Benign Cartilage Lesions

Krista A. Goulding, MD, MPH, FRCSC

Tom Joris Crijns, MD, PhD

Neither of the following authors nor any immediate family member has received anything of value from or has stock or stock options held in a commercial company or institution related directly or indirectly to the subject of this chapter: Dr. Goulding and Dr. Crijns.

This chapter is adapted from Goulding KA, Hinckley NB: Benign cartilage lesions, in Biermann JS, Siegel GW, eds: Orthopaedic Knowledge Update^®: Musculoskeletal Tumors 4. American Academy of Orthopaedic Surgeons, 2021, pp 111-123.

ABSTRACT

It is important to review the more common benign cartilage lesions encountered in an orthopaedic practice. Although most of these tumors are incidental findings encountered during the evaluation of an unrelated disease, an understanding of their key clinical, radiographic, and pathologic features is crucial to avoiding unnecessary intervention, providing appropriate surgical management where needed, and recognizing precursors of malignancy requiring surveillance or referral. An update on advancements in radiologic imaging and genetic profiling is necessary, as both chromosomal translocations and specific gene mutations have been implicated in the genesis of these lesions. The clinician should have a working understanding of the etiology, diagnosis, natural history, and management of patients presenting with both singular and multiple benign chondrogenic lesions on a gross and genetic level.

INTRODUCTION

Benign chondrogenic tumors are a relatively common imaging finding and make up more than 80% of all benign bone tumors in population-based studies. Most benign cartilage tumors are found incidentally during the evaluation of an unrelated disorder and do not require treatment. Correctly identifying these lesions is essential to avoiding unnecessary or inappropriate surgical intervention. Distinguishing between benign and malignant cartilage lesions can be challenging because of tumor heterogeneity and overlapping radiographic characteristics. Biopsy of cartilage tumors is notoriously difficult as the heterogeneity typical of these lesions is associated with a high likelihood of sample error. Furthermore, the pathologic discrimination between benign and malignant cartilage tumors is challenging, as there is significant histologic overlap, often requiring the input of a multidisciplinary team. The clinical and pathologic features of the more common benign cartilage tumors of bone are reviewed in the next paragraphs.

OSTEOCHONDROMA

Osteochondroma is the most common benign lesion of the bone, accounting for approximately 30% of all benign bone lesions.¹^,²^,³ The true incidence of this lesion is likely underestimated because most are asymptomatic and may never undergo radiographic evaluation.⁴ Approximately 15% of patients have multiple lesions, referred to as multiple osteochondromatosis. Because of the resemblance of the cartilage cap to the normal physis, the etiology of osteochondroma was originally believed to be caused by a developmental disorder affecting physeal growth. However, recent research has shown these lesions to be true neoplasms generated by the loss of function of the EXT tumor suppressor genes.⁵^,⁶ Grossly, an osteochondroma is a variable-sized stalk that is confluent with the normal medullary canal, attached to a
cartilage cap that grows away from the normal physis. The size of the cartilage cap has been implicated in spontaneous regression of the lesion and has been debated as an indication of malignant potential.⁷

Clinical Features and Radiographic Findings

Osteochondromas are typically found centered around the physis in skeletally immature individuals.⁸ The most prevalent locations affected are the knee (distal femur, proximal tibia, proximal fibula), followed by the proximal humerus, and less commonly the scapula, pelvis, and spine. Most osteochondromas present as a painless, firm mass, and are found incidentally during the evaluation of an unrelated complaint. Lesions may less commonly present following irritation of an overlying bursa, fracture of the stalk, or impingement on muscle or an adjacent neurovascular structure (Figure 1). A common presentation is an adolescent patient with a medially based distal femoral osteochondroma who has painful knee flexion because of an inflamed bursa overlying the lesion, or impingement as the quadriceps contracts over the prominence. Growth of a previously dormant lesion, particularly in a skeletally mature patient, or pain that was not previously present may be an indication of malignant degeneration and is an indication to pursue advanced cross-sectional imaging. Approximately 1% of solitary osteochondromas and up to 5% of multiple osteochondromas undergo malignant transformation.⁹^,¹⁰

FIGURE 1 Imaging studies from a 42-year-old man with a mass involving the proximal fibula that had been present for more than 30 years.

Numbness and weakness developed in the right lower extremity, prompting electromyography, which revealed evidence of chronic peroneal nerve compression. A, Plain radiograph of a benign osteochondroma involving the proximal fibula. B, Axial CT scan demonstrating underlying cancellous bone confluent with the lesion, which is distorting and flattening the peroneal nerve. Removal of the lesion resulted in complete resolution of the patient’s symptoms.

Plain radiographs reveal a rounded periarticular lesion that grows away from the adjacent physis. Solitary lesions are either sessile or pedunculated, based on the size of the stalk connecting the lesion to the underlying cancellous bone. Mild intralesional calcification is commonly seen on plain radiographs in benign lesions, although a disproportionate amount of calcification may indicate malignant transformation. Plain radiographs are particularly useful to document changes in the lesion on serial images.

Ultrasonography is a useful modality to dynamically visualize adjacent tendons or soft tissues that may be mechanically involved with the lesion. Additionally,
ultrasonography can help distinguish bursal fluid from the cartilage cap overlying the lesion. Nuclear medicine studies are infrequently used because they have poor potential for differentiating between benign osteochondroma and low-grade chondrosarcoma.

Cross-sectional imaging is helpful in symptomatic cases to determine the proximity of the lesion to surrounding neurovascular structures and assess for malignant transformation. Osteochondromas demonstrate characteristic T2-weighted signal hyperintensity related to the high water content of the extracellular matrix produced by chondrocytes within the hyaline cartilage cap.¹¹ Quantitative MRI techniques, such as T2 relaxation time mapping (T2 map), reflect cartilage water mobility and biochemical changes within the extracellular matrix microstructure. A comparison of age- and sex-matched skeletally immature patients with benign osteochondromas shows higher T2 relaxation times in the cartilage cap compared with other forms of hyaline cartilage (patella), which is postulated to be caused by greater water content and different collagen fiber orientation in the cap.¹²

Increased thickness of the cartilage cap has been debated as a radiographic feature of malignancy. A thick, irregular cartilage cap larger than 2 cm is concerning for malignant degeneration in adults a cartilage cap larger than 3 cm is concerning for malignant degeneration in children.⁷^,¹¹^,¹² One study compared MRI and CT findings of 67 benign osteochondromas to 34 biopsy-proven secondary chondrosarcomas.¹² The study authors describe the use of a novel method to measure cap thickness, which involves (1) determining the tidemark of mature mineralization between the cancellous stalk and cartilage cap, (2) excluding crevasses between undulations in the cap by connecting the peaks of tidemark mineralization between crevasses, and (3) measuring the thickness perpendicular to a line delineating the tidemark. Using this method, the sensitivities and specificities of MRI and CT were 100% and 98%, and 100% and 95%, respectively, when a cartilage cap of 2 cm was used to distinguish benign osteochondroma from secondary chondrosarcoma. The study authors cautioned that formation of bursae, particularly adjacent to lesions involving the ventral surface of the scapula or the hip, may confound accurate measurement of the cartilage cap. The use of fluid-sensitive sequences (particularly a cartilage-sensitive, fat suppressed spoiled gradient-echo sequence) may reduce the incidence of false-positive measurements of cap thickness because of adjacent bursal fluid collections. There was a high degree of interobserver reliability for measurements of cap thickness on CT scan. A recommended approach to the patient included an initial measurement of cap thickness with CT, followed by selective MRI or ultrasonography to distinguish lesions with cap thickness greater than 2 cm from bursal fluid.

Pathology and Genetics

The gross appearance of an osteochondroma is that of a sessile or pedunculated bony mass with a cartilage cap of variable thickness. The cortex of the lesion’s base on gross inspection is typically confluent with the underlying bone, showing characteristic corticomedullary continuity, or flowing of intramedullary contents on cross-sectional imaging. This feature is helpful in distinguishing osteochondroma from other surface lesions such as periosteal chondroma, periosteal or parosteal osteosarcoma, or juxtacortical heterotopic ossification.

Histology classically reveals three layers, including the perichondrium, cartilage, and bone. The fibrous perichondrium is confluent with the surrounding periosteum of the normal host bone. Between the underlying bone and the perichondrium lies a variable-sized cartilage cap. In the regions closest to bone, the cartilage cap resembles the cords seen in the normal epiphyseal plate. This site of enchondral ossification results in lesion growth and expansion. Toward the periphery of the lesion, the cartilage cells are less organized.

Growth or expansion of an osteochondroma following skeletal maturity is worrisome for malignant transformation. Evidence points to the cartilage cap as the most likely neoplastic component of a benign osteochondroma. A thick (>2 cm), irregular cartilage cap is worrisome but not diagnostic of malignancy.¹²^,¹³ Histologically, features that signal malignant transformation include myxoid change, increased cellularity or nuclear atypia, and mitotic activity. Homozygous deletion of the EXT1 gene is found within the cartilage cap in 90% of osteochondromas that undergo malignant transformations.¹⁴^,¹⁵ Biallelic loss of the EXT1 gene has not been documented within the perichondrial ring, nor the bony stalk of nonhereditary osteochondromas, suggesting these components are likely reactive rather than neoplastic.¹⁶ Single mutations in the EXT1 gene, resulting in the loss of function of the normal product exostosin-1, have been demonstrated in numerous studies to occur in solitary lesions. In contrast with hereditary cases of multiple osteochondromas, where multiple mutations in EXT1 and EXT2 are commonly involved, sporadic cases almost exclusively involve an EXT1 mutation.

Treatment

Asymptomatic osteochondromas do not require treatment, and the use of routine surveillance radiographs for a solitary lesion is debatable. A reasonable approach would be to inform the patient of the rare (approximately 1%) incidence of malignant degeneration, to obtain a
repeat radiograph to document stability of the lesion, and to counsel patients to return for evaluation if symptoms develop, or the lesion grows.

Symptomatic lesions warrant consideration of surgical excision. The goal of resection is to remove the entire cartilage cap, while minimizing associated morbidity. Osteochondromas infrequently abut neurovascular structures that make removal difficult. Although recurrence is rare with complete excision, osteochondroma is the most common precursor of chondrosarcoma, suggesting that in locations that are difficult to achieve complete excision, adequate clinical follow-up and radiographic surveillance are important.

MULTIPLE OSTEOCHONDROMAS

Multiple osteochondromatosis, or multiple hereditary exostosis (MHE), is an autosomal dominant condition that results in multiple skeletal deformities. MHE is caused by mutation in either the EXT1 gene or EXT2 gene, located on chromosomes 8q24.11-q24.13 and 11p11-12 (OMIM Nos. 133,700 and 133,701), respectively.¹⁷ Most mutations result in a loss of protein function encoded by the gene and are heterozygous in nature. Both EXT1 and EXT2 mutations are associated with MHE, but EXT1 mutations are associated with a more severe phenotype.¹⁰ Both EXT1 and EXT2 proteins function in heparan sulfate proteoglycan (HSPG) biosynthesis. This process is critical to signaling pathways in the normal physis, including the Indian hedgehog (IHH), hypogonadotropic hypogonadism-parathyroid hormone-related peptide (PTHrP), and fibroblast growth factor (FGF) pathways. Recent studies have discovered amplified expression of abnormal microRNA (miRNA) to be present in osteochondroma tissues. Altering their effect on the aforementioned signaling pathways may allow for a breakthrough in the treatment of these lesions in the future.¹⁸

In the presence of multiple osteochondromas, histology alone is insufficient to diagnose malignant transformation. Lesions may frequently exhibit nodularity, presence of binucleate cells, irregular calcification, mucoid changes, and necrosis. Measurement of cartilage cap thickness, along with careful review of the history and radiographic appearance in these cases, is likely more reliable in differentiating benign from malignant lesions. In one study, interobserver variability was determined between 12 experienced musculoskeletal pathologists who interpreted 38 surgical specimens.¹⁹ Although there was substantial agreement among pathologists (correlation coefficient, 0.78), the study authors noted that interpretation should take into account the entire clinical picture, including the thickness of the cartilage cap and radiographic appearance.

ENCHONDROMA

Enchondromas are the second most common benign cartilage tumor. An enchondroma is a benign growth of hyaline cartilage, typically located in the medullary bone. These lesions make up approximately 3% of all bone tumors, and 13% of benign bone tumors.²⁰ Enchondromas are thought to be a portion of enchondral ossification that has become trapped in the medullary space. In the long bones, a metaphyseal enchondroma will seem to become more diaphyseal in location as the bone grows proximally and distally.

Clinical Features and Radiographic Findings

Enchondromas are frequently found incidentally (Figure 2). Population-based studies have demonstrated that these lesions peak at approximately age 30 to 50 years in both sexes,²¹ although they may be identified at any age. The true incidence of this lesion is unknown because many are asymptomatic and likely do not come to the attention of the patient or the clinician, although patients may present with a slow-growing mass that becomes increasingly painful. One example is a 41-year-old woman who presented with a large, painful cartilaginous lesion arising from the proximal fibula (Figure 3, A). Biopsy revealed a benign cartilaginous lesion, but MRI was concerning for malignant transformation (Figure 3, B). The patient underwent proximal fibula resection, with final pathologic analysis consistent with chondroma (Figure 3, C). This illustrates that there is a wide spectrum of disease in cartilaginous tumors.

FIGURE 2 Radiograph of the chest shows benign enchondroma noted incidentally during routine preoperative evaluation.

The lesion is characterized by areas of rounded calcification (popcorn calcification). Note the lack of endosteal scalloping, cortical thickening or erosion, or associated soft-tissue mass.

FIGURE 3 Imaging studies and pathology photograph from a 41-year-old woman show enchondroma, a large, painful cartilaginous lesion arising from the proximal fibula.

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