Enchondroma

Etiology

The persistence of growth plate chondrocytes in bone leads to enchondroma formation.[8] However, the reason for chondrocyte persistence is unknown. Genetic mutations are rare and often sporadic if involved.

Somatic isocitrate dehydrogenase-1 (IDH1) and 2 (IDH2) gene mutations have been implicated. Such mutations lead to the synthesis of defective isocitrate dehydrogenase—a tricarboxylic acid cycle enzyme that catalyzes isocitrate conversion to α-ketoglutarate.[9][10] The mutated enzyme catalyzes α-ketoglutarate reduction to the oncometabolite D-2-hydroxyglutarate (D-2-HG). D-2-HG competitively inhibits α-ketoglutarate-dependent enzymes, leading to DNA hypermethylation and histone modification.[11] These processes promote cartilaginous tumor formation and prevent normal osteogenic differentiation of mesenchymal stem cells.[12]

Somatic parathyroid hormone 1 receptor (PTHR1) gene mutations have also been found in enchondromas. The parathyroid hormone 1 receptor signaling pathway is a key regulator of enchondral ossification. Additionally, the Indian Hedgehog pathway is constitutively active in some cases of enchondromas. Wnt/β-catenin signaling downregulates Indian Hedgehog activity in enchondromas. Thus, the Wnt/β-catenin signaling pathway is a potential therapeutic target in treating enchondromas.[13]

Epidemiology

Enchondromas are the most prevalent intraosseous cartilage neoplasms, accounting for approximately 3% of bone tumors and 13% of benign bone growths. Most appear in the small hand and foot bones, but femoral and humeral enchondromas have also been documented.[14]

Enchondromatosis is the growth of multiple enchondromas. Ollier disease is a condition arising from enchondromatosis with an asymmetric distribution in the appendicular skeleton. This bone disorder has an estimated prevalence of 1 in 100,000.[15]

Maffucci syndrome is a condition presenting with enchondromatosis and multiple soft tissue hemangiomas and lymphangiomas. This disorder is rare, with fewer than 200 cases reported in the literature.[16] Although histologically similar to a solitary enchondroma, the cytological changes in this syndrome appear more bizarre.

Both Ollier disease and Maffucci syndrome are associated with an increased risk of chondrosarcoma and visceral malignancies.

Pathophysiology

Terminal chondrocyte differentiation in the growth plate is dysregulated in enchondroma formation. Most enchondromas begin in the medullary portion of the diaphysis. The tumors arise from ectopic cartilaginous nests in the metaphyseal region and expand outward toward the cortex. Enlarging lesions may cause a pathologic fracture.[17] 

The enchondromatous tumors of Ollier disease are typically located at the epiphysis, metaphysis, and diaphysis, potentially hindering normal bone growth. Limb shortening may occur due to epiphyseal invasion, metaphyseal widening, and long-bone bowing.[18] 

Histopathology

On gross examination, the typical enchondroma is smaller than 3 centimeters. Microscopically, enchondromas appear as gray-blue, translucent, hypocellular, avascular tumors with abundant hyaline cartilage. The nuclei of these cells are fairly regular, with few mitotic figures. Juxtacortical chondromas and enchondromas in regions like the hands may be hypercellular and atypical but remain benign.[19]

Chondroid matrix punctate calcifications define the microscopic appearance of enchondromas. The tumor is composed of well-circumscribed, benign hyaline cartilage nodules. Limited engulfment of the adjacent lamellar and cortical bone is seen. Chondrocyte nuclei are small and uniformly round with condensed chromatin. Binucleate forms are rare. Endochondral ossification foci may be found in heavily calcified enchondromas.

Long bone enchondromas often appear benign microscopically but can recur after removal. As with many tumors, staging systems are used to classify the tumor further. Bone sarcoma staging follows the tumor, node, and metastasis (TNM) guidelines.[20]

The enchondromas in syndromes like Ollier disease and Maffucci syndrome exhibit more cellularity and atypia than the classic, single enchondroma.[21] The increased cellularity and atypia make distinguishing enchondromatosis tumors from chondrosarcoma more difficult, especially when the malignancy is in its early stages. Benign, atypical cartilaginous lesions and chondrosarcoma grade 1 are nearly indistinguishable. However, cartilaginous lesions are typically hypocellular, while chondrosarcoma grade 1 has a hypercellular appearance. Additionally, chondrosarcoma exhibits more binucleated chondrocytes, pleomorphism, cortical destruction, host bone engulfment, and irregular cellular distribution.

History and Physical

Enchondromas may manifest at any age. However, the onset of presentation of the solitary enchondroma is classically in the 2nd or 3rd decade of life. Enchondromatosis syndromes become symptomatic earlier, typically before age 10.[22] The tumor is often discovered after the patient develops a pathologic fracture. Pain, swelling, and deformity are common. Pathologic fractures are seen in 40-60% of patients at presentation.[23] Others are detected incidentally on radiographic imaging.[24] 

The classic location of the lesions is in the proximal metaphyses of proximal phalanges, with a predilection for the ulnar side of the bones.[25] Distal phalangeal enchondromas may have associated nail deformities.

A thorough examination of the hand and wrist is necessary for patients with hand enchondromas. Passive movements of the interphalangeal and metacarpophalangeal joints need to be evaluated. Flexor and extensor tendon function must also be assessed, as distal phalangeal tumors can cause flexor tendon avulsion.

The skin, chest, abdomen, and neuromuscular function must be fully evaluated in patients with suspected enchondromatosis syndromes. These individuals are at risk of developing multiple hemangiomas and ovarian and brain malignancies.

Evaluation

Plain hand radiographs with posteroanterior, lateral, and oblique views should be obtained during the initial evaluation of hand enchondromas (see Image. Enchondroma Radiography). These tumors have varied radiographic appearances, influenced by location and extent of calcification. Enchondromas typically appear as well-defined, solitary metaphyseal defects, especially in the long bones. Centrally located lesions usually appear as well-circumscribed areas of rarefaction, most frequently diaphyseal, with an expanded surrounding cortex. Juxtacortical lesions are eccentric. located beneath the periosteum in well-defined cortical defects. Small, flocculent foci of calcification are visible within the tumors. Some may resemble medullary bone infarcts.[26]

Radiographically visible calcifications usually appear as fine, punctate stipplings. A bone infarct may be present if these areas are more pronounced. Some calcifications appear as rings. Larger lesions can cause endosteal scalloping and cortical expansion and thinning. Heavily calcified lesions may resemble bone infarction or bone islands, while an unclassified lesion may appear lytic. Cortical thinning or breach, tumor expansion, and soft tissue involvement are associated with advanced lesions or chondrosarcoma.[27]

Computed tomography (CT) is useful in evaluating matrix mineralization and cortex integrity. Magnetic resonance imaging (MRI) helps identify aggressive and destructive features. Enchondroma and chondrosarcoma often appear similarly on first-pass analysis. Both exhibit low signal intensities on T1 and reciprocal high-intensity changes with a lobular growth pattern on T2-weighted imaging. Both show enhancement with gadolinium contrast in peripheral and spatial areas.

Neither dynamic contrast-enhanced MRI nor advanced techniques like diffusion-weighted imaging and hydrogen proton spectroscopy have proven effective in differentiating enchondroma from chondrosarcoma. However, peritumoral edema may differentiate these tumors. A case series analysis revealed that chondrosarcoma is more likely to have peritumoral edema than enchondroma. Both CT and MRI can easily distinguish bone infarct from enchondroma.

Evidence of a lesion in a radiologic study is often insufficient to diagnose an enchondroma. Diagnostic confirmation requires histopathologic examination of the biopsied lesion. However, differentiating between benign and malignant hyaline cartilage lesions poses an even greater challenge. In some cases, the diagnosis may remain in question despite extensive tissue examination unless the suspicion of enchondroma or early chondrosarcoma is strong. Indicators of potential malignancy include the following:[28] 

• Large size
• Presence of a large unmineralized component
• Significant thinning of the adjacent cortex
• Bone scan activity greater than that of the anterior superior iliac spine
• Progressive chondrite matrix destruction due to an expanding non-mineralized component
• Rapidly enlarging, painful lesion
• Expansile soft tissue mass

Only 2 known biomarkers can distinguish enchondroma from chondrosarcoma: periostin and α-methylacyl-CoA racemase (AMACR). Periostin, a stroma-related protein, is reportedly absent in enchondroma but present in low-grade chondrosarcoma.[29] Meanwhile, AMACR, a mitochondrial and peroxisomal enzyme, is often expressed by enchondroma but rarely by chondrosarcoma.[30] Further investigation is needed to validate the reliability of these biomarkers in enchondroma and chondrosarcoma diagnosis.

Treatment / Management

Currently, no standardized algorithm for enchondroma surgery exists. Asymptomatic enchondromas may be observed, though routine radiographic follow-up for asymptomatic lesions is usually unnecessary. Symptomatic lesions and tumors producing pathologic fractures often improve with surgery. Operative management also helps establish a definitive diagnosis. However, the optimal timing of surgical intervention is unknown. Early and delayed surgical intervention was shown to have similar functional outcomes.

The surgical technique typically used for treating symptomatic enchondroma is simple curettage with bone grafting. The bone graft may be allogeneic, autogenous, or synthetic. The graft type's impact on healing, recurrence, complications, and malignant transformation is unknown. The necessity of curettage with grafting remains unproven.

Care must be taken to prevent tumor dissemination during surgery. Tourniquet control without exsanguination using an esmarch bandage is performed during the procedure. Adjuncts used to kill the residual tumor cells and help reduce recurrence include phenol, liquid nitrogen, cryotherapy, polymethyl methacrylate, and electrocautery.[31][32] However, no data suggests which adjunct is superior among the various treatment options. A frozen section is not recommended in these procedures.(B2)

The bone void can be filled using an autograft, allograft, bone substitute, or bone cement after curettage. However, some studies have demonstrated that leaving the void unfilled renders equivalent functional outcomes. This technique saves surgical time, prevents donor site morbidity, and minimizes foreign body-induced complications, as when allografts and bone cement are used.

Fracture prophylaxis by internal fixation methods is controversial. Previous guidelines based on retrospective studies were limited by the use of plain radiographs, subjective patient information, and inadequate understanding of the biomechanical factors involved in the neoplastic process. The Mirels criteria were developed to quantify bone neoplasm-related fracture risk. These criteria consider the location, pain, and lesion type and size.[33] Scores greater than 8 indicate a significant fracture risk. Thus, prophylactic internal fixation may be recommended in such cases. Lesions with scores less than 7 have a reduced fracture risk and may simply be observed.

A 23-year retrospective review of enchondroma patients reported that enchondroma treatment with biopsy, curettage, and allograft implantation resulted in a full range of motion in more than 80% of the patients. Additionally, recurrence was rarely seen and was more common with Ollier's disease and giant-form lesions. Preoperative pathologic fractures are associated with a greater risk of postoperative extension deficit.

Various surgical techniques have been used for enchondroma treatment. One case report described a successful endoscopic curettage and bone grafting of a proximal finger phalangeal enchondroma.[34] Another case series reported bone fixation with headless intramedullary screws after long-hand bone enchondroma resection with good results.[35] A 10-year retrospective cohort study found that osteoscopic surgery leads to earlier functional recovery and fewer complications than open surgery.[36] Radiofrequency ablation was recently shown to have value in treating flat pelvic bone enchondromas.[37](B2)

Differential Diagnosis

Conditions that may present similarly to enchondromatous lesions include the following:[38][39]

• Bone infarction, which has a similar radiographic appearance
• Tuberculous dactylitis, due to bone pain in the absence of a fracture
• Low-grade chondrosarcoma, also due to non-fracture-related bone pain
• Other benign neoplasms like giant cell reparative granuloma, giant cell tumors, and chondroblastoma

These conditions may be differentiated from enchondromas with a good clinical evaluation, appropriate laboratory and imaging studies, and histopathology.

Staging

Takigawa proposed a radiographic classification for enchondromas, which had 5 morphological categories:

• Type A: central
• Type B: eccentric
• Type C: associated
• Type D: polycentric
• Type E: giant form

One study found that the Takigawa classification could predict the optimal enchondroma treatment option.[44] However, more large-scale studies are necessary to evaluate the reliability of this system in predicting prognosis and surgical outcomes of enchondromatous growths.

Prognosis

Solitary enchondromatous lesions are typically self-limited. Recurrence is rare following curettage and bone grafting. However, giant-form tumors and long bone involvement are associated with a higher recurrence risk. Meanwhile, enchondromatosis increases not only the risk of recurrence but also the probability of malignant transformation. 

Complications

The potential complications of delayed enchondroma treatment include the following:

• Intramedullary enchondroma growth and cortical bone encroachment may produce a pathologic fracture.
• Enchondromas may interfere with proper bone development in children.
• Pathologic fractures requiring primary surgery increase hospitalization costs.
• Delayed surgery of pathological fractures, ie, when surgical intervention is postponed until bone union is achieved, may lead to prolonged immobilization. The time to return to work may be longer.
• Stiffness, joint deformities, and contractures may be seen following surgeries, especially in the hands.
• Malignant transformation to chondrosarcoma may occur following skeletal maturity. However, transformation of a solitary enchondromatous lesion is rare (less than 1%).[40]
• Malignant transformation risk is increased in Ollier disease and Maffucci syndrome.[41][42] These two conditions are also associated with non-sarcomatous, extraosseous neoplasms, including brain tumors.[43]

Prompt consultation with an orthopedic specialist regarding this condition helps minimize complications.