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Page 6 of 15 Pacheco et al. J Cancer Metastasis Treat 2020;6:49 I http://dx.doi.org/10.20517/2394-4722.2020.85

Invasion of the underlying cortex is present, even in tumors less than 5 cm. Also, involvement of medullary
canal is seen in a proportion of cases, as is invasion of soft tissues. In a subset of cases (50%, in our
experience) the periphery of the tumor is encased by a complete or incomplete layer of mature cortical
bone [16,22] .

Pathogenesis
A subset of periosteal chondrosarcomas harbors heterozygous, somatic IDH1 R132C mutations [17,22,23] .
IDH1 is a metabolic enzyme of the tricarboxylic acid cycle that catalyzes the conversion of isocitrate to
α-ketoglutarate.

Mutated IDH1 has reduced catalytic activity for the production of α-ketoglutarate and increased catalytic
[24]
activity for the production of 2-hydroxyglutarate, due to an acquired neomorphic activity .
The elevated level of the oncometabolite 2-hydroxyglutarate epigenetically inhibits osteogenic
differentiation of mesenchymal stem cells through histone hypermethylation in the promoter regions
of alkaline phosphatase. It also promotes chondrogenic differentiation through histone modifications of
promoter regions of master transcription factors for chondrogenesis, SOX9 and COL2A1 [25,26] .

Loss of protein expression of cell cycle regulator CDKN2A/P16/INK4A is found in 50% of cases of
[22]
periosteal chondrosarcomas suggesting that the pRB pathway is involved in tumoral progression .
Diagnostic ancillary techniques
The commercially available IDH1 R132H antibody is a highly specific and sensitive marker for the
detection of the R132H mutant allele, but does not detect other IDH mutants, including the R132C found
[17]
in periosteal chondrosarcomas .
IDH mutational analysis can be useful in differentiating periosteal chondrosarcoma from the more
aggressive periosteal osteosarcoma, but it does not discriminate between periosteal chondroma and
periosteal chondrosarcoma.

Main differential diagnosis
The main differential diagnosis is periosteal chondroma, which occurs predominantly in younger adults
and children (peak incidence in the second decade) in the proximal humerus and the short tubular bones
[27]
of the hands . Radiographically, it shows solid periosteal bone buttressing, which is absent in periosteal
chondrosarcoma. Although some overlap in size might exist, periosteal chondromas are, on average,
smaller than periosteal chondrosarcomas, the former only rarely exceeding 3 cm. Periosteal chondroma can
erode and scallop the cortical bone, thus tumor nodules within the sclerotic cortex can be seen sometimes.
They do not represent true invasion, but an artifact due to tangential sectioning. Real invasion of cortical
bone and soft tissues is absent. Histologically, periosteal chondromas are usually hypocellular and devoid of
cytological atypia.

Periosteal osteosarcoma is diaphyseal and has a pathognomonic radiological appearance. The cartilaginous
areas in periosteal osteosarcoma show marked pleomorphism compared to the cartilage of periosteal
chondrosarcoma. Also, the intervening bands of bone-producing primitive mesenchymal cells present in
periosteal osteosarcoma are, by definition, absent in periosteal chondrosarcoma.

Secondary peripheral chondrosarcoma exhibits the characteristic corticomedullary continuity of the stalk
of the tumor and the bone of origin, which is absent in periosteal chondrosarcoma [Figure 2].