Central Atypical Cartilaginous Tumor / Chondrosarcoma, Grade 1

Staging is according to bone sarcoma protocols (see TNM staging of tumors of bone). See also the information on staging in the section Bone tumors: Introduction.

Similar to enchondromas, about 50% of primary central ACT/CS1s and as many as 78% of secondary central ACT/CS1s (in enchondromatosis) harbor somatic mutations in the isocitrate dehydrogenase genes IDH1 and IDH2.

Tissue fragments obtained from curettage are composed of translucent, bluish-grey or greyish-white tissue, usually admixed with red fragments of bone marrow. Yellowish-white chalky areas of calcification are often present. In resection specimens, the tumor is usually sharply demarcated and may demonstrate erosion of the surrounding cortex, which corresponds to the cortical scalloping seen in imaging studies. Soft tissue extension is usually not seen in central ACT/CS1. Extensive sampling is required to rule out areas of dedifferentiation.

Central ACT/CS1 has abundant hyaline cartilage matrix. A lobulated growth pattern is often recognized, and lobules can be irregularly shaped and vary in size. The lobules may be separated by fibrous bands containing small vessels. The lobular growth pattern can cause typical cortical thinning represented in radiographs by cortical scalloping. The typical encasement pattern (deposition of bone surrounding the tumor lobules, a sign of indolent growth as seen in slow-growing enchondromas) is highly uncommon. Instead, as a sign of more-rapid growth, the tumor lobules usually permeate and entrap the pre-existing lamellar bone trabeculae, although this may be difficult to appreciate in fragmented curettage specimens. Entrapment is defined as the presence of tumor around three sides of a normal spicule of medullary trabecular bone. The cellularity in central ACT/CS1 is low, but slightly higher than in enchondroma. The nuclei can be small and condensed (lymphocyte-like), although they sometimes have more-open chromatin with a visible nucleolus. The nuclei are generally uniform in size. Binucleation is frequently seen, but mitoses are absent. The surrounding matrix is predominantly hyaline, sometimes with more mucoid or myxoid changes. Necrosis may be present. Areas of a pre-existing enchondroma, with extensive calcifications, may be recognized in central ACT/CS1.

Immunohistochemistry
The tumor cells strongly express S100 and are negative for brachyury. Because the p.Arg132His mutation–specific IDH1 antibody only recognizes a small percentage of the IDH mutations in central ACT/CS1, its usefulness is limited.

Differential diagnosis
There is overlap between the histological features of enchondroma and those of central ACT/CS1, and the distinction is made by the higher cellularity, irregular distribution of the cells, and occurrence of binucleated cells in central ACT/CS1. A very important criterion is the growth pattern, in which the presence of entrapment (of pre-existing lamellar bone) and the absence of encasement are indicative of central ACT/CS1. The presence of > 20% myxoid changes of the matrix also favors the diagnosis of ACT/CS1 over enchondroma. The distinction can be extremely difficult on small biopsy specimens, and clinicoradiological correlation is essential. When these criteria are used, the localization of the lesion and the age of the patient are important}. With regard to localization, if the tumor is located in the medullary cavity of a long tubular bone, then increased cellularity with irregular distribution, more-open chromatin with visible nucleoli, and the presence of binucleated cells are indicative of central ACT/CS1, whereas if the tumor is located in the phalangeal bone, these histological features are accepted in an enchondroma because they are not indicative of more-aggressive behavior. Similarly, in patients with enchondromatosis and for tumors arising in patients before puberty (before growth plate fusion), increased cellularity, more-open chromatin, and the presence of binucleated cells do not exclude the diagnosis of enchondroma. Thus, a multidisciplinary approach with clinicoradiological correlation is often indispensable. Grade 2 conventional central chondrosarcoma is distinguished from ACT/CS1 on the basis of its increased cellularity, the presence of mitoses, myxoid matrix degeneration, spindle cell changes at the periphery of the lobules, increased vascularization, and increased nuclear pleomorphism.

Not clinically relevant

Central ACT/CS1 has a locally aggressive behavior. Local recurrence is seen in 7.5–11% of the cases, compared with 0% in enchondroma. In about 10% of recurring central ACT/CS1s, progression to a higher grade is seen. Reported 5-year overall survival rates for ACT/CS1 are 87–99%, and 10-year overall survival rates are 88–95%. Patients die from locally recurrent tumors that are sometimes difficult to manage surgically, depending on the location. In the long bones, central ACT is treated with curettage and local adjuvants, giving a good prognosis. Overall, tumors located in the axial skeleton have a worse outcome. Therefore, CS1s of the pelvis and spine are treated with surgical excision and negative margins. For skull base CS1, the mortality rate is 5%. A large proportion of the mortality of ACT/CS1 is probably caused by intracranial or axial tumors that are difficult to treat because of their location. Therefore, the location determines whether to diagnose ACT (in the appendicular skeleton) or CS1 (in the axial skeleton and pelvis), to better reflect outcome. It is at present unclear whether the presence of an IDH mutation is associated with prognosis.

Hotspot mutations are exclusively found at the IDH1 p.Arg132 and the IDH2 p.Arg172 positions; the IDH1 p.Arg132Cys mutation is the most frequently found mutation. About 50% of primary central ACT/CS1s and as many as 78% of central ACT/CS1s occurring in enchondromatosis have IDH1 or IDH2 mutations. Mutations at the IDH1 p.Arg140 position are extremely rare. In the rare occurrence in the skull base, the mutation frequency is very high (85.7%), whereas mutations are rare to absent in the laryngeal and tracheal tumors (11.8%).

Essential: location in the medulla of bone; abundance of cartilaginous matrix, often hyaline, sometimes with myxoid changes; lobular growth pattern with entrapment of pre-existing lamellar bone trabeculae; increased cellularity, with small condensed nuclei; binucleated cells are common; absence of mitoses, severe nuclear atypia, and encasement.