Differential Diagnosis of Cartilaginous Lesions of Bone

Osteochondroma is a benign cartilage-capped tumor arising on the surface of bones and is the most common benign cartilage tumor of bone. More than 80% of osteochondromas are solitary; they are usually diagnosed by the second decade of life. There is a slight male predominance. They typically arise in the area of the metaphysis of long bones derived from endochondral ossification, most commonly the distal femur, proximal tibia, and proximal humerus, but they can also arise on the surface of flat bones, such as the ilium or scapula.^1,2,5–7 

Although initially believed to be a developmental anomaly, it has been shown subsequently that sporadic osteochondromas harbor homozygous EXT1 and EXT2 deletions within a subset of chondrocytes within the cartilaginous cap, indicating that it is a neoplastic process.³  Additionally, families with MHE have been shown to harbor germline mutations in the EXT1 or EXT2 genes.^8,9 

Radiographic findings in osteochondroma show that osteochondroma arises from the surface of the bone with continuity of the cortices and of the medullary cavities (Figure 1, A and B), often pointing away from the nearest joint. Rarely, osteochondroma is sessile with a broad-based stalk.¹⁰  Magnetic resonance imaging (MRI) is the most useful imaging modality for assessing the thickness of the cartilaginous cap, which can be variable.^11,12 

Grossly, osteochondroma contains a cartilaginous cap and an underlying stalk. The outer layer consists of a thin fibrous sheath overlying the bluish gray cartilaginous cap (Figure 1, C). It is important to document the maximum thickness of this cap. Microscopically, this outer fibrous layer is the perichondrium. The cartilage cap is of variable thickness and at the base undergoes endochondral ossification (Figure 1, D).^1,2,11  The chondrocytes within the cap are usually organized in a similar fashion to the normal growth plate. Both the cellularity of the cartilage and the size of the chondrocytes increase within the deeper layers of the cap, with the chondrocytes arranged in a vaguely columnar fashion. The cartilaginous matrix at the base of the cap often shows calcifications with residual columns of cartilage upon which new bone deposition occurs.² 

The pathologic diagnosis of osteochondroma is generally straightforward, with a differential diagnosis that includes bizarre parosteal osteochondromatous proliferation, surface chondroma, and parosteal osteosarcoma. None of these lesions have a medullary connection to underlying bone; thus, radiologic correlation can differentiate among these tumors.^13–15 

The rate of malignant transformation of an osteochondroma into a low-grade chondrosarcoma is very low (<2%). Some authors consider an increased size of the cartilaginous cap a worrisome feature of malignancy; however, a thickened cartilage cap alone is not sufficient for the diagnosis of a malignant transformation. In addition to a thick cartilage cap with prominent calcifications, soft tissue invasion, infiltration of the stalk, erosion of bone, and tumor invasion of the underlying bone are features of malignant transformation (Table 1).^{1,2,9,11,16,17} 

Osteochondromas are usually observed or resected in symptomatic patients. Symptoms may be due to mechanical issues, impingement on adjacent nerves, development of a bursa on the surface of the cap, or a pathologic fracture through the stalk.

Multiple hereditary exostosis is an autosomal dominant condition in which patients develop multiple osteochondromas by the second decade of life. Approximately 60% of patients have a family history. Multiple hereditary exostosis has an incidence of approximately 1 in 50 000 and, in rare patients, presents as part of a separate genetic syndrome, such as trichorhinophalangeal syndrome or Potocki-Shaffer syndrome.¹  It is now known that germline alterations in the EXT1 (8q24) or EXT2 (11p11-p12) gene drive the disease. Similar to nonhereditary osteochondromas, aberrations of the EXT genes lead to dysfunctional proteins exostosin 1 and exostosin 2 and the subsequent failure of heparin sulfate polymerization required for normal cartilaginous development.^4,5,9,18 

From an early age, these patients present with multiple osteochondromas, which continue to grow in size until skeletal maturity with the closure of the growth plates. Similar to solitary osteochondromas, the majority of these tumors are asymptomatic; however, patients with increased numbers of osteochondromas can develop various bone deformities, leading to functional impairment that may require surgical correction.¹⁹ 

Radiographically, the presence of multiple osteochondromas can be confirmed with conventional radiographs (Figure 2, A), and the size of the cartilage cap can be assessed with MRI. Grossly and microscopically, the osteochondromas of MHE are identical to solitary osteochondromas, only more numerous.

Multiple hereditary exostosis carries an increased risk of malignant transformation reportedly ranging from 0.2% to 25% (Figure 2, B).^9,19,20  As with solitary osteochondromas, the same clinicopathologic features are used to evaluate patients for possible malignant transformation (Table 1).

Studies have shown that there is significant interobserver variability in the histologic diagnosis of cartilaginous tumors,²¹  especially grade 1 chondrosarcoma, in patients with MHE. A multidisciplinary approach to the management of these patients with clinical and radiologic correlation is recommended, especially in cases in which malignant transformation is suspected.

Enchondroma is the second most common benign primary hyaline cartilage–forming tumor of bone, accounting for 12% to 24% of primary bone tumors. These tumors typically present during the third to fourth decade of life and are most frequently located within the distal appendicular skeleton. They arise in bones that form by endochondral ossification. Approximately 90% of enchondromas are solitary; they are frequently detected as incidental findings during radiologic workup for pain associated with other adjacent lesions such as osteoarthritis or tendon/ligamental tears.^1,2,22  Most enchondromas are asymptomatic; however, they may be associated with pain in the setting of a gross or microscopic pathologic fracture.²³  If they are painful, the possibility of a chondrosarcoma should be considered and excluded.

Genetic aberrations described in enchondromas include mutations in isocitrate dehydrogenase IDH1 (R132C; R132H) or IDH2 (R172S), which are found in approximately 40% of solitary lesions, with even higher rates in patients with multiple enchondromas.^5,24  Rare cases have been described to harbor aberrations in PTHR1; cytogenetic abnormalities involving chromosomes 5, 6, 7, 12, and 17 have also been reported.^25–27 

Radiographically, x-rays show spherical or oblong, sometimes elongated, well-circumscribed lucent lesions with scattered radiodensities, which represent irregular calcifications of the cartilage matrix. These calcifications are sometimes present at the periphery of the lobules and are seen as rings or arches (Figure 3, A and B). Scalloping and thinning of the cortex may be present, especially in small tubular bones; however, extension into soft tissues or overt bone destruction is not seen. Computed tomography scan often shows a well-circumscribed, lobulated lesion with similar calcifications to those seen on the x-rays. On MRI, enchondromas are hyperintense on T2-weighted images.^2,7 

Grossly, enchondromas are composed of well-circumscribed, gray, glistening nodules (Figure 3, C). Microscopically, the tumors are composed of variably sized nodules of hyaline-type cartilage, which are well circumscribed, sharply demarcated from the surrounding bone, and often encased by reactive bone formation (corresponding to the rings and arches seen radiographically). Variable numbers of benign-appearing chondrocytes are present, with frequent scattered calcifications of the hyaline matrix and associated necrosis of chondrocytes in these areas (Figure 3, D). Rare binucleated chondrocytes may be present. Enchondromas in the digits or in patients with multiple enchondromatosis may demonstrate increased cellularity and cytologic atypia (Figure 3, E).² 

Immunohistochemistry is largely unhelpful in the diagnosis of cartilaginous tumors, as most are positive for S100 protein and ERG. The diagnosis relies mainly on histologic examination with close clinical and radiologic correlation. IDH1 and IDH2 mutations represent by far the most common genetic aberrations in enchondromas, a finding that is shared with chondrosarcomas, thus preventing these alterations from being used diagnostically as a discriminator among these differential diagnoses. The main differential diagnosis is low-grade chondrosarcoma. In our experience, the most useful approach for the diagnosis of enchondroma even in problematic cases is strict radiologic correlation in conjunction with the histologic assessment, with a permeative growth pattern seen in chondrosarcoma but not in enchondroma.

Multiple enchondromas present typically as a manifestation of either of 2 related clinical syndromes, Ollier disease or Maffucci syndrome, or as part of an unrelated syndrome, metachondromatosis. These disorders are rare; although the tumors developed by these patients are benign, there is an increased risk of malignant transformation.^28,29  In all 3 syndromes, patients present at an early age, frequently being diagnosed with multiple enchondromas during early childhood.

Ollier disease and Maffucci syndrome are 2 related sporadic disorders that are characterized by the presence of multiple enchondromas from a young age. Maffucci syndrome differs from Ollier disease by the presence of vascular lesions, most commonly spindle cell hemangiomas.³⁰  Both disorders are caused by somatic mosaic mutations of IDH1 or IDH2.^31,32  The short tubular bones of the hands and feet are frequently involved, although the tumors may be found within long bones, scapulae, pelvis, or some flat bones.²  The large number of lesions can lead to deformation and functional impairment.

Radiographically, patients with Ollier disease and Maffucci syndrome present with multiple enchondromas, and the severely affected bones will appear shortened and deformed (Figure 4, A). In long bones, columns of dysplastic cartilage that originate in the growth plate produce linear radiolucencies that extend from the metaphysis into the diaphysis; this radiologic finding is characteristic for both Ollier disease and Maffucci syndrome.² 

Malignant transformation has been reported to occur in up to 40% of patients. The most common malignant tumor is conventional-type chondrosarcoma (Figure 4, B and C); however, rarely patients can develop dedifferentiated chondrosarcoma.^33,34  In addition, both Ollier disease and Maffucci syndrome have been associated with the development of other tumor types, such as ovarian juvenile granulosa cell tumors.^2,35 

Metachondromatosis is an inherited autosomal dominant disease caused by loss of function mutations in the PTPN11 gene.³⁶  Patients with metachondromatosis present early with the development of numerous enchondromas as well as osteochondromas. Unlike patients with Ollier disease or Maffucci syndrome, patients with metachondromatosis do not appear to have an increased risk of malignant transformation, though it has rarely been reported.³⁷ 

Although pathologic assessment may play a limited role in the initial diagnosis of these syndromes, as they are primarily diagnosed on clinical-radiologic grounds, it can be crucial to guide clinical management, particularly in patients for whom there is a concern for malignant transformation. When evaluating biopsies from these patients, it is important to remember that enchondromas in Ollier disease and Maffucci syndrome can show increased cellularity and cytologic atypia, histologically mimicking chondrosarcoma. Given the propensity for malignant transformation as well as the association with other rare nonskeletal tumor types, these patients are closely followed by imaging and screened for any signs of malignant transformation.^38,39 

Chondromyxoid fibroma is a rare cartilaginous tumor (<1% of primary bone tumors)⁴⁰  that was previously classified as an intermediate biologic potential (locally aggressive) tumor,¹  but will be reclassified as a benign neoplasm in the upcoming WHO classification of bone tumors. Microscopically, it is characterized by lobulated chondromyxoid areas, multinucleated giant cells, and, in approximately 25% of tumors, scattered coarse calcifications. These tumors usually arise in the second to third decade of life, show a slight male predilection, and typically involve the long bones but also occasionally flat bones including the ilium, ribs, vertebral bodies, scapula, and the small bones of the foot. Patients often present with pain, which may be of long duration. The treatment is surgical with curettage or conservative resection. Local recurrence rate is 10% to 20%.^1,2,41–44 

Clonal rearrangements of chromosome 6 including t(6;9)(q25;q22) and inv(6)(p25q13) have been described as either an isolated genetic aberration or in concert with other karyotypic abnormalities including deletions of 6q24.^25,45–48  Recurrent fusions of the GRM1 gene have been implicated in the pathogenesis of chondromyxoid fibroma; upregulation of the glutamate metabotropic receptor 1 (GRM1) through promoter swapping and gene fusion events has been shown to be a specific driver event in the development of these tumors.⁴⁹  DNA microarray studies comparing chondromyxoid fibroma to chondroblastoma did not show any differential gene expression in cartilage-related genes; however, higher expression levels of CD166, cyclin D1, and p16INK4A were seen in these tumors as compared to high-grade central chondrosarcoma.⁵⁰ 

Radiographically, chondromyxoid fibromas are expansile, lytic, radiolucent, and multilobulated, with internal septations and sharply demarcated sclerotic borders (Figure 5, A). When they arise in long bones, they are often eccentrically located. Some cases show prominent calcifications that are evident on imaging modalities, particularly computed tomography scans. Geographic bone destruction and scalloped borders can be seen as well. On MRI, chondromyxoid fibromas are hypointense on T1- and hyperintense on T2-weighted images.⁴⁵ 

Grossly, chondromyxoid fibromas are solid, lobulated, and well circumscribed, with a gelatinous cut surface that may have gritty calcifications. Histologically, the tumor displays a lobulated architecture, with central areas composed of a chondromyxoid matrix with bland-appearing spindle- and stellate-shaped cells. The cells tend to become more condensed near the periphery of the lobules and are often cuffed by areas of bland round or spindle-shaped cells with osteoclast-type giant cells and prominent hemangiopericytoma-like staghorn vessels (Figure 5, B). Coarse calcifications and degenerative changes can be seen within the areas of chondromyxoid stroma (Figure 5, C).^1,2  The tumor may undergo secondary cystic changes (aneurysmal bone cyst–like).

The tumors may show areas with pseudomalignant cells with enlarged hyperchromatic nuclei, which resemble the degenerative atypia seen in benign peripheral nerve sheath tumors; mitotic activity, however, should be absent. In small core biopsies, a distinguishing feature for chondromyxoid fibroma from other cartilaginous lesions is the character of the chondroid matrix, which is usually less well formed and has a more myxoid quality than the mature hyaline matrix present in other cartilage tumors.

Immunohistochemistry is unhelpful, as the chondrocytic cells in chondromyxoid fibroma are positive for markers such as S100 protein, Sox9, and ERG, similar to other cartilaginous lesions. The peripheral myofibroblastic areas stain diffusely for smooth muscle actin, whereas desmin, h-caldesmon, and calponin show negative staining. CD34 immunohistochemical stain strongly highlights the peripherally located blood vessels.^51–53 

The diagnosis of chondromyxoid fibroma can be a challenge, because of its variegated morphology as well as the rarity of the lesion itself. The differential diagnosis includes chondroblastoma, enchondroma, low-grade chondrosarcoma, and the exceedingly rare chondromyxoid fibroma–like osteosarcoma.⁵⁴  Given the broad differential diagnosis, careful clinical and radiologic correlation is required (Table 2).

Chondroblastoma is a rare tumor with chondrogenic differentiation and was previously classified as having intermediate biologic potential (rarely metastasizing)¹ ; however, in the upcoming WHO classification, it is reclassified as benign. It typically affects young, skeletally immature individuals. Among the well-differentiated cartilaginous lesions, chondroblastoma can show the least amount of apparent cartilaginous differentiation. Chondroblastomas are more common in males and typically arise in the epiphysis of long tubular bones.²  The peak incidence is during the second decade of life. Although chondroblastoma can occur in adults, primarily in flat bones and short tubular bones of the foot, it is rare to see a chondroblastoma in patients older than 30 years.⁵⁵  Chondroblastomas follow a benign course and are generally cured with curettage or ablative techniques; however, 5% to 12% of tumors locally recur.^56,57 

K36M mutations of the H3F3B gene (and rarely of the H3F3A gene), which encodes for histone H3.3, have recently been described in chondroblastomas and can help distinguish these lesions among histologic mimics.⁵⁸  Behjati et al⁵⁹  reported the presence of histone H3.3 mutations in 73 of 77 cases (95%); the H3.3 mutations in the 73 chondroblastomas were all K36M, with 68 identified in the H3F3B gene and 5 in the H3F3A gene. A mutation-specific antibody against the H3F3B K36M mutation as found in most chondroblastomas has been shown to be diagnostically helpful in separating this lesion from other primary bone tumors.^60,61 

Radiologically, chondroblastoma appears as a radiolucent lesion that shows well-defined sclerotic borders and is centered about the epiphysis (Figure 6, A and B). Scattered calcifications may be present. Chondroblastoma commonly undergoes secondary aneurysmal bone cyst–like changes and can show fluid-fluid levels on MRI. These secondary changes may cause a periosteal expansion that gives the appearance of a more aggressive lesion.² 

Grossly, chondroblastoma is well circumscribed, red to white, and gritty and may have areas of hemorrhage and cystic degeneration. Histologically, it is composed of an admixture of mononuclear chondroblastic cells and multinucleated osteoclast-type giant cells, with associated calcifications and deposition of poorly formed eosinophilic chondroid matrix.^1,2  The mononuclear neoplastic cells tend to grow in sheets and have eccentric eosinophilic cytoplasm with well-demarcated cell borders; the nuclei frequently have prominent nuclear grooves (coffee bean–like) (Figure 6, C and D). The calcifications are characteristically present in a fine reticular pattern (“chicken-wire” calcifications) surrounding individual mononuclear cells that may undergo necrosis. Rare mitotic figures may be seen. Immunohistochemistry for chondroblastoma shows expression of cartilaginous markers such as S100 and Sox9, as well as variable expression of keratin and p63 and scattered strong membranous DOG1 staining.^52,62,63 

Usually, the diagnosis of chondroblastoma is straightforward, with the differential diagnosis including other giant cell–rich tumors such as giant cell tumor of bone, aneurysmal bone cyst, chondromyxoid fibroma, and rarely chondroblastoma-like osteosarcoma. Radiologic and pathologic correlation can be particularly helpful in distinguishing chondroblastoma-like osteosarcoma, as it shows aggressive radiologic and pathologic features such as cortical destruction, infiltration, and focal malignant osteoid deposition.⁶⁴  Furthermore, immunohistochemistry for the H3F3B K36M mutation may be helpful in differentiating chondroblastoma from other giant cell–rich lesions and cartilage-producing tumors.

Chondrosarcoma is defined as a malignant cartilage matrix-producing tumor and comprises a heterogenous family of tumors, which includes conventional chondrosarcoma, secondary chondrosarcoma, periosteal chondrosarcoma, clear cell chondrosarcoma, dedifferentiated chondrosarcoma, and mesenchymal chondrosarcoma.¹  For simplicity, this review will focus on the differential diagnosis between benign cartilaginous lesions and low-grade conventional or secondary chondrosarcoma. Conventional chondrosarcoma is a primary chondrosarcoma, which arises in the absence of a precursor lesion, whereas secondary chondrosarcoma is associated with a preexisting bone tumor, such as enchondroma or osteochondroma.² 

Since the fourth edition of the WHO classification¹  in 2013, the term atypical cartilaginous tumor has emerged as a new concept that is used to denote a low-grade cartilaginous neoplasm that is microscopically identical to a grade 1 chondrosarcoma and is located in the appendicular skeleton. The concept of atypical cartilaginous tumor is akin to the concept of atypical lipomatous tumor used to denote peripheral adipocytic tumors that are histologically identical to well-differentiated liposarcoma in deep-seated locations. As atypical cartilaginous tumors/low-grade chondrosarcoma are clinically relatively indolent as compared to other types of chondrosarcomas, they can be treated by surgical curettage for sufficient local control, rather than other more extensive/morbid procedures as were done in the past. The term atypical cartilaginous tumor should be used for tumors of the appendicular skeleton, whereas the term chondrosarcoma grade 1 should be reserved for tumors of the axial skeleton, including the pelvis, scapula, and base of skull.

Primary central chondrosarcoma accounts for approximately 20% of malignant bone tumors and is the most common malignant cartilage-forming tumor of bone.⁶⁵  Primary central chondrosarcoma makes up approximately 90% of all chondrosarcomas, with the other 10% being of the several histologic variants mentioned above. Primary central chondrosarcoma usually develops during the fifth to seventh decade of life and shows a slight male predominance. The tumors can arise in any bone that forms by endochondral ossification, with the most common locations being the pelvis, followed by the proximal and distal femur, proximal humerus, and ribs. In rare cases, primary chondrosarcomas can arise in the small bones of the hands and feet.²  Patients typically present with pain and an enlarging mass. Radiographically, the tumors are lytic with scattered radiodensities and irregular spiculations, which can often show cortical changes including thinning and scalloping (Figure 7, A and B). Magnetic resonance imaging can be helpful in identifying the extent of the tumor.^66,67  The histologic grading of chondrosarcoma is the most important prognostic factor; grade 1 lesions act in a locally aggressive manner, with a 5-year survival of ∼80% and a very low (if any) rate of metastasis. The treatment for tumors in the appendicular skeleton is by surgical curettage; however, for tumors located in some deep-seated sites such as the pelvis, wide resection is needed, as recurrences are common and can be difficult to control.^2,68,69 

Secondary chondrosarcoma is subdivided into secondary central chondrosarcoma (which arises from an enchondroma) and secondary peripheral chondrosarcoma (which arises from the cartilaginous cap of an osteochondroma).^1,2  Secondary chondrosarcomas have a bimodal age distribution, as they can arise at an earlier age in syndromic patients with Ollier disease, Maffucci syndrome, or MHE, but can also occur later.²  As mentioned previously, syndromic patients have a higher incidence of malignant transformation, as noted in up to 40% in patients with Ollier disease or Maffucci syndrome and up to 25% of patients with MHE.^28,32  Radiologically, secondary chondrosarcoma displays similar characteristics to primary chondrosarcoma; furthermore, the primary underlying associated lesion may be apparent radiographically or histologically.^2,70  The tumors are usually low grade, although rarely higher-grade chondrosarcomas (grades 2 and 3) and dedifferentiated chondrosarcoma can arise in association with an underlying benign cartilage lesion. Secondary chondrosarcomas are treated in the same fashion as primary chondrosarcomas; when the lesions are low grade, they have a very good prognosis.

Genetically, chondrosarcomas of primary and secondary types are characterized by mutations in the isocitrate dehydrogenase isoforms IDH1 and IDH2, which have been detected in approximately 50% to 60% of primary and secondary central chondrosarcomas.^71,72  Peripheral chondrosarcomas appear to show similar EXT1 and EXT2 aberrations to solitary and hereditary osteochondromas.⁷³  The genetic underpinnings mediating the transformation from benign cartilaginous lesions to malignant lesions are not entirely elucidated; however, complex karyotypic abnormalities, mutations in TP53, and defects in the RB1 pathway have been described in these lesions as they transform into higher-grade chondrosarcomas.⁷⁴ 

Grossly, these tumors are often large and composed of gray, glistening lobules of cartilage. They often fill the medullary cavity, showing changes in the overlying cortical bone such as scalloping or thinning and extension into adjacent soft tissue (Figure 7, C). In secondary lesions arising from enchondroma, there may be a transition from the well-formed cartilage representing the enchondroma to a more ill-defined gelatinous area representing the chondrosarcoma.²  Lesions arising from the cartilaginous cap of an osteochondroma may show increased thickness of the cartilaginous cap with irregular borders and soft tissue extension, features that can be apparent radiographically. In addition, evaluation of contrast-enhancement characteristics on MRI has been used to aid distinction between osteochondroma and its transformed malignant counterpart.⁶⁶ 

Microscopically, both primary and secondary low-grade chondrosarcomas are characterized by a neoplastic chondrocyte population that is embedded within a cartilaginous matrix. This matrix may be of the myxoid or hyaline type. The neoplastic chondrocytes vary in size, although they often appear bland in low-grade chondrosarcoma and show a lower cellularity than grades 2 and 3 chondrosarcoma. The nuclei of the cells are usually small and dark with fine chromatin. Mitotic activity is limited for low-grade tumors. Extension into the surrounding soft tissue may be seen, and infiltration of preexisting bony trabeculae is a helpful histologic feature for identifying the malignancy (Figure 7, D).² 

The diagnostic distinction of low-grade chondrosarcomas from other cartilaginous lesions in this review requires strict clinical and radiologic correlation combined with histologic examination, with the most important histologic feature being infiltration and encasement of preexisting trabecular bone. Distinction between secondary chondrosarcoma and a benign cartilage lesion can nonetheless be problematic and challenging in some patients, in which a multidisciplinary approach is required for optimal management.