Lesions Characterized by Cartilage Deposition and Aggressive Radiology

Definition

Chondrosarcomas may be either primary, in which the tumors arise de novo, or secondary, in which they arise in association with a preexisting condition, most typically a benign cartilaginous lesion. In the case of the latter, tumors associated with an enchondroma are referred to as secondary central chondrosarcoma, whereas those associated with an osteochondroma are called secondary peripheral chondrosarcoma. Very rarely, chondrosarcomas may arise directly at the surface of bone; these tumors are referred to as periosteal chondrosarcomas. Conventional chondrosarcomas can occur in any bone that is formed by enchondral ossification.

Brief Historical Overview

Mummies show evidence of chondrosarcomas, thus verifying their presence since antiquity. Therefore, no one person or group is credited with its modern definition, but one can find descriptions of their clinical presentation and pathology in the European, especially German, literature of the late 19th and early 20th centuries.

Incidence and Demographics

Conventional chondrosarcomas constitute approximately 85% of skeletal chondrosarcomas, and more than 85% of these are primary central chondrosarcomas. The remaining 15% of cases represent secondary peripheral chondrosarcomas arising from the cartilaginous cap of an osteochondroma. Less than 1% of cases arise from the surface of the bone (“periosteal chondrosarcoma”).

Primary central chondrosarcoma affects patients in the fifth to seventh decades of life, and the condition is slightly more common in males. Secondary central chondrosarcoma is strongly associated with Ollier disease and Maffucci syndrome (see Chapter 9 ); approximately 40% of patients with Ollier disease and about 53% of those with Maffucci syndrome develop secondary chondrosarcomas. These patients are typically younger than those affected by primary central chondrosarcoma.

Secondary peripheral chondrosarcomas, which account for approximately 15% of chondrosarcomas, arise from the cartilaginous cap of osteochondromas (exostoses). Malignant transformation of solitary osteochondromas is quite rare (less than 1%). However, in cases of hereditary multiple exostoses, the incidence of secondary chondrosarcoma has been reported as approximately 3%.

Periosteal chondrosarcomas are extremely rare (<1% of chondrosarcomas). These are tumors of adults in their second to fourth decades and have a slightly increased incidence in males.

Localization and Clinical Manifestations

Primary central chondrosarcoma most commonly affects the pelvic bones, especially the ilium, and the metaphysis and diaphysis of long bones, particularly the femur and humerus. Only rarely does chondrosarcoma arise in the small bones of the hands and feet.

Secondary central chondrosarcoma follows the distribution pattern of enchondromas—namely, proximal humerus, distal tibia, and the femur. Secondary peripheral chondrosarcoma is most common in the bones of the pelvis and shoulder girdle. Periosteal chondrosarcoma most commonly arises at the metaphysis of long bones, particularly the distal femur and humerus.

The classic presentation of chondrosarcoma is localized swelling and/or pain that may persist for months to years. Pathologic fracture may also occur. In the case of secondary peripheral chondrosarcoma, malignant change of an osteochondroma may be heralded by a rapid increase in size of a known lesion in an adult.

Radiologic Features and Gross Pathology

Conventional radiographs of central chondrosarcoma usually display the typical features of cartilaginous tumors, including punctate (“popcorn”) calcifications, endosteal scalloping, and cortical thickening ( Fig. 10-1 ). This latter feature gives a fusiform appearance to those tumors arising in the long bones. More aggressive lesions can show cortical breakthrough and a soft tissue mass. Secondary peripheral chondrosarcoma should be suspected in an osteochondroma with a cartilage cap that is greater than 2 cm in thickness in an adult; the optimal study for this evaluation is magnetic resonance imaging.

On a conventional radiograph, periosteal chondrosarcoma manifests as a periosteal soft tissue mass with punctate calcifications and sharply defined borders, similar to periosteal chondroma. which is typically less than 3 cm in size. Histologic evaluation is necessary to differentiate these two entities.

Grossly, chondrosarcoma is composed of lobules of blue-gray hyaline cartilage with a gritty texture due to scattered calcifications, which may coalesce into areas of chalky calcium deposition. Myxoid change may manifest as a viscous substance, and cysts, necrosis, and hemorrhage may be present. These features are suggestive of higher grade lesions.

Histopathology and Grading

In general, the morphologic appearance of chondrosarcoma consists of atypical chondrocytes distributed in a cartilage matrix ( Fig. 10-2 ). The degree of cellularity, cytologic atypia, architectural organization, mitotic activity, and amount of myxoid change relates to the tumor grade. As one progresses from low to high grade, the cytomorphology shows increases in pleomorphism, nuclear hyperchromasia, and mitotic activity ( Fig. 10-3 ).

Enchondromas of the small tubular bones of the feet and hands generally show greater cytologic atypia and cellularity than enchondromas occurring elsewhere in the body, and a diagnosis of chondrosarcoma may be entertained by the inexperienced pathologist. However, chondrosarcomas in these sites are extremely uncommon.

Grading central chondrosarcoma is challenging even for expert pathologists. Interobserver reliability is low, not only in distinguishing low grade from high grade tumors, but also in determining whether a given tumor is benign or malignant! Interestingly, despite the lack of consistency in grading, grade does correlate with prognosis.

Histologic Variants

The term “myxoid chondrosarcoma” has been used for (1) central chondrosarcomas that show prominent myxoid change and (2) tumors that were presumed to be skeletal (as opposed to extraskeletal) examples of myxoid chondrosarcoma, a tumor characterized by a reciprocal t(9;22) translocation ( Fig. 10-4 ). Due to the possibility of confusion, the preferred term for conventional chondrosarcoma with abundant myxoid stroma is “chondrosarcoma with extensive myxoid change” ( Fig. 10-5 ). Cases of true skeletal myxoid chondrosarcoma are extremely rare and should be confirmed by molecular evaluation for the t(9;22) translocation.

Differential Diagnosis

The primary challenge in diagnosing low-grade central chondrosarcoma is in excluding enchondroma. Low-grade chondrosarcoma shows significant histologic overlap with enchondroma; microscopic features that support malignancy include host bone entrapment (“permeation of trabecular bone”), increased cellularity, open chromatin, and more than 20% mucoid matrix. Morphologic features should not be considered in isolation. Useful clinical and radiologic criteria that support malignancy include age greater than 45 years, spontaneous pain, the absence of pathologic fracture ( P < .05), a soft tissue mass, and cortical disruption, thickening, or erosion ( Fig. 10-6 ).

Chondroblastic osteosarcoma may also enter the differential diagnosis; however, osteosarcoma more commonly affects adolescents and young adults, a population less likely to develop chondrosarcoma. Furthermore, careful examination usually reveals at least focal areas of osteoid deposition ( Fig. 10-7 ).

Ancillary Diagnostic Studies

Molecular evaluation to exclude the t(9;22) translocation seen in true skeletal myxoid chondrosarcoma may be useful. When chondroblastic osteosarcoma is considered in the differential diagnosis, identification of isocitrate dehydrogenase 1/2 (IDH1/2) mutations, either by immunohistochemistry or molecular analysis, supports a diagnosis of chondrosarcoma.

Genetics

A number of genes have been implicated in the development and progression of this heterogeneous group of tumors; a recent study of 49 cases of central, peripheral, and dedifferentiated chondrosarcomas has shown frequent mutations in IDH1/2 (59% of cases), COL2A1 (37%), tp53 (20%), the retinoblastoma 1 (RB1) pathway (33%), and Hedgehog signaling molecules (18%). IDH1 and IDH2 encode the metabolic enzymes isocitrate dehydrogenase 1 and 2, respectively, and mutations in these genes have been identified in central chondrosarcomas (primary, secondary, and dedifferentiated types), but not in peripheral chondrosarcomas. Mutations in IDH1/2 are also present in sporadic enchondromas and in Ollier disease and Maffucci syndrome (see Chapter 9 ), which suggests that this is an early event in cartilage neoplasia. Although the exact role of these mutations in tumorigenesis is not known, DNA and histone hypermethylation and alterations in the hypoxic response have been hypothesized.

Based on loss of heterozygosity (LOH) data, it appears that primary central and secondary peripheral chondrosarcomas arise through different aberrant genetic pathways. In a recent series, 95% of peripheral chondrosarcomas showed loss of heterozygosity of the EXT genes, EXT -like genes, 9p21, 13q14, 17p13, and chromosome 10; in contrast, only 30% of central chondrosarcomas showed loss of heterozygosity, which was restricted to 9p21, 10, 13q14, and 17p13. Furthermore, central chondrosarcomas were found to be predominantly peridiploid, whereas peripheral chondrosarcomas showed near-haploidy.

Genetic changes associated with increasing tumor grade in central chondrosarcoma include loss of heterozygosity in the 9p21 region, which encodes the INK4a/INK4A-ARF locus and loss of CDKN2A , aberrations in the RB1 pathway, and increased expression of parathyroid hormone–related peptide and BCL2. In peripheral chondrosarcoma, increasing grade is associated with a shift from near-haploid to polyploidy, as well as down-regulation of IHH and Wnt signaling and up-regulation of tumor growth factor-β signaling.

Treatment and Prognosis

Surgical excision is the mainstay of chondrosarcoma treatment because these tumors are largely resistant to conventional radiation and chemotherapy. Low-grade chondrosarcoma may be treated by curettage with local adjuvants; recurrence is rare but approximately 10% of those tumors show histologic progression. Higher grade tumors should be widely resected.

Prognosis in conventional chondrosarcoma is closely correlated with histologic grade. For primary central chondrosarcoma, patients have 10-year survival rates of 83%, 64%, and 29% for grades I, II, and III, respectively. Although grade I chondrosarcomas rarely metastasize, approximately 70% of patients with grade III chondrosarcomas develop metastases.

Definition

Clear cell chondrosarcoma is an uncommon variant of usually lower grade chondrosarcoma characterized by sheets of cells with abundant clear cytoplasm. Most common in patients in the third to sixth decade, this tumor shows a predilection for men and typically arises at the ends of long bones.

Brief Historical Overview

This tumor was first described by Unni and colleagues as a series of 16 cases in 1976.