Enchondroma Pathology

Enchondromas are benign, intramedullary, usually solitary cartilaginous neoplasms that predominantly grow in the metaphyseal portion of tubular bones. They arise from foci of displaced or remodeling cartilage of the growth plate. Chondrocytes start proliferating during childhood, leading to enlargement of the tumor. In adulthood, enchondromas usually stop growing but persist.

Multiple enchondromas (enchondromatosis) are typically seen in Ollier disease and Maffucci syndrome. ^[1]  Ollier disease features multiple intraosseous enchondromas with variable numbers, sizes, and locations. ^[2]  Maffucci syndrome is characterized by multiple enchondromas and extraosseous hemangiomas. ^[3]  Ollier disease and Maffucci syndrome are typically not inherited; however, there are exceedingly rare subtypes of enchondromatosis that show autosomal dominant and recessive inheritance.

Enchondromas are relatively common lesions, accounting for up to a quarter of benign bone tumors and roughly 10% of all bone tumors. They may present at any decade of life, but more than half of cases occur between the second and fourth decades of life with an equal sex distribution. ^{[4, 5, 6]}

The exact etiology of enchondromas remains unknown. The lesions can be described as masses of hyaline cartilage in a lobular pattern resulting from growth plate remnants that are not resorbed, and they either persist or begin to grow in the medullary canal. ^[4]  The vast majority of enchondromas occur in the medullary portion of the diaphysis or metaphysis, and they expand toward the cortex, sometimes producing bone weakness and pathologic fractures.

In both solitary and syndromic enchondromas, frequent gain of function mutations in the isocitrate dehydrogenase-1 and -2 (IDH1 and IDH2) genes are observed. ^[7]  IDH1 and IDH2 encode isocitrate dehydrogenase enzymes that ultimately lead to inhibition of osteogenic differentiation. Additionally, chondrocyte-specific deletion of fibroblast growth factor receptor 3 (FGFR3) induces multiple chondroma-like lesions, including enchondromas and osteochondromas, adjacent to disordered growth plates. ^[8]

Enchondromas have a distinct predilection for the appendicular skeleton. ^[9] The most frequently involved location is the hand, with the proximal phalanx being the most commonly involved site. ^[10]  Less often enchondromas involve the feet, followed by the long tubular bones. ^[11]  The proximal or distal femur and the proximal humerus are the most commonly involved long tubular bone sites. ^[12]   Enchondroma of the spine, pelvis, and ribs are uncommon. ^{[13, 14]}  A case of a rare enchondroma arising in the mandibular body has been reported in the literature. ^[15]

Enchondromas are often discovered incidentally and are not usually painful. When they occur on the extremities, they can present with swelling and as a palpable mass. If pain is present, it probably correlates with growth activity. Sometimes, the presenting sign of of these tumors is a pathologic fracture.

The distinction between enchondroma and low-grade chondrosarcoma is especially pertinent when the lesion involves the long bones. A painful lesion, with histology showing myxoid change, hypercellularity, and atypia would all point to a diagnosis of chondrosarcoma. ^[9]

Initially, radiography is the imaging modality of choice for suspected enchondromas. On x-rays, they appear as lytic lesions with scalloped borders, predominantly lucent with internal mineralization. ^{[16, 17]}  The calcified foci vary from powderlike to dense aggregates. This mineralization is a result of the endochondral ossification that accompanies these tumors. 

Enchondroma Pathology. Plain radiographs will reveal lytic lesions with scalloped borders. When internal matrix is present, it is arranged in arc and ring or stippled patterns. A fracture can be associated with the lesion, especially in the small bones of the hands and feet.

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If further characterization is necessary, magnetic resonance imaging (MRI) or computed tomography (CT) scanning is performed. If uncertainty remains, bone scanning may be helpful, but some lesions require biopsy. Enchondromas may be located centrally, eccentrically, or they may occasionally be multicentric. In large tubular bones, enchondromas produce little if any endosteal cortical erosion, and if endosteal scalloping is present that is more than two thirds of the cortical thickness, a diagnosis of chondrosarcoma must be considered.

CT scans can help reveal the internal matrix production in the form of rings and arcs, which correspond to calcification around lobules of cartilage.

MRI shows lobulated borders with a cluster of numerous tiny locules of high-signal-intensity foci on T2-weighted images that appear to coalesce with one another and reflect the high fluid content of hyaline cartilage. MRI can also be useful to distinguish enchondromas from bone infarcts.  ^[18]   

See the Medscape Drugs and Diseases article Enchondroma and Enchondromatosis Imaging for additional information on this topic.

Most enchondromas are treated by curettage, and resected specimens are rare. The curetted material presents as confluent masses of grayish-blue and glistening hyaline cartilage with a distinct lobular arrangement. In the rare instances in which an enchondroma is received intact, the cartilage tissue is usually clearly noticeable on gross examination. The lesion is characterized by confluent lobules of cartilage, and the periphery of the lesion is frequently irregular. Calcifications seen on imaging may be confirmed at gross examination of the specimen.

The microscopic appearance of enchondromas may vary based on their anatomic location, which should always be considered before describing the lesion histologically. The enchondroma is composed of well-circumscribed lobules of benign hyaline cartilage. Lobules can be completely or partially separated by interposed bone marrow spaces or fibrovascular septa. Although uncommon, lobules can grow around the lamellar medullary bone, mimicking aggressive tumors such as chondrosarcoma with bone invasion.

The cellularity is typically low, and a few chondrocytes with small, dark, round regular nuclei with condensed chromatin are observed, usually located in lacunar spaces. Large chondrocytes with open nuclear chromatin or double/multinucleated cells can focally be present, but no atypia should be seen.

Fine-purple irregular or granular calcifications can be observed. Foci of endochondral ossification may be present in heavily calcified enchondromas. Necrosis, myxoid change, and atypical mitoses are typically absent, and their presence should heighten suspicion for malignancy. However, enchondromas of the small bones of hands and feet may show myxoid change; these should be considered within the spectrum of changes observed in enchondromas of this location, as long as the findings are not diffuse. If there is a concomitant fracture, mitotic figures may be present as a result of the bone healing process. ^[19]

Cytology smears usually show thick hyaline cartilages, and it is hard to discern the cellular or lacunar outline. Fluid and degenerated material and debris may be obtained as a result of the aspiration. The smear shows small round to oval chondrocytes, with small dark nuclei, no apparent nucleoli, and ill-defined cytoplasm embedded in the chondroid matrix. Double nucleated cells can rarely be focally seen, but no cytologic atypia should be present. ^{[20, 21]}

The following images depict histologic characteristics of enchondromas.

Enchondroma Pathology. Chondromas display large areas of basophilic extracellular cartilage matrix with broadly scattered bland chondrocytes.

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Enchondroma Pathology. A focal increase in the cellularity of enchondromas can occur when they are traumatized or when an associated fracture is present. This is especially true of lesions in the hands and feet. Care should be taken not to diagnose these lesions as malignant based solely upon their cytology.

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Enchondroma Pathology. Enchondromas can show endochondral ossification, and they are generally well demarcated from the surrounding marrow and trabecular bone.

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Enchondroma Pathology. Myxoid degeneration can be seen in enchondromas in the hands and feet.

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Immunohistochemistry is not routinely used to evaluate enchondromas. Chondrocytes are positive for S-100 protein, vimentin, and SOX9 (a marker of cartilage differentiation). Cytogenetic studies have shown heterogeneous findings, and they may reveal aberrations, inversions, or translocations involving chromosomes 2, 6,12, 15, and 21. ^[22]

Most enchondromas are followed conservatively, but when treatment is indicated, they are treated by curettage, with or without bone grafting. Cartilage lesions are resistant to chemotherapy and radiotherapy, and these treatments are not used for enchondromas. The recurrence rate for curetted enchondromas is less than 5%, especially in areas of complicated anatomy. ^{[23, 24]}