Central atypical cartilaginous tumors/chondrosarcomas grade 1 (ACT/CS1) or low-grade central chondrosarcomas are locally aggressive chondral neoplasms that arise centrally within bone from the medullar cavity. They constitute the most common form of conventional chondrosarcoma.
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Terminology
The terminology depends mainly on localization. Low-grade tumors arising from the long and short tubular bones of the extremities should be termed ‘central atypical cartilaginous tumors’, whereas tumors arising from the axial skeleton, including the flat bones of the pelvis scapula and skull base, are called chondrosarcoma grade 1 1-4.
Epidemiology
Central ACT/CS1 incidence has been estimated at 6-7 per million person-years and has increased significantly compared to the 1990s, likely due to increased diagnostic imaging use and aging 1,5. The estimated prevalence is approximately 0.4%, with a prevalence of all cartilaginous lesions in the knee, including low-grade chondrosarcomas and enchondromas, being as high as 2.8% 1,6.
Low-grade central chondrosarcomas are mainly found in the adult population from the third to the sixth decade, with no gender predilection 1. Primary tumors are much more common than secondary ones, and central atypical cartilaginous tumors are more common than peripheral tumors 1.
Associations
Central chondrosarcomas are associated with enchondromatosis 1.
Diagnosis
A provisional diagnosis can be often made by a combination of clinical examination and imaging especially MRI 2,7,8 as well as histology 1-3, should there be a doubt after advanced imaging with the collaboration of a multidisciplinary team 2.
Diagnostic criteria
Diagnostic criteria according to the WHO classification of soft tissue and bone tumors (5th edition) 1:
location in the osseous medulla
abundant chondroid matrix mostly hyaline sometimes myxoid changes
lobular growth pattern
entrapment of pre-existing lamellar trabecular bone
increased cellularity, condensed small nuclei, commonly binucleated cells
no mitoses, no severe nuclear atypia
Clinical presentation
Tumors can be found incidentally in imaging studies, and cause pain or swelling 1,7. Low-grade central chondrosarcomas of the skull base can cause neurological symptoms 1,7. They can also present with a pathological fracture 9.
Pathology
Central atypical cartilaginous tumors/chondrosarcomas grade 1 (ACT/CS1) are aggressive cartilage matrix-forming tumors evolving from endochondral ossification 1,3. Primary lesions develop without precursor lesions, secondary lesions arise from a pre-existing benign precursor lesion such as an enchondroma 1.
Etiology
Individuals with enchondromatosis and a somatic mosaic mutation in IDH1 or IDH2 have a high risk to develop atypical cartilaginous tumors/chondrosarcomas grade 1, especially those with enchondromas in the pelvis or multiple enchondromas in both small and long or flat bones (~46%) 1,10. The risk in patients with multiple enchondromas confined to the hand and feet is substantially lower (~15%) 1,10.
Location
The most common sites are 1:
femur: 30-35% (proximal>distal>midshaft)
pelvic bones: 20-25% (ilium most common)
humerus: 10-15%
tibia: 5-10%
ribs: 5-8%
The short tubular bones of hands and feet are rarely affected 1,3.
Concerning the long bones approximately half of the cases are located in the metaphysis, one-third in the diaphysis and the remainder or one-sixth in an epiphyseal location of long bones 1.
Macroscopic appearance
Grossly, ACT/CS1 are characterized by the following features 1,3:
translucent grey-bluish or grey-white tissue mixed with fragments of bone marrow
frequent chalky yellow-white areas of calcification
possible bone erosion of the surrounding cortex
soft tissue extension is very unusual and should raise suspicion of higher-grade chondrosarcoma
Microscopic appearance
Microscopically, ACT/CS1 display the following histological features 1,3:
an abundant chondroid matrix consisting of hyaline cartilage
sometimes mucoid or myxoid changes
commonly lobulated growth pattern with variable lobule form and size
possible cortical thinning
entrapment of pre-existing lamellar bone (presence of tumor around three sides of normal trabeculae)
low cellularity (but usually higher than in enchondroma)
small condensed uniform nuclei, sometimes visible nucleolus
frequent binucleation
no mitoses
possible necrosis
possible areas of pre-existing enchondroma
Immunophenotype
Immunohistochemistry stains are positive for S100 and negative for brachyury. Only a small percentage of IDH mutations are recognized with limited use 1.
Genetics
About 50% of primary and 75-80% of secondary low-grade chondrosarcomas display somatic mutations in the IDH1 and IDH2 genes 1,3.
Radiographic features
General radiographic signs that favor ACT/CS1 are 11:
lesion size >5 cm
deep endosteal scalloping
cortical remodeling
location in the proximal metaphysis
Plain radiograph/CT
Radiographic features of low-grade chondrosarcomas include the following 1,3:
geographical lobulated shape
ill-defined margins
intralesional calcifications: rings and arcs or popcorn calcification
deep endosteal scalloping: >2/3 of the cortex or >2/3 lesion length
On CT imaging features are the same as on plain radiographs but are more readily seen and better assessable.
MRI
MRI is an important tool in the detection, grading and differentiation of low-grade chondrosarcoma versus enchondroma and intermediate to higher-grade chondrosarcoma as well as to other bone tumors.
General MR imaging characteristics are similar to features seen on CT and include the following 7,8,12:
lobulated, intramedullary, geographical shape
intralesional signal voids indicating calcifications
ill-defined margins
deep endosteal scalloping >2/3 of the cortex
trapped fatty bone marrow
The following imaging features are considered aggressive and especially highly suspicious of high-grade chondrosarcoma 13:
cortical destruction/breakthrough
loss of entrapped fatty marrow
Further imaging features pointing towards high-grade chondrosarcoma include 7,8,14-16:
peritumoral bone marrow edema
soft tissue edema
abundant mucoid changes >50%: fluid signal intensity on all sequences 11,16
Signal characteristics
T1: low to intermediate signal (iso- to slightly hyperintense vs muscle)
T2: high intensity in non-mineralized/calcified portions with or without signal voids
GRE/SWI: blooming of mineralized/calcified portions
T1 C+ (Gd): heterogeneous moderate to intense contrast enhancement
DCE: arterial enhancement within 10s favors chondrosarcoma vs enchondroma 11
Diffusion-weighted imaging does not help in the differentiation between low-grade chondrosarcoma and enchondroma 1,4 whereas dynamic contrast enhancement has been perceived as potentially useful with limitations 1,4.
Nuclear medicine
Low-grade chondrosarcomas show an intense uptake on bone scintigraphy 4,6, 17. High uptake on FDG PET-CT points to higher-grade chondrosarcoma 6, 18,19. The utility of PET-CT to differentiate between low-grade chondrosarcoma and enchondroma is still under debate 11,20.
Radiology report
The radiological report should include a description of the following 6,11:
shape and size (especially >5 cm)
location (tubular short and long bones, axial skeleton)
tumor margins and transition zone
entrapped fatty marrow and/or fat replacement (during follow-up) 12
contrast enhancement pattern (DCE – arterial enhancement)
cortical remodeling (cortical thickening)
endosteal scalloping (depth and fraction of lesion length)
cortical breakthrough
periosteal reaction
soft tissue component
neurovascular involvement
Treatment and prognosis
Central atypical cartilaginous tumors/chondrosarcoma grade 1 display a locally aggressive behavior with local recurrence seen in about ~7-11% after local excision.
Overall survival rates are approximately 88-99% after 5 years and 88-95% after 10 years 1,5,10,20. Death usually occurs from local recurrence and tumors in locations that are difficult to manage surgically such as the skull base carry a mortality rate of ~5% 1.
Treatment of central atypical cartilaginous tumors (ACT) is intralesional excision with curettage and local adjuvant therapies 1-3,7-9 such as high-speed burring and bone void augmentation 2,21.
Chondrosarcomas grade 1 (CS1) located in the axial skeleton such as the pelvis and spine should be surgically excised with negative margins, due to a worse prognosis than peripheral tumors 1,3.
The chance of metastasis is relatively low and the has been reported approximately 5% at 5 years and 8% at 10 years 2,22.
Complications
Dedifferentiation into high-grade chondrosarcoma can happen in a very low percentage of cases which has been estimated at <1% 15. However, recurring low-grade chondrosarcomas can progress to higher-grade chondrosarcomas in about 10% of cases 1.
Pre-operative histology carries the risk of tumor seeding within the biopsy tract 6,7,11.
History and etymology
Chondrosarcomas were first described by the American bone pathologists Louis Liechtenstein and Henry Lewis Jaffe in 1939 22,23.
The term atypical cartilaginous tumor has appeared since the fourth edition of the WHO classification of bone tumors describing a low-grade chondroid tumor located in the extremities that are histologically identical to a chondrosarcoma grade 1 in the axial skeleton with a slightly better prognosis 3. This concept is similar to the concept of atypical lipomatous tumor/well-differentiated liposarcoma 3.
Differential diagnosis
Conditions or tumors which can mimic the presentation and/or the appearance of central atypical cartilaginous tumors/chondrosarcoma grade 1 include 1:
enchondroma (rarely causes pain, no endosteal scalloping >2/3 cortex, no early enhancement)
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