Central intermediate and high-grade chondrosarcoma

Last revised by Tom Foster on 28 Jul 2023

Central chondrosarcomas grade 2 and 3 (CS2/CS3) are malignant intermediate- and high-grade conventional chondrosarcomas that arise intramedullary 1-3.

Similar to low-grade chondrosarcoma, the incidence of central intermediate and high-grade chondrosarcomas has also risen compared to the 1990s and has been last estimated at 1.5-2 per million person-years 1,2.

Intermediate-grade to high-grade chondrosarcomas are mainly found in the adult population in the third to the sixth decade with equal gender distribution 1, though patients with enchondromatosis are usually younger than patients with primary tumors 1.

Central chondrosarcomas are associated with enchondromatosis 1,4.

A provisional diagnosis can be often made by a combination of clinical examination and imaging and is confirmed by histology.

Diagnostic criteria according to the WHO classification of soft tissue and bone tumors (5th edition) 1:

  • location in the bony medulla

  • cartilaginous tumor with a lobular growth pattern

  • entrapment of pre-existing lamellar trabecular bone

  • myxoid matrix

  • increased cellularity, presence of mitoses

  • no osteoid production of the malignant cells

Pain and/or swelling are common symptoms. Tumors growing from the pelvic bones or thoracic cage can grow quite large before they are discovered 1. They can also present with a pathological fracture 1. Chondrosarcomas of the skull base and spine can cause neurological symptoms 1.

Intermediate- and high-grade chondrosarcomas grades 2 and 3 are malignant cartilage matrix-forming tumors arising from endochondral ossification 1. They can develop without or from a pre-existing precursor lesion.

Individuals with enchondromatosis and a somatic mosaic mutation in IDH1 or IDH2 are at higher risk to develop chondrosarcomas 1.

The most common sites are the following 1:

  • long tubular bones: especially proximal femur > proximal humerus > distal femur

  • flat bones: ileum most common

  • ribs

The spine and skull are occasionally affected 1.

Grossly, intermediate- to high-grade chondrosarcomas are characterized by the following features 1:

  • translucent grayish-blue or grey-white tissue cut surface

  • chalky yellow-white areas of calcification

  • cystic and myxoid changes

  • frequent cortical erosion, cortical destruction and soft tissue extension

Microscopically, intermediate- to high-grade chondrosarcomas display the following histological features 1,6,7:

  • lobular growth pattern

  • entrapment of pre-existing lamellar bone (tumor around three sides of normal trabeculae)

  • chondroid matrix consisting of hyaline cartilage and a variable extent of myxoid changes

  • higher cellularity than low-grade chondrosarcoma

  • small condensed nuclei, variable nuclei with visible nucleoli

  • presence of mitoses especially in high-grade chondrosarcoma (grade 3), some nuclear atypia

  • frequent cortical destruction and breakthrough

  • mostly spindled and less differentiated cells in the periphery of high-grade tumors

Immunohistochemical staining is reactive for S100 and negative for brachyury. Only a small percentage of IDH mutations are recognized with limited use 1.

About 50% of chondrosarcomas display somatic mutations in the IDH1 and IDH2 genes 1.  They are also characterized by aneuploidy and complex karyotypes as well as alterations in the p53 and RB1 signaling pathways in >80% of high-grade chondrosarcomas 7. Other alterations include mutations in the COL2A1 gene in more than one-third of the cases 7,8.  Copy number variations of CDKN2A are found in about ¾ of high-grade central chondrosarcomas, but not in low-grade chondrosarcomas or enchondromas 1,7.

General radiographic features of central intermediate and high-grade chondrosarcomas include 9-12:

Radiographic features of low-grade chondrosarcomas include the following 1:

  • lytic lesion

  • geographical, lobulated shape

  • expansile remodeling, cortical thickening and periosteal reaction

  • ill-defined margins with moth-eaten or permeative bone destruction

  • intralesional calcifications: (rings and arcs calcification or popcorn calcification)

On CT imaging features are the same as on plain radiographs but are more readily seen and better assessable.

MRI is an important tool in the detection, grading and differentiation of intermediate- to higher-grade chondrosarcomas versus low-grade chondrosarcoma as well as other bone tumors. MR imaging characteristics include the following 1,9-16:

  • intramedullary location, lobulated or geographical shape

  • abundant mucoid changes (>50%) with fluid signal intensity on all sequences 11

  • absence or loss of entrapped fatty marrow 10 (e.g. on follow-up studies)

  • bone expansion, cortical thickening and cortical destruction

  • peritumoral bone marrow edema and soft tissue edema

  • periostitis 13

  • soft tissue extension

  • intralesional hemorrhage or necrosis 15

It is important to realize typical imaging features of cartilaginous tumors such as lobulated growth patterns and the rings and arcs appearance can become lost due to poor cell differentiation in higher-grade tumors 12.

The clinical utility of diffusion-weighted imaging in the evaluation of intermediate to high-grade chondrosarcoma remains inconclusive  10.

Also of note is, that there are no particular MR imaging features predictive in small bones 14.

  • T1: low to an intermediate signal

  • T2: high intensity with or without signal voids indicating calcifications

  • GRE/SWI: blooming of mineralized/calcified portions

  • T1 C+ (Gd): peripheral and septal contrast enhancement 9

  • DCE: arterial enhancement favors chondrosarcoma vs enchondroma

PET-CT can show a high FDG uptake in intermediate- and high-grade chondrosarcomas with a SUVmax of >4.4 and a high specificity of 99% versus enchondromas and low-grade chondrosarcomas 11,17, with the limitation that almost half of the intermediate and high-grade chondrosarcoma cases will reveal a SUVmax in an inconclusive range of 2-4.4 not helping the differentiation versus low-grade chondrosarcomas 1.

The radiological report should include a description of the following 10-16:

  • shape and size (especially >5 cm)

  • location (long bones, axial skeleton)

  • tumor margins and transition zone

  • absence or loss of entrapped fatty marrow and/or fat replacement (during follow-up) 12

  • expansile remodeling

  • cortical destruction/breach

  • periosteal reaction

  • soft tissue component

  • neurovascular involvement

Treatment consists of en bloc resection to achieve tumor-free margins 1,4. They are relatively resistant to radiotherapy 3. Local recurrences are more frequent than in low-grade chondrosarcomas and occur in about 19-26% 1 being more frequent in higher-grade tumors 1,2.

Overall survival rates for chondrosarcoma grade 2 (CS2) are in the range of 70-90% and 60-85% after 5 and 10 years and for chondrosarcoma grade 3 (CS3) 5-year and 10-year survival rates are in the range of 31-75% and 26-55% respectively 1,2,10,18,19.

The chance of metastasis is approximately 10-30% in intermediate-grade chondrosarcomas (CS2) and about 30-70% in high-grade chondrosarcomas 1.

The main complications include 1,

  • tumor recurrence

  • distant metastases

  • pathologic fracture

  • pre-operative histology carries the risk of tumor seeding within the biopsy tract 11

Chondrosarcomas were first described by the American bone pathologists Louis Liechtenstein and Henry Lewis Jaffe in 1939 20.

Intermediate and high-grade chondrosarcoma have been separated from low-grade chondrosarcoma since the fourth edition of the WHO classification of bone tumors in 2013 2,3,16,21.

Conditions or tumors which can mimic the presentation and/or the appearance of central intermediate- to high-grade chondrosarcoma include 1,16:

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