Tumors of the Osteoarticular System

Osteochondroma

Osteochondroma accounts for approximately 35% of benign bone tumors. However, when they are small, osteochondromas are asymptomatic; hence their true incidence is likely underestimated. They most commonly occur as a solitary lesion, but approximately 15% of patients present with multiple lesions, characteristic of hereditary multiple osteochondromas syndrome, an autosomal dominant condition, resulting from germline inactivating mutations or deletions of the EXT1 and EXT2 genes and, less commonly, EXT3. Mutations in these genes lead to abnormalities in the IHh/PTHrP pathway, which controls chondrocyte differentiation and proliferation. In contrast, sporadic osteochondromas lack such mutations, but instead show homozygous deletions of EXT1 .

Osteochondromas may produce symptoms by their sheer size (by infringing on nearby structures such as nerves) or may become painful because of a fracture through the stalk. Most osteochondromas seen in surgical practice are in young patients, and there is a slight male predominance. While osteochondromas can arise anywhere in the skeleton, the metaphysis of long bones is the preferred site, and they are exceptionally rare in the hands and feet.

Imaging studies characteristically show a broad-based (sessile) or pedunculated osseous projection from the surface of the bone ( Fig. 25.11 ). In either case, there is a corticomedullary continuity between the underlying bone and the osteochondroma. When the lesion involves the metaphysis of a long bone, it typically grows away from the nearest joint.

Grossly, an osteochondroma has a thin, smooth cartilage cap (typically <2 cm) and an underlying bony stalk ( Fig. 25.12 ). Microscopically, the cartilage cap contains chondrocytes in lacunae. Toward the base of the cap, the cartilage undergoes endochondral ossification to form trabecular bone. It is not unusual to see islands of residual cartilage in the middle of the bony elements within the stalk. The spaces between the bony trabeculae contain either fatty or hematopoietic marrow ( Fig. 25.13 ). Occasionally, degenerative change is present within the cartilage cap, a feature that is not indicative of malignancy.

Benign lesions in the differential diagnosis include bizarre parosteal osteochondromatous proliferation (BPOP) and subungual exostosis (discussed later). Unlike osteochondromas, BPOP usually involves the small bones of the hands, and subungual exostosis typically occurs under the nail bed, especially of the great toe. The histologic resemblance of these lesions to an osteochondroma results from a combination of proliferating cartilage and maturation into trabecular bone. However, the cartilage in BPOP is frequently abundant, hypercellular with bizarre-appearing chondrocytes, and has a characteristic basophilic (blue) tinctorial quality. In contrast to osteochondroma, a cytologically bland intertrabecular spindle cell proliferation is commonly seen in both lesions.

Parosteal osteosarcoma can simulate osteochondroma, particularly because approximately 25% of parosteal osteosarcomas have a cartilage cap. Careful attention to the histologic features below the cap as well as the imaging features will lead to a correct diagnosis. The intertrabecular space within parosteal osteosarcoma is occupied by spindled cells with minimal nuclear atypia within a collagenous stroma. This differs from the stalk of an osteochondroma, in which the intertrabecular space is filled with hematopoietic marrow and fat.

The majority of osteochondromas are benign, and complete excision is typically curative. However, the cartilage cap of an estimated 1% of sporadic osteochondromas and 5% of syndrome-associated osteochondromas undergo morphologic malignant transformation into secondary peripheral chondrosarcoma (see later discussion). Most frequently, this occurs in osteochondromas arising in the pelvis or shoulder girdle.

Bizarre Parosteal Osteochondromatous Proliferation

Bizarre parosteal osteochondromatous proliferation was first described by Nora and colleagues in 1983 as an unusual reactive process involving the small bones of the hands and, less commonly, the feet. However, subsequent cytogenetic studies have shown a recurrent chromosomal translocation t(1;17)(q32;q21), supporting the clonal neoplastic nature of the lesion.

Although the majority of lesions involve the small tubular bones, approximately 25% involve the long bones. A slight female predominance is seen, and the lesion can involve patients in any age group. Radiography shows a heavily calcified mass attached to the underlying cortex by a broad base ( Fig. 25.14 ). Histologically, under low power, the lesion simulates the appearance of an osteochondroma. A large amount of cartilage may be arranged in the form of a cap or lobules. Typically, the cartilage undergoes endochondral ossification, producing bone with a characteristic dark blue tinctorial quality, especially at the interface with the cartilage ( Fig. 25.15 ). The intertrabecular spaces contain proliferating spindle cells that lack cytologic atypia. This lesion differs histologically from florid reactive periostitis and fibro-osseous pseudotumor of the digits.

The proliferative nature of the hyaline cartilage and the presence of spindle cells between trabeculae may lead to a mistaken diagnosis of either chondrosarcoma or osteosarcoma. However, the typical radiographic appearance and the maturation of cartilage into bone with the unusual blue color should lead to the right diagnosis. Recurrences are common, but malignant transformation has never been described.

Subungual Exostosis

Subungual exostosis is an uncommon lesion that occurs exclusively under the nail bed, with a marked predilection for the great toe. Patients are usually in the second decade of life and present with a painful lesion that may lift off the nail and ulcerate the skin. The lesion may be black and confused clinically with a subungual melanoma. Radiographs show a mineralized lesion that is attached to the distal phalanx of the toe but lacks the corticomedullary continuity of an osteochondroma. The gross appearance may appear osteochondromatous with a thick, irregular cartilage cap and a bony stalk. Histologically, the hyaline cartilage is proliferative, with increased cellularity and frequent binucleate chondrocytes; however, orderly maturation with endochondral ossification into woven bone trabeculae occurs ( Fig. 25.16 ). The intertrabecular spaces contain proliferating spindle cells. This combination of bone, cartilage, and spindle cell proliferation may lead to a mistaken diagnosis of osteosarcoma. However, the typical location and the benign radiographic appearance suggest the correct diagnosis. Notably, a rare form of subungual melanoma that produces metaplastic bone and cartilage has been described that may be mistaken for subungual exostosis.

Cytogenetic analysis has shown that subungual exostosis is characterized by the chromosomal translocation t(X;6)(q24-q26;q15-21). This rearrangement seems to cause elevated expression of insulin receptor substrate 4 (IRS4) , likely caused by disruption of the COL12A1 locus.

Chondroma

The term chondroma refers to a benign cartilaginous neoplasm. The lesions may occur within the bone, in which case the term enchondroma is used; on the surface of the bone, as periosteal chondromas ; or in the soft tissues, as soft tissue chondromas .

Enchondromas are usually asymptomatic lesions, thus their true incidence is unknown. There is no sex or age predilection. Most enchondromas involve the small bones of the hands and feet. Asymptomatic enchondromas of larger bones may be incidental radiologic findings and are frequently identified on radionuclide skeletal scans in routine workup for metastatic disease. Radiographically, enchondromas are well-circumscribed lesions, confined to the medullary cavity with no significant erosion of the cortex. They typically show uniform calcification throughout the lesion ( Fig. 25.17 ).

Grossly, enchondromas have the characteristic pale blue, glassy appearance of hyaline cartilage. Flecks of chalky-white calcification may be seen. Microscopically, enchondromas are lobulated, hypocellular lesions with chondrocytes arranged in clusters with abundant intercellular matrix. The matrix does not show extensive myxoid change or cyst formation. A rim of ossification at the periphery of the cartilage lobules is common (host bone encasement) ( Fig. 25.18 ). Enchondromas grow by slow expansion and compressive destruction of medullary bone and thus do not permeate between or entrap bony trabeculae ( Fig. 25.19 ). The chondrocyte nuclei are inconspicuous, small, and round with rare binucleation. The matrix lacks liquefactive myxoid change, but degenerative necrosis can be seen in older tumors.

In contrast to enchondromas of the long bones, patients with enchondromas of the small tubular bones of the hands and feet often present with pain secondary to a pathologic fracture. Radiologic images show a medullary cartilaginous tumor, often with marked thinning of the overlying bony cortex ( Fig. 25.20 ). While this feature in a cartilage tumor of a larger bone might be worrisome, in a small bone, the diagnosis of chondrosarcoma should only be entertained if there is cortical breach with lesional infiltration into the soft tissues.

Grossly, enchondromas of the small tubular bones usually fill and expand the affected bone with marked thinning of the overlying cortex. Microscopically, enchondromas of the small bones are hypercellular relative to those of the long bones ( Fig. 25.21 ). Binucleate chondrocytes are frequent, and focal myxoid change may be seen. The expansile growth pattern may lead to a lobulated pushing border into surrounding soft tissue. However, only destructive permeation through the bony cortex into soft tissue and/or host bone entrapment should prompt a diagnosis of chondrosarcoma.

One of the more difficult problems in bone tumor pathology is the differentiation of an enchondroma from chondrosarcoma. When evaluating an intraosseous cartilage tumor, review of the imaging studies by an experienced radiologist is imperative. Imaging features demonstrating extensive destruction of the cortex or soft tissue infiltration by the cartilage tumor should be considered evidence of malignancy. On gross examination, a diffuse myxoid quality or cyst formation of the matrix must be considered worrisome for malignancy. Microscopically, permeation of surrounding structures, including entrapment of host lamellar bone, is probably the best single criterion to differentiate a chondrosarcoma from an enchondroma.

Enchondromas are cytogenetically characterized by simple karyotypes with frequent rearrangements of chromosomes 6 and 12. HMGA2 on chromosome 12q15 is often rearranged, but this finding has limited diagnostic value. Enchondromas frequently harbor heterozygous mutations in genes encoding isocitrate dehydrogenase (IDH1/2), an enzyme involved in the tricarboxylic acid cycle. Mutations in IDH result in aberrant production and accumulation of D2-hydroxyglutarate, a putative oncometabolite that is associated with histone and DNA hypermethylation. Somatic mosaic IDH mutations in cartilaginous tumors were initially identified in patients with Ollier or Maffucci syndrome. However, an estimated 50% to 70% of sporadic benign and malignant central cartilaginous tumors also contain IDH mutations. As they occur in both benign and malignant central and periosteal cartilaginous tumors (see upcoming discussion), IDH mutational testing has no value in the differentiation of enchondroma from chondrosarcoma.

Periosteal chondromas are rare, benign cartilaginous tumors arising on the surfaces of bone. They usually arise in the proximal humerus or the distal femur and occasionally involve the small bones of the hands and feet. Radiologic imaging shows a well-circumscribed lesion on the surface of bone, with saucerization of the underlying cortex. Periosteal chondromas are typically small lesions, measuring less than 5 cm. Macroscopically, the lesion has the typical appearance of a cartilage tumor and shows no tendency to permeate surrounding tissues. Histologically, periosteal chondromas tend to be more cellular then enchondromas of the long bones. The chondrocytic nuclei are usually hyperchromatic, and binucleated cells are common. Taken out of context, these cytologic features mimic those of a low-grade chondrosarcoma. However, in small (<5 cm), well-circumscribed periosteal chondromas, these cytologic features are not indicators of malignancy. Once again, radiologic correlation is essential

Most soft tissue chondromas occur in the hands or feet. It is extremely unusual to see benign hyaline cartilage tumors of the soft tissues at any other anatomic site. Grossly, soft tissue chondromas are lobulated and may have multiple nodules. Calcification is a common finding. Histologically, the chondrocytes are clustered but may show mild to moderate cytologic atypia. The histologic features strongly resemble those of synovial chondromatosis (see later discussion). Occasionally, soft tissue chondromas show features resembling those of chondroblastoma. Soft tissue chondromas are benign, but local recurrences are not unusual. Rearrangements of HMGA2 have been identified in soft tissue chondroma with one case harboring a HMGA2-LPP fusion. Unlike enchondromas, soft tissue chondromas do not appear to have IDH1/2 mutations.

Enchondromatosis, defined by the presence of multiple enchondromas, encompasses a number of rare syndromes categorized by the skeletal distribution of enchondromas (e.g., spinal involvement), associated clinical findings, and mode of inheritance. The tumors in enchondromatosis typically involve the ends of long bones and flat bones, may be confined to one limb or half the body, or may be bilateral. Among the enchondromatoses, Ollier disease and Maffucci syndrome are by far the most common subtypes. Both conditions are nonhereditary disorders characterized by multiple enchondromas, particularly involving the extremities; however, patients with Maffucci syndrome also present with multiple hemangiomas, including spindle cell hemangiomas, and lymphangiomas of the soft tissues, skin, or viscera. Both disorders are also associated with a spectrum of other tumor types. As mentioned earlier, somatic mosaic mutations of IDH1 and IDH2 frequently occur in these patients; approximately 80% to 90% of cartilaginous and noncartilaginous tumors from patients with Ollier disease or Maffucci syndrome have IDH1 or IDH2 mutations.

Radiographically, the metaphyseal-diaphyseal portions of the long bones appear expanded and show longitudinal striations of mineralization ( Fig. 25.22 ). Histologically, in comparison to sporadic examples, enchondromas arising in Ollier disease and Maffucci syndrome are usually hypercellular, with binucleated chondrocytes and enlarged hyperchromatic nuclei. However, in the setting of enchondromatosis, these histologic features do not denote malignancy, and the lesions may regress following skeletal maturation. Nevertheless, patients with Ollier disease and Maffucci syndrome have a higher risk of malignant transformation of one or more enchondroma(s) to secondary central chondrosarcoma, particularly in tumors affecting the long bones (see later discussion).

Chondroblastoma

Chondroblastoma is a benign neoplasm that typically occurs in skeletally immature patients. There is a slight male predominance, and the clinical presentation is nonspecific. Chondroblastomas most commonly arise in the femur, proximal tibia, and proximal humerus; however, any skeletal site may be involved, and the calcaneus, talus, and patella are also classic sites of involvement. The incidence of chondroblastomas involving the temporal bone is lower than previously reported as several have been reclassified as tenosynovial giant cell tumors. The vast majority of chondroblastomas arise in the epiphysis or epiphyseal-equivalent apophysis (e.g., greater trochanter of the femur and tuberosity of the humerus) ( Fig. 25.23 ), although metaphyseal or diaphyseal examples have been described. The radiologic features are quite characteristic: a well-circumscribed lytic lesion, sometimes with a sclerotic border, and extensive perilesional edema. Typically, chondroblastomas have an epiphyseal epicenter, wherein over 50% extend to the metaphysis through an open epiphyseal plate, and one-third show mineralization.

Grossly, chondroblastomas tend to be white and firm with occasional macroscopic cyst formation. Microscopically, chondroblastomas are composed of a mixture of chondroblasts and variable numbers of osteoclast-type giant cells. Cytologically, the mononuclear cells have oval nuclei with longitudinal grooving, similar to the cells of Langerhans cell histiocytosis. The cytoplasmic membranes are usually distinct, and the cytoplasm is eosinophilic or clear. Scattered chondroblasts with atypical hyperchromatic nuclei can be seen but are not an indicator of malignancy. Mitoses are commonly seen, but atypical mitoses are absent.

Chondroid differentiation is a characteristic feature, forming amorphous islands of chondroid material juxtaposed to the mononuclear cell proliferation. Mature hyaline cartilage formation is rare. Notably, the oft-described pericellular chicken-wire calcification is conspicuously absent in more than half of chondroblastomas, and its absence should not preclude the diagnosis ( Fig. 25.24 ).

Approximately one-third of chondroblastomas undergo secondary aneurysmal bone cyst formation. This may be a focal phenomenon or a predominant feature and does not affect prognosis. Chondroblastomas are benign lesions that typically are treated with simple curettage followed by bone grafting. Local recurrence rates are low, with the exception of chondroblastomas involving the temporal bone, which can recur in up to 50% of patients. Notably, pulmonary metastasis from histologically benign chondroblastomas has been well documented in the literature, but simple surgical excision appears to be curative in the majority of cases.

The differential diagnosis of chondroblastoma chiefly includes chondromyxoid fibroma and chondrosarcoma, especially clear cell chondrosarcoma. Chondromyxoid fibromas are metaphyseal lesions, whereas chondroblastomas arise in the epiphysis. The two tumors have overlapping histologic features; however, chondroblastoma does not show the lobulation of chondromyxoid fibroma, and chondromyxoid fibroma lacks pericellular calcification. Radiologic correlation can be very helpful in difficult cases (see later discussion). In contrast, both chondroblastoma and clear cell chondrosarcoma are epiphyseal tumors. However, clear cell chondrosarcoma usually occurs in skeletally mature patients with closed growth plates and often has areas of conventional chondrosarcoma.

Chondroblastomas very often show cytogenetic abnormalities involving chromosomes 5 and 8. Recently, mutations in H3F3A/B , encoding the histone 3.3 protein, have been identified as frequent events in chondroblastoma, with the vast majority of cases harboring H3F3B mutations. Most commonly, these H3F3 mutations result in the p.K36M amino acid substitution, and immunohistochemical testing with a H3K36M mutant antibody has a high sensitivity and specificity for chondroblastoma.

Chondromyxoid Fibroma

Chondromyxoid fibromas are extremely unusual and occur only half as frequently as chondroblastomas. Patients are usually in the second or third decade of life. These lesions are most frequently located in the metaphysis of long bones, particularly the proximal tibia and distal femur. The small bones of the feet and ilium are also commonly involved. Occasional lesions are juxtacortical and extend into soft tissue. They can be especially difficult to recognize when located at uncommon sites such as the craniofacial bones. Radiographic images show an extremely well-circumscribed, purely lytic defect involving the metaphysis. The lesion usually has a sclerotic border, which may be undulating and give rise to a scalloped appearance ( Fig. 25.25 ).

Macroscopically, chondromyxoid fibromas tend to be grayish white, well circumscribed, lobulated, and may appear to “pop out” of the surrounding bone. Microscopically, chondromyxoid fibromas form variably sized lobules ( Fig. 25.26 ), which are centrally hypocellular, with increasing cellularity toward the lobule periphery, imparting the appearance of hypercellularity between adjacent lobules. The chondromyxoid stroma is basophilic, and coarse calcification occurs in a subset of cases, but liquefactive myxoid degeneration is unusual. Mature hyaline cartilage differentiation is not usually seen in chondromyxoid fibroma. Secondary aneurysmal bone cyst changes may be seen but are not as common as in chondroblastoma. Cytologically, the cells are spindle or stellate shaped. While they may be enlarged or hyperchromatic, these features are not indicators of malignancy. In cellular examples, the cytologic features can resemble those of chondroblastoma.

Cytogenetic analysis has shown that these lesions often have rearrangements of chromosome 6. More recent work has shown rearrangement of the glutamate receptor GRM1 with several gene partners in a promoter swapping mechanism, leading to the overexpression of the intact protein.

The differential diagnosis chiefly includes chondroblastoma, phosphaturic mesenchymal tumor, conventional chondrosarcoma with myxoid features, and chondromyxoid fibroma-like osteosarcoma. Chondrosarcomas almost always have an aggressive-looking radiographic appearance, whereas chondromyxoid fibromas always have a benign radiographic appearance. Histologically, in contrast to chondromyxoid fibroma, the lobules of chondrosarcoma are uniformly hypercellular, typically lack osteoclastic giant cells, and show an infiltrative growth pattern. Similarly, chondromyxoid fibroma-like osteosarcoma has an aggressive radiologic appearance and microscopic features of an infiltrative tumor with cytologic atypia beyond what is acceptable in a chondromyxoid fibroma.

Chondroblastomas usually do not show the distinct lobulation of chondromyxoid fibroma. However, in some cases, or with minimal tissue, the distinction may be very difficult. In these cases, radiologic correlation can be helpful. Moreover, as H3F3A/B mutations have not been identified in chondromyxoid fibromas, by immunohistochemistry the tumors are negative for H3K36M.

Chondrosarcoma

Chondrosarcoma is a common primary sarcoma of bone, second only to osteosarcoma. By the current WHO classification, conventional chondrosarcoma is subclassified by its location on or in bone (central/intraosseous, periosteal, or peripheral chondrosarcomas), whether it arises de novo (primary chondrosarcoma) or within a preexisting lesion (secondary chondrosarcoma) and the presence of dedifferentiation. Other rare subtypes of chondrosarcoma include clear cell chondrosarcoma, dedifferentiated chondrosarcoma, and mesenchymal chondrosarcoma, which will be considered separately.

Conventional central chondrosarcomas comprise the largest group and are defined as malignant hyaline cartilage-producing tumors without neoplastic osteoid matrix production, arising within the bone. Conventional chondrosarcomas typically occur in the shoulder and pelvic girdles; however, they can arise at any skeletal site. Patients with chondrosarcoma are usually in the fourth to sixth decades of life and present with long-standing or progressing pain at the affected site. Pediatric chondrosarcomas are rare. Pathologic fracture is unusual.

Radiographically, chondrosarcomas are more aggressive and destructive appearing than enchondromas. They typically demonstrate significant endosteal scalloping, cortical thickening, cortical destruction, and periosteal reaction ( Fig. 25.27 ). Although present in only a fifth of cases, the combination of expansion of bone and thickening of the cortex is highly suggestive of chondrosarcoma. The tumor usually shows heterogeneous calcific densities. Calcific densities in a benign cartilage tumor are usually evenly distributed within the lesion. When a cartilage tumor shows lucent areas and areas of mineralization, chondrosarcoma should be considered. Magnetic resonance imaging can delineate the extent of medullary involvement and soft tissue extension.

Chondrosarcomas usually have a characteristic macroscopic appearance; they are composed of blue-white hyaline cartilage with gritty white calcification. Liquefied, oozing, or mucoid-appearing lesions, often with cystic areas, are additional gross features ( Fig. 25.28 ).

The microscopic appearance of chondrosarcoma varies, depending on the histologic grade of the neoplasm. As described earlier, low-grade chondrosarcomas can be difficult to differentiate from enchondromas. At low magnification, low-grade chondrosarcomas are more cellular than enchondromas. They tend to fill the marrow spaces and permeate preexisting bone, entrapping bony trabeculae ( Fig. 25.29 ). In curettage specimens, artifactual pseudoentrapment of bone can be caused due to tissue fragmentation, and is a common pitfall. True entrapment requires circumferential entrapment of the bone trabeculae by neoplastic cartilage. The nuclei of chondrocytes in enchondroma are small, round, and regular; in chondrosarcomas, the nuclei are larger and may in fact be less densely stained than the benign cells. Chondrocytes are located within lacunae and do not generally show spindled morphology. Binucleated cells may be found. Extensive myxoid change usually manifests as a grainy, stringy, or bubbly appearance to the matrix ( Fig. 25.30 ). Many authors have pointed out the difficulty in differentiating a low-grade chondrosarcoma from an enchondroma. The cytologic changes (cellularity and atypia), myxoid quality of the matrix, and permeative characteristics are important. The presence of myxoid matrix degeneration in more than 20% of the lesion or host bone entrapment favors a diagnosis of chondrosarcoma over enchondroma. The diagnosis also relies heavily on the radiologic interpretation, and the anatomic site provides an additional clue. Large cartilaginous tumors in the axial skeleton are likely to be chondrosarcomas, whereas tumors involving the small bones of the hands and feet are much more likely to be benign.

The most important predictor of biologic behavior in chondrosarcoma is histologic grade. Several different grading systems have been suggested for chondrosarcoma. Historically, they have been graded on a scale of 1 to 3. However, in the current WHO classification system, grade 1 chondrosarcoma is designated as atypical cartilaginous tumor/chondrosarcoma grade 1 due to its negligible potential for metastasis. Furthermore, this term was placed into the biologic potential group of an intermediate (locally aggressive) category rather than malignant.

Grading is assessed by tumor cellularity, nuclear size, and nuclear hyperchromasia. The role of mitotic activity in grading chondrosarcomas is debatable. The majority of chondrosarcomas are either grade 1 or 2 tumors. Atypical cartilaginous tumor/grade 1 chondrosarcomas show an overall increased cellularity compared with enchondromas. The chondrocytes are enlarged and more irregular. Grade 2 chondrosarcomas show even more cellularity than grade 1 chondrosarcomas, and the nuclear atypia is more pronounced ( Fig. 25.31 ). Grade 3 chondrosarcomas show marked cellularity, marked pleomorphism of the nuclei, and some spindling at the periphery of the lobules ( Fig. 25.32 ).

While the distinction between enchondroma and grade 1 chondrosarcoma is often difficult, it does not carry the prognostic significance attached to separating grade 1 from grade 2 tumors. In a large retrospective study of patients with chondrosarcoma from the Netherlands Cancer Registry, the 5- and 10-year survival rates were, respectively, 93% and 88% for ACT/CS I, 74% and 62% for grade 2 CS, and 31% and 26% for grade 3 CS. Similarly, Björnsson and colleagues found a 5-year survival rate of 89% for grade 1 chondrosarcoma and 57% for the combined group of patients with grade 2 and 3 tumors. Intralesional curettage with adjuvant local therapy (i.e., intralesional cryotherapy, phenol, liquid nitrogen, or argon-beam laser) has emerged as an effective treatment for tumors of the long bones classified as Grade 1 chondrosarcomas or atypical/borderline tumors, provided the tumors show no radiologic evidence of aggression (i.e., cortical permeation or soft tissue extension). In contrast, patients with higher grade chondrosarcomas of the extremities or chondrosarcoma of any grade involving the axial skeleton are usually treated with en bloc resection. Chondrosarcomas do not respond to chemotherapy. Local recurrence rates vary from 15% to 28%, depending on the type of surgical procedure. On occasion, recurrent tumor is of a higher histologic grade.

Although the majority of cartilage lesions of the small bones of the hands and feet are benign, chondrosarcomas do occur at this anatomic site. However, the criteria for malignancy of a cartilage tumor of the small bone differ from those for a larger bone. As previously mentioned, enchondromas of small bones frequently thin the cortex, and histologically benign tumors have increased cellularity and mild cytologic atypia. Thus extensive myxoid degeneration of the stroma and unequivocal radiologic or histologic evidence of tumoral cortical permeation and soft tissue infiltration are the main features for diagnosis of chondrosarcoma in a small bone. Although the prognosis for patients with these tumors is generally very good, metastasis does occur rarely.

Chondrosarcomas often show complex and nonspecific genetic abnormalities. With regard to IDH mutational testing, as both benign and malignant central and periosteal cartilage tumors frequently harbor IDH1/2 mutations, testing is not useful to support a diagnosis of malignancy. However, in most series to date, chondroblastic osteosarcomas lack IDH mutations. Thus IDH mutational testing may be of use in distinguishing a high-grade or dedifferentiated chondrosarcoma with an osteosarcomatous component from a chondroblastic osteosarcoma.

Secondary Chondrosarcoma.

Most chondrosarcomas arise de novo in bone as primary chondrosarcomas. However, a small percentage of chondrosarcomas arise in the presence of a preexisting lesion and are designated secondary chondrosarcomas. In the Mayo Clinic files, approximately 14% of chondrosarcomas were considered secondary tumors. Secondary chondrosarcomas arising within a surface lesion (i.e., osteochondroma) are peripheral secondary chondrosarcomas, whereas those arising within enchondromas are central secondary chondrosarcomas. This latter event occurs most frequently in the context of Ollier disease or Maffucci syndrome.

Secondary Peripheral Chondrosarcoma.

Approximately 1% of solitary and up to 5% of multiple osteochondromas undergo malignant transformation to a chondrosarcoma, usually low grade. Rarely, osteochondroma undergoes malignant transformation into a dedifferentiated chondrosarcoma (dedifferentiated peripheral chondrosarcoma).

When malignant transformation does occur in osteochondroma, it develops earlier in patients with hereditary multiple osteochondromas syndrome (average 25–30 years) than those with sporadic osteochondroma (average 50–55 years). Generally, a previously quiescent osteochondroma that starts to grow in adulthood should raise suspicion of chondrosarcoma.

As most peripheral secondary chondrosarcomas are extremely well differentiated, the histologic diagnosis is difficult, and radiologic correlation is essential. Worrisome radiographic findings include an irregular or indistinct lesional surface, focal areas of radiolucency within the mass, erosion or destruction of adjacent bone, and a soft tissue mass with scattered or irregular calcifications. In skeletally mature patients, osteochondromas typically have a smooth, thin cartilage cap that measures less than 2 cm in maximal thickness. When chondrosarcomatous transformation occurs in the cap, the cartilage cap thickens and develops indistinct borders, often with significant myxoid and cystic change, and infiltration of cartilaginous nodules into the surrounding soft tissue. In early malignant transformation, measurement of the cartilage cap can be very helpful: A cap thickness exceeding 2 cm should prompt consideration of chondrosarcoma ( Fig. 25.33 ). Low-grade secondary peripheral chondrosarcomas are usually treated with en bloc surgical resection. Adjuvant therapy is typically not indicated. The prognosis in secondary peripheral chondrosarcoma is generally good but depends on the anatomic site and histologic grade. Rarely, secondary peripheral chondrosarcomas are dedifferentiated tumors; they have different clinicopathologic and treatment considerations and are included in the discussion of dedifferentiated chondrosarcoma.

Secondary Central Chondrosarcoma.

Patients with multiple enchondromas in the setting of Ollier disease or Maffucci syndrome have a markedly elevated risk of malignant transformation, presumably in part due to their increased numbers of enchondromas. Patients with Ollier disease have an estimated 40% lifetime cumulative risk of chondrosarcomatous transformation, while the risk is 50% for patients with Maffucci syndrome. Due to the hypercellularity and mild cytologic atypia of enchondromas seen in Ollier disease and Maffucci syndrome, the histologic diagnosis of low-grade chondrosarcoma may be difficult. Radiologic images show destruction and invasion. Marked myxoid change of the matrix and invasion of surrounding tissue should be considered signs of malignancy.

Clear Cell Chondrosarcoma.

Clear cell chondrosarcoma is an unusual chondroid neoplasm, representing approximately 2% of all chondrosarcomas. The lesion tends to occur at the ends of long bones, similar to chondroblastomas and giant cell tumors ( Fig. 25.34 ). The radiographic appearance may mimic that of a chondroblastoma in that the lesion is usually well circumscribed and may even have a sclerotic border. Several years may pass before the radiographic appearance suggests malignancy. Grossly, clear cell chondrosarcomas are composed of hyaline cartilage with gray fleshy firm areas and cystic components ( Fig. 25.35 ).

Microscopically, clear cell chondrosarcomas are lobulated tumors. Osteoclastic giant cells are usually found at the edge of the lobules, which would be an unusual finding in conventional chondrosarcoma. The center of the lobule usually shows osteoid or bone formation. The tumor cells have well-defined cytoplasmic borders and a centrally placed round nucleus ( Fig. 25.36 ), often containing prominent nucleoli. Approximately 50% of clear cell chondrosarcomas show areas of conventional chondrosarcoma. Aneurysmal bone cystlike changes are often found in clear cell chondrosarcoma and can be so prominent that residual tumor forms only a small mural nodule. The clinical behavior of clear cell chondrosarcoma is typically that of a low-grade chondrosarcoma. IDH1/2 mutations have not been found in these tumors. Only a few rare examples of dedifferentiated clear cell chondrosarcoma have been described.

Dedifferentiated Chondrosarcoma.

Dedifferentiated chondrosarcoma was first delineated as a distinct clinicopathologic entity in 1971. Dedifferentiated chondrosarcoma occurs in older adults, often presenting a decade later than patients with conventional chondrosarcoma. Although most dedifferentiated chondrosarcomas arise from conventional central chondrosarcomas, they also may occasionally form as a secondary peripheral (dedifferentiated) chondrosarcoma arising in a preexisting osteochondroma.

Dedifferentiated chondrosarcoma arises at the same skeletal sites as conventional chondrosarcoma. Patients may report symptoms for several years and then have a sudden increase in the number or intensity of symptoms. The imaging studies usually show classic features of chondrosarcoma with a juxtaposed, destructive-appearing lytic area ( Fig. 25.37 ). The presence of a large unmineralized soft tissue mass, usually picked up on MRI or CT scans, associated with an intraosseous cartilage tumor is highly suspicious for dedifferentiated chondrosarcoma. However, in one-third of dedifferentiated chondrosarcomas, radiologic studies do not identify a dedifferentiated component. Nevertheless, for patients with radiologic features suggestive of dedifferentiation, targeted biopsy of these areas is strongly encouraged to facilitate appropriate patient management.

Grossly, dedifferentiated chondrosarcomas have a bimorphic appearance; they are composed of a low-grade chondrosarcoma component with nodules of glassy, pale blue cartilage juxtaposed to a soft, fleshy sarcoma-like tumor ( Fig. 25.38 ). Similarly, the histologic features are those of a distinctly bimorphic tumor. The well-differentiated chondrosarcoma component is usually low grade, although grade 2 chondrosarcomas with dedifferentiation are seen in a quarter of cases. These areas show an abrupt transition to a high-grade sarcoma ( Fig. 25.39 ). Most often, the dedifferentiated component resembles a high-grade spindle cell sarcoma, undifferentiated pleomorphic sarcoma, or osteosarcoma. Rarely, it may show features of rhabdomyosarcoma, leiomyosarcoma, angiosarcoma, adamantinoma-like or epithelial differentiation.

Dedifferentiated chondrosarcoma must be distinguished from chondroblastic osteosarcoma. Chondroblastic osteo­sarcoma usually affects adolescents, whereas dedifferentiated chondrosarcoma involves older adults. In chondroblastic osteosarcoma, the cartilaginous component has high-grade cytology and merges into a spindle cell sarcoma. In contrast, in dedifferentiated chondrosarcoma, the cartilaginous component is typically well differentiated, and the spindle cell malignancy is abruptly juxtaposed to it rather than merging into it. This distinction is important because the prognosis and management protocols differ between dedifferentiated chondrosarcoma and chondroblastic osteosarcoma. It is important to keep dedifferentiated chondrosarcoma in the differential diagnosis of a biopsy sample in an adult patient who shows a high-grade sarcoma. Imaging studies are often helpful in determining if there is an underlying cartilaginous component. Sarcomatoid carcinoma is also in the differential diagnosis when a biopsy specimen contains only the high-grade sarcoma component. Notably, immunohistochemical detection of cytokeratins is not always helpful, because a significant subset of the spindled cells in dedifferentiated chondrosarcomas show robust immunoreactivity with cytokeratin antibodies. Therefore, radiologic correlation should always be performed in the evaluation of malignant spindle cell lesions involving bone. IDH mutational testing may also be helpful because IDH1/2 mutations frequently occur in dedifferentiated chondrosarcoma and are absent in other types of sarcoma, including chondroblastic osteosarcoma.

Patients with dedifferentiated chondrosarcoma have a poor prognosis with 5-year survival rates ranging from 7% to 24%. Radiation and chemotherapy have not been shown to improve prognosis.

Mesenchymal Chondrosarcoma.

Originally described in 1959, mesenchymal chondrosarcoma primarily affects adolescents and young adults, with an equal sex distribution. About one-third of mesenchymal chondrosarcomas occur as primary soft tissue tumors or arise in the meninges, and they show similar clinicopathologic features to their osseous counterparts. In bone, mesenchymal chondrosarcoma tends to involve the axial skeleton, particularly the craniofacial bones, spine, and ribs. Rare examples of periosteal mesenchymal chondrosarcoma have also been described. Radiologically, the features are nonspecific and show a malignant-appearing tumor, with or without mineralization. Grossly, the lesion is usually pink and fleshy but may show foci of calcification.

The microscopic appearance of mesenchymal chondrosarcoma shows a characteristic bimorphism composed of islands of a well-differentiated cartilaginous component, resembling a low-grade chondrosarcoma, admixed with a primitive small cell component ( Fig. 25.40 ). The relative abundance of each component varies considerably. This variation can be a diagnostic pitfall in the evaluation of limited tissue.

Foci of ossification and calcification within the cartilage may be seen. The primitive appearing small cells have hyperchromatic nuclei. While they are usually round-to-ovoid, areas of frank spindling may be found in mesenchymal chondrosarcoma. Characteristically, the small cells are arranged around variably gaping, staghorn-shaped vascular spaces in a hemangiopericytoma-like pattern ( Fig. 25.41 ).

The differential diagnosis includes other small cell malignancies, such as Ewing sarcoma, and lymphoma, particularly when the cartilaginous component is not evident because of sampling error. Potential misdiagnosis of Ewing sarcoma is exacerbated by the fact that more than 90% of mesenchymal chondrosarcomas show strong, diffuse membranous immunoreactivity for CD99. Alternatively, FLI1 is positive in 75% of Ewing sarcomas, and mesenchymal chondrosarcoma is negative. Sox9 has been shown to be a helpful marker in the differential diagnosis with other small round cell tumors. Areas of ossification can be seen in mesenchymal chondrosarcoma, so it is important to pay close attention to the cytologic features of the tumor cells and consider ancillary testing when the differential diagnosis includes osteosarcoma.

The identification of a recurrent chromosomal translocation in mesenchymal chondrosarcoma has greatly facilitated its diagnosis. Until quite recently, only a few reports with cytogenetic data on mesenchymal chondrosarcoma had been published, most of them showing complex cytogenetic alterations, including identical robertsonian translocation t(13;21)(q10;q10) in a few cases. However, a genome-wide screen of exon-level expression data identified the novel HEY1 - NCOA2 gene fusion as a recurrent event in these tumors. NCOA2 is a member of the p160 nuclear hormone receptor transcriptional coactivator family that facilitates chromatin remodeling and transcription of nuclear receptor target genes. HEY1 seems to participate in the regulation of bone morphogenetic protein 9 (BMP9)–induced osteoblastic-lineage differentiation of mesenchymal stem cells. Future studies are needed to decipher the molecular events driven by this gene fusion. The HEY1 - NCOA2 fusion can be detected with molecular genetic techniques in most cases and is a valuable tool for the diagnosis of mesenchymal chondrosarcoma. More recently, a novel fusion IRF2BP2-CDX1 has been described in an example of mesenchymal chondrosarcoma with t(1;5).

The prognosis in mesenchymal chondrosarcoma is unpredictable, with published 10-year overall survival ranging from 21% to 54%. While a subset of patients presents with disseminated metastasis and dies within months, other patients have a protracted clinical course. Improved survival has been reported in patients who receive chemotherapy.

Primary Extraskeletal Myxoid Chondrosarcoma of Bone (Chordoid Sarcoma)

As the name implies, the vast majority of extraskeletal myxoid chondrosarcomas arise in the soft tissues. On rare occasions, extraskeletal myxoid chondrosarcomas occur as a primary osseous sarcoma. The histologic, immunohistochemical, and molecular genetic features of the tumoral subset arising in bone are identical to those arising in soft tissue (see Chapter 24 for discussion). The histologic differential diagnosis when it occurs as a primary in bone includes metastatic mucinous adenocarcinoma, myoepithelioma, epithelioid hemangioendothelioma, and chordoma.

Extraskeletal myxoid chondrosarcoma is characterized by the EWSR1 - NR4A3 fusion gene as a result of the t(9;22)(q12;q22). The fusion gene is present in approximately 75% of cases. As is often seen in chimeric transcripts involving EWSR1, the transactivation domain of EWSR1 is fused to the DNA binding domain of NR4A3 . NR4A3 is an orphan nuclear receptor that can activate the FOS promoter and plays a poorly understood role in the regulation of hematopoietic growth and differentiation. Alternate NR4A3 gene partners include TAF2N, t(9;17)(q22;q11), TCF12, t(9;15)(q22;q21), and TFG gene on chromosome 3q11-q12.

FISH with break-apart probes for the EWSR1 locus may be used as a diagnostic option in the appropriate histologic context, but as a subset of myoepitheliomas has EWSR1 rearrangements, a NR4A3 break-apart probe is a more specific approach for extraskeletal myxoid chondrosarcoma. RT-PCR is a less attractive option because of the large number of fusion partners.