with an equal male to female ratio. Approximately 90% of chondrosarcoma are described as conventional type.  Chondrosarcoma are subdivided into central and peripheral subtypes, based upon radiological presentation. Central chondrosarcoma compose about 75% of all chondrosarcoma, the majority are low-grade (grade I). They arise centrally in the metaphysial region of long bones, but can also develop in flat bones such as pelvis, rib and scapula. A minority (up to 15%) of conventional chondrosarcoma develop from the surface of bone as a result of malignant transformation within the cartilage cap of a pre-existent osteochondroma and is therefore called secondary or peripheral chondrosarcoma.
Rarer subtypes include mesenchymal chondrosarcoma and clear cell chondrosarcoma. Conventional chondrosarcoma can  “dedifferentiate” into a very high-grade tumors with dismal prognosis, so-called de-differentiated chondrosarcoma.[18]
Most chondrosarcoma are solitary, but they can occur as multiple lesions in patients with syndromes as multiple osteochondroma and enchondromatosis (M. Ollier, Maffuccis disease).[24, 27, 31]

Clinical presentation
Central low grade chondrosarcoma are frequently asymptomatic and are coincidentally found on radiographs. High grade cartilage tumors almost always are symptomatic. Pain at the site of a cartilaginous lesion may be an indicator of malignancy. The differentiation between enchondroma and grade I chondrosarcoma can be difficult.
Peripheral chondrosarcoma often present with a painless mass, but can be symptomatic because of size and related functional loss.
Malignant cartilage tumors in the phalanges of the hand and feet are extremely rare, but in the other long bones central cartilaginous lesions should be considered low-grade chondrosarcoma till proven otherwise. Treatment is therefore mandatory for all grades of chondrosarcoma. Preferred surgical management is related to grade type and site of the lesion. Chemo- and radiotherapy do not have a significant role in the treatment of these patients. Adequate medical imaging by conventional X-ray and (enhanced) MRI is essential in the work-up and is indicative for optimal treatment options.

Radiology
On conventional radiography, the distinction between enchondroma and central grade I chondrosarcoma cannot be reliably made. The localization in the axial skeleton and size greater than 5 cm are the only reliable predictors for malignancy. Low grade central chondrosarcoma can be geograhic in appearance and may show mild cortical expansion and/or endosteal scalloping. The presence of chondroid matrix is variable, ranging from pure lytic lesions, to few or dense calcifications. They have no associated soft tissue mass. On MR imaging low grade chondrosarcoma will show a lobulated endomedullary mass with high signal intensity on T2-weighted MR images and typical peripheral and septonodular (guirlande-like) enhancement on MR images after intravenous contrast injection corresponding to the fibrovascular septation between lobules of hyaline cartilage. Although dynamic contrast enhanced MR-imaging shows increased sensitivity, suggesting that chondrosarcoma tend to show more rapid enhancement than enchondroma, an absolute distinction between enchondroma and low-grade chondrosarcoma cannot be made on radiological grounds alone.[12] The differential diagnosis of osteochondroma versus low grade peripheral chondrosarcoma can reliably be made measuring the thickness and enhancement characteristics on MR of the cartilaginous cap.
Aggressive chondrosarcoma subtypes, such as mesenchymal and dedifferentiated chondrosarcoma often contain less extensive areas of matrix mineralization that suggest a chondroid neoplasm,. They may demonstrate intra-osseous lytic areas and show aggressive patterns of bone destruction with a moth-eaten to permeate pattern in combination with large soft tissue masses. Evidence of a large nonmineralized soft tissue mass associated with a lesion with radiological features indicative of a chondrosarcoma should raise the level of suspicion for dedifferentiation.(Figure 7)

   

Figure 7. Central chondrosarcoma grade II
Radiograph (A) of the shoulder in a 24-years-old female shows a well-defined lobulated lytic lesion in the acromion. Axial T1-weighted MR image after intravenous contrast injection shows typical peripheral (guirlande-like) enhancement consistent with a chondroid tumor. A CT guided percutaneous biopsy (C) in prone position was performed because the bony expansion, the cortical disruption in combination with the age of the patient suspected a higher grade of malignancy.

Abundant hyaline matrix with moderate cellularity, some spindle shaped nuclei and more than sparce double nuclei

Clear cell chondrosarcoma typically has a predilection for the proximal end of the femur and humerus, often with epiphyseal involvement. Radiographs reveal a predominantly lytic lesion. Matrix mineralization is not as frequently apparent in clear cell chondrosarcoma as compared with conventional chondrosarcoma. Clear cell chondrosarcoma is often mistaken for a chondroblastoma because it is non aggressive in appearance and arises in the epiphysis. However, clear cell chondrosarcoma occurs in older patients than osteoblastoma.
CT is only recommended in the pelvis and other flat bones where it may be difficult to discern the pattern of bone destruction and the presence of matrix mineralization. MRI is used to delineate the extent of the intraosseous and soft tissue involvement.
Core needle biopsy is the preferred when grading is at debate due to imaging studies. [15]

Histology
Central and peripheral chondrosarcoma are histological similar, and for both three different grades are discerned, which is at present the best predictor of clinical behaviour [14], but subject to interobserver variability [12]. Grade I chondrosarcomas are lowly cellular, with an abundant hyaline cartilage matrix and do not metastasize. In contrast, grade III chondrosarcoma are highly cellular, with a mucomyxoid matrix, nuclear atypia and mitoses, with metastases developing in 70% of the patients [14] Up to 13% of recurrent chondrosarcoma exhibit a higher grade of malignancy than the original neoplasm [3, 14] suggesting chondrosarcoma may biologically progress.
Genetics
At the genetic level a multi-step genetic model is assumed, with increased genetic instability with increasing histological grade [4]. Central and peripheral chondrosarcoma differ at the genetic level [5]. EXT mutations, disturbing hedgehog diffusion in the growth plate as a result of a lack of heparan sulphate, underlie the development of osteochondroma [4]. Additional as yet unidentified genetic hits are expected to cause malignant transformation of osteochondroma towards secondary peripheral chondrosarcoma. Peripheral chondrosarcoma is aneuploid, and a subset of tumours demonstrates near-haploidy [5] with polyploidization upon progression towards higher grade. This is however not specific for peripheral chondrosarcoma and is also seen in central chondrosarcoma [20]. Different signalling pathways have been studied and indian hedgehog, PTHLH/Bcl-2, Cox-2 and estrogen signalling have been suggested as therapeutic targets for peripheral chondrosarcoma. [4, 21] Systematic genetic studies in the rare chondrosarcoma subtypes are lacking.

Rare chondrosarcoma subtypes

In addition to conventional chondrosarcoma, several rare subtypes of chondrosarcoma are discerned, together constituting 10-15% of all chondrosarcoma.
Dedifferentiated chondrosarcoma is a highly anaplastic sarcoma next to a (usually low-grade) malignant cartilage-forming tumour, with a remarkably sharp junction between the two components. The rare genetic reports on dedifferentiated chondrosarcoma demonstrate that both components share identical genetic aberrations [5, 30] with additional genetic changes in the anaplastic component [5, 8, 19, 30] indicating a common precursor cell with early diversion of the two components. [10, 18]. No targets for therapy have been reported for dedifferentiated chondrosarcoma so far.(Figure 8)

Figure 8. Clearcell chondrosarcoma

Radiographs (A, B) show a well-demarcated lytic lesion, slightly lobulated, in the proximal epiphysis of the femur. The lesion is surrounded by a thin sclerotic rim.  No matrix calcification is present.
Coronal T1 and T2- weighted MR images (C,D) show the lobulated lesion.
Axial T2-weighted MR image (E) with fat suppression shows surrounding bone marrow edema. The differential diagnosis is chondroblastoma or avascualr necrosis. Because of the classical location in the epiphyses of long bones the radiographic pattern of clear cell chondrosarcoma is mostly indistinguishable from chondroblastoma. Patient age is considered as an important discriminator between both entities. 


Histology Cell with round large centrally located nuclei with clear cytoplasm and distinct cytoplasmic membranes. Multinucleated giant cell may be present.

Mesenchymal chondrosarcoma is a highly malignant lesion that can occur in bone and soft tissue of relatively young patients and is characterized by scattered areas of differentiated cartilage intermingled with undifferentiated small round-cells with typical staghorn-like vessels [26]. Sixty-one percent of the tumours demonstrate p53 over-expression, but no mutations were found. Recent evidence suggests that mesenchymal chondrosarcoma may be chemotherapy sensitive, and may be considered for adjuvant or neoadjuvant therapy [6, 9]. (Figure 9.)

 

Figure 9. Dedifferentiated chondrosarcoma

  1. Macroscopy of distal femur resection specimen of a dedifferentiated chondrosarcoma. Permeative cortex destruction anterior and posterior with soft tissue extension
  2. Low grade cartilaginous component abrupt entrapped in a high grade sarcoma with atypical high cellularity suggesting dedifferentiated chondrosarcoma

Clear cell chondrosarcoma is a tumour of low-grade malignancy characterized by tumour cells with clear, empty cytoplasm depositing both hyaline cartilage as well as scattered mineralizing osteoid. Metastases are rare but may occur up to 24 years after initial diagnosis, thus long term follow-up is mandatory [11]. A cytogenetic study on four cases suggested that extra copies of chromosome 20 and loss or rearrangements of 9p may be recurrent.(Figure 10.)


Figure 10. Mesenchymal chondrosarcoma

Biphasic tumor pattern composed of small round cells with lack of differentiation and islands of hyaline cartilage. The small blue round cells can simulate Ewing sarcoma.

Treatment
Although, for all grades of non-metastatic chondrosarcoma en-block resection offers the best  recurrence free survival, surgical management is related to grade, type and site. 
In low grade central chondrosarcoma of the long bones extensive intralesional curettage, followed by local adjuvant treatment has become the treatment of choice.[23] 
Local adjuvant in lesions confined to the bone includes phenolization, cryosurgery (liquid nitrogen) and the use of polymethylmetacrylate (PMMA).[29] Promising long term clinical results and satisfactory local control have been published using all of the above.[33, 34] Application of phenol (85%) as adjuvant treatment with additional washing with ethanol (96%) has been proven effective causing sufficient tissue necrosis in chondrosarcoma-derived cell lines. The use of phenol as adjuvant following intralesional curettage in low-grade chondrosarcoma of long bones is safe and has a 7% recurrence rate after an average follow-up of 6 years. Additional osteosynthesis is not necessary due to its use, therefore MRI-scans can be readily used for follow-up.[22, 33]
Cryosurgery uses very low temperatures to induce tissue necrosis with the intent of ablation by freezing, holding of freeze, thawing and repetition of this cycles. The local extend of treatment with cryosurgery is at least 7 to 12 mm. beyond the surgical margin.  Side effects of cryosurgery are (temporarily) nerve damage, fractures and infections..
The use of polymethylmetacrylate (PMMA) is based on the hypothesis that it would kill the residual tumour cells following curettage by thermal heating of the bone cavity. The maximum peripheral extent of a thermal lesion induced by PMMA varies from 2-5 mm. in cancellous bone. An advantage of using PMMA is the possibility of early weight bearing.
The use allograft bone chips does not provide the possibility for early weight bearing, but does result in a biological repair resulting in normal bone stock after two years. Presumed infectious risk of allograft use is negligible.
In some cases of low grade chondrosarcoma intralesional excision is not a reliable treatment, because of the large size, site (pelvis) and extension (intra-articulair). In these cases wide resection is preferred.
In peripheral chondrosarcoma complete surgical removal of the osteochondroma including the cartilage cap with the pseudo-capsule is the preferred treatment with excellent long term clinical and local results.
For intermediate (grade II) and high grade (grade III) chondrosarcoma
en-bloc resection is considered the preferred surgical treatment.
High grade chondrosarcoma (including clear cell chondrosarcoma) and all chondrosarcoma of the axial skeleton should be surgically resected with wide margins with a intermediate risk of local recurrence.. There is a very high risk of local recurrence following resection of dedifferentiated chondrosarcoma, particularly in the presence of a pathological fracture. The presence of a pathologic fracture must be considered as a sign of a higher grade of malignancy. If wide margins cannot be reliably achieved with limb salvage then amputation must be considered. Chondrosarcomas in the skull and spine are often not resectable with sufficient margins. In these occasions proton beam radiotherapy could be considered following debulking. (Flowchart 1 and 2.)

Local recurrences can occur ten years postoperatively and demand for long term follow-up. The clinical course cannot always be predicted by histological grade alone. Outcome of low-grade chondrosarcoma of long bones and metacarpals are good.  Location of the lesion, especially in the pelvis and skull, is an important risk factor for local recurrence and dedifferentiation. Distant metastasis in low-grade chondrosarcoma average at two to five percent. Survival rates after 5 years are described between 85-90%.

Prognosis
Grade I tumours do not have 100% survival, mainly due to problematic local recurrence or progression into high grade upon occurrence. The histological grading is subject to variability in interpretation, with grade II and III chondrosarcoma often grouped together even though there is a wide spectrum of outcome.[12]
The most important predictors in chondrosarcoma for poor survival are histological grade and age above 50.
In case of a pathological fracture of the long bones, wide excision with adequate reconstruction is preferable to reduce the risk for local recurrence.
The prognosis in dedifferentiated chondrosarcoma is very poor, despite adequate wide surgical resection and adjuvant therapy. Inoperable, locally advanced and metastatic high grade chondrosarcoma are insensitive to conventional adjuvant treatment such as radio- and chemotherapy, reducing life expectancy to minimal.[17]

Adjuvant treatment

Recent evidence suggests that mesenchymal chondrosarcoma may be chemotherapy sensitive, and may be considered for adjuvant or neoadjuvant chemotherapy. Uncertainty remains on the use of chemotherapy for de-differentiated chondrosarcoma, however with poorer outcome they can be treated with a chemotherapy-protocol comparable to the treatment of osteosarcoma.[10]
Chondrosarcoma are considered relatively radiotherapy insensitive. In cases where wide resection is not possible or would cause unacceptable morbidity, doses over 60 Gy are needed for maximal local control.  As high dose radiotherapy is not always feasible, new techniques, such proton-beam radiotherapy or charged particles are used. Particle therapy with protons has the advantage of a minimal exit dose after energy deposition in the target volume, and hence better sparing of critical structures close to the tumor. Proton RT has been found beneficial in cartilage tumors of the skull base and axial skeleton. Local control rates of  85-100% with mixed photon-proton or proton only protocols (doses up to 79 CGE) are reported by several authors, with limited severe late effects (<10% RTOG Grade 3 toxicity).[16]
Chemotherapy is possibly effective in mesenchymal chondrosarcoma, and of uncertain value in dedifferentiated chondrosarcoma. Chemotherapy should preferably be used is clinical trials to define its definite role in chondrosarcoma. Several new drug targets have been identified and phase II studies are currently ongoing. There is an urgent need for new standard systemic treatment options for the minority of patients with unresectable or metastatic disease.

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