Peripheral atypical cartilaginous tumor/ low-grade peripheral chondrosarcoma
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Peripheral atypical cartilaginous tumors/chondrosarcomas grade 1 (ACT/CS1) or low-grade peripheral chondrosarcomas are locally aggressive chondral neoplasms that grow within the cartilaginous cap of pre-existing osteochondromas as a result of malignant transformation. Thus these peripheral chondrosarcomas are also called secondary peripheral atypical cartilaginous tumors or chondrosarcomas grade 1 1-4. Secondary peripheral high-grade chondrosarcomas are not covered in this article.
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Similar to central atypical cartilaginous tumor/chondrosarcoma grade 1 the terminology depends on the localization. Tumors in the tubular bones of the appendicular skeleton are called ‘peripheral atypical cartilaginous tumors’ whereas tumors of the axial skeleton are called chondrosarcoma grade 1, this includes low-grade chondrosarcomas of the pelvis, scapula and skull base 1,2.
Secondary peripheral chondrosarcomas are usually found in significantly younger patients than primary chondrosarcomas and are most often seen in the 3rd and 4th decades of life 1,2. Correspondingly patients with secondary peripheral chondrosarcomas are usually 10-20 years younger than patients with primary central chondrosarcoma 1,5. The vast majority of chondrosarcomas (>90%) are low-grade neoplasms 1,5 whereas approximately 9-10% of progressed lesions are high-grade chondrosarcomas 5.
Low-grade peripheral chondrosarcomas are associated with osteochondromas and hereditary multiple exostoses from which they progress 1-3.
The diagnosis of secondary peripheral chondrosarcoma is made by a combination of clinical information, location of the tumor and typical imaging features such as the size of the cartilaginous cap 2 and cannot be done based on histomorphological features 1,6. Differentiation between peripheral low-grade and high-grade chondrosarcomas might require histology 1,6, however, tumor grade determined by preoperative biopsy seems to be inaccurate in a significant number of cases 7.
Diagnostic criteria according to the WHO classification of soft tissue and bone tumors (5th edition) 1,2:
cartilaginous tumor originating from a pre-existing osteochondroma
cartilaginous cap with a size exceeding 2 cm, perpendicular to the bone-cartilage interface (tidemark)
no mitoses or nuclear pleomorphism
A longstanding mass lesion with recent enlargement and/or pain 1,4. Likewise, tumor growth after puberty is suspicious 1.
Peripheral atypical cartilaginous tumors/chondrosarcomas grade 1 (ACT/CS1) are locally aggressive cartilage matrix-forming tumors evolving at the surface of bone within the cartilaginous cap of pre-existing osteochondromas, especially in the setting of multiple osteochondromas and EXT1 or EXT2 germline mutations 1,3.
Individuals with osteochondromas in particular multiple osteochondromas and germline mutations in EXT1 or EXT2 are at risk of tumor progression to secondary peripheral chondrosarcoma 1. Estimated risk:
solitary osteochondroma: ~1%
multiple osteochondomas: ~5%
The most common sites involve the following bones 1:
axial skeleton – peripheral chondrosarcoma grade 1(CS1):
pubic bone: ~10%
extremities - peripheral atypical cartilaginous tumor (ACT):
Grossly, peripheral ACT/CS1 are characterized by a thick lobular cartilaginous cap exceeding 2 cm measured at its thickest portion from the chondro-osseous junction 1.
Microscopically, ACT/CS1 display the following histological features 1,6:
coarse and irregular calcifications
often evidence of pre-existing osteochondroma
cystic spaces with mucoid material
sometimes nodules in the surrounding soft tissues separate from the main mass
absent nuclear pleomorphism and no mitoses
However, there are no widely accepted histological features indicating a clear progression from osteochondroma to secondary peripheral low-grade chondrosarcoma 1,6.
The presence of nuclear pleomorphism and mitoses indicate progression to high-grade chondrosarcoma 1,6. A further indicator of progression is an invasion in the stalk, which is rare 1.
Immunohistochemistry stains are reactive for S100 1.
Secondary peripheral chondrosarcomas are associated with germline mutations in EXT1 or EXT2 with a proportion of EXT1 or EXT2 mutations among all EXT alleles of about 40% and coexisting EXT-mutant and EXT-wildtype cells. The wild-type cells are thought to be the cell type prone to tumor progression 1,2. Mutations in cell-cycle regulatory genes such as CDKN2A are also thought to be involved 1.
General radiographic signs of secondary peripheral ACT/CS1 overlap with the imaging features of osteochondroma except for the size of the cartilaginous cap which can be best assessed on MRI 1,9.
Radiographic features of low-grade peripheral chondrosarcomas include the following 1,5,9,10:
enlargement of a previously non-growing osteochondroma after skeletal maturation
irregular or indistinct lesion surface
intralesional focal osteolytic areas
irregular lesion calcification
extensive erosion or destruction of the adjacent bone
soft tissue mass with scattered or irregular chondral calcifications
The cartilage cap of peripheral chondral tumors including osteochondromas, and peripheral low-grade and high-grade chondrosarcomas is best evaluated with fat-saturated T2 weighted images 9-12.
The cut-off thickness of the chondral cap >2 cm measured from the tidemark of the subchondral bone plate has high sensitivity, specificity, and positive and negative predictive values of 100%, 98%, 96% and 100% 1,11. Very few osteochondromas (~1.5%) have a cartilaginous cap >2 cm.
T1: low signal vs muscle
T2/STIR: high signal intensity with punctate or curvilinear signal voids indicating matrix mineralization 9,10
T1 C+ (Gd): peripheral and septal enhancement
Greater cap thickness and a diffuse cap type (>75% of the circumference of the cartilage cap are thickened) indicate the presence of high-grade or dedifferentiated peripheral or periosteal chondrosarcoma. Likewise, an intraosseous extension is also suggestive of a high-grade lesion indicating aggressive growth 13.
Increased uptake on bone scintigraphy in patients with multiple osteochondromas indicates malignant transformation and progression to peripheral chondrosarcoma 7.
The radiological report should include a description of the following 9-12:
tumor size and location (tubular bones of extremities, axial skeleton)
intralesional calcifications with irrelugalities and/or lytic zones
the thickness of the cartilaginous cap 13
measured from the tidemark of the subchondral bone plate: cut-off value >2 cm
estimation of the abnormally thickened cap type (focal/regional/diffuse) 13
intraosseous extension or involvement of the stalk
adjacent bone destruction
Treatment and prognosis
Surgical excision with wide margins is the treatment of choice. Recurrences are a common problem occurring in about 10-20% of cases 1,8 and seem to be related to the width of the surgical margin at least in the pelvis 7. Prognosis is variable depending on operability and localization of the tumors with 5-year and 10-year mortality rates of up to 2% and 5% 1,5. Patients with pelvic chondrosarcomas and a negative surgical margin ≥1 mm seem to have a significantly better outcome than those with a positive surgical margin or negative surgical margin <1 mm 7. Also, low-grade peripheral chondrosarcoma seems to have a significantly better outcome than intermediate and high-grade peripheral chondrosarcomas.
The main complication is tumor recurrence or multiple recurrences with inoperability 1.
History and etymology
Chondrosarcomas in general were first described by the American bone pathologists Louis Liechtenstein and Henry Lewis Jaffe. In their work from 1942, they already differentiated between central and peripheral chondrosarcoma the latter developing in the cartilaginous cap of an osteochondroma 15. The term atypical cartilaginous tumor has appeared since the fourth edition of the WHO classification of bone tumors and is used for the appendicular skeleton in the same way as its central partner lesions 16.
The main differential diagnoses of low-grade peripheral chondrosarcomas are 12,13:
osteochondroma: cap thickness <2 cm
periosteal chondrosarcoma: no precursor osteochondroma, association with the periosteum
periosteal chondroma: originates from the periosteum, lesion size <3 cm 17
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