Enchondroma

Etiology

Enchondromas are benign, lobulated neoplasms of hyaline cartilage, most commonly occurring in the short tubular bones of the hands and feet. The femur and humerus are the two most common sites for long bone involvement. These tumors can, however, arise in any bone formed from cartilage. Enchondromas are the most prevalent intraosseous cartilage tumors, accounting for approximately 3% of bone tumors and 13% of benign bone tumors.[6]

Most enchondromas begin in the medullary portion of the diaphysis, arising from ectopic cartilaginous nests in the metaphyseal region, and expand outward towards the cortex.[4] Enlarging lesions may cause a pathologic fracture.[7][6] The terminal differentiation of the chondrocytes gets dysregulated during the growth plate development in enchondroma.

Epidemiology

Besides solitary lesions, sometimes an individual can display multiple enchondromas; the condition is called enchondromatosis. One such syndrome is Ollier disease.[8] With a prevalence estimated to be about 1 in 100,000, Ollier disease characteristically demonstrates multiple enchondromas in the appendicular skeleton in an asymmetric manner. The enchondromatous tumors of Ollier disease are typically located at the epiphysis and the adjacent regions of the metaphysis and diaphysis. The location of the tumor can prevent normal bone growth: shortening due to the epiphyseal invasion, metaphyseal widening, and long bone bowing.[9] 

Another condition presenting with multiple enchondromas is Maffucci syndrome. In this syndrome, the enchondromas are associated with multiple soft tissue hemangiomas and lymphangiomas. Maffucci syndrome is very rare, with fewer than 200 cases reported in the English literature.[10] Although histologically similar to a solitary enchondroma, cytologically, the changes seen in this syndrome appear more bizarre. In both conditions, Ollier disease and Maffucci syndromes, there is an associated increased risk of malignant transformation to chondrosarcoma. In addition, both conditions carry an increased risk for visceral malignancy.

Pathophysiology

Enchondromatosis possesses associations with somatic mutations in isocitrate dehydrogenase-1 (IDH1) and 2 (IDH2) genes. The mutations are rare and often sporadic. Isocitrate dehydrogenase is an enzymatic component of the tricarboxylic acid (TCA) cycle functioning to convert isocitrate to alpha-ketoglutarate.[11][12] 

Mutations in IDH1 and IDH2 cause malfunction of this enzyme resulting in increased levels of the oncometabolite D-2-hydroxyglutarate (D-2-HG.) D-2-HG competitively inhibits alpha-ketoglutarate-dependent enzymes. DNA hypermethylation and histone modification ensue, affecting differentiation.[13] Inhibition of the osteogenic differentiation of mesenchymal stem cells occurs via elevations in D-2-HG resulting from IDH1 and IDH2 mutations. All-in-all, blocking osteogenic differentiation during the formation of the skeleton results in cartilaginous tumor formation.[14]

Histopathology

Evidence of a lesion in a radiologic study is not definitive enough to diagnose an enchondroma. Diagnostic confirmation requires histopathologic examination of the specimen sample. Differentiation between benign and malignant lesions poses an even greater challenge. One must examine all available tissue; even then, the diagnosis may remain in question and based on clinical evidence and suspicion. Microscopically enchondromas appear as gray-blue, translucent, hypocellular, non-vascular tumors with abundant hyaline cartilage. The nuclei of these cells are fairly regular, with few mitotic figures. Juxtacortical chondromas and enchondromas in regions such as the hands, however, may be hypercellular with atypia and still maintain a benign nature.[15]

Conversely, long bone enchondromas often appear benign microscopically but can recur after removal. As with many tumors, staging classifications are used to classify the tumor further. The staging of bone sarcomas follows the tumor, node, and metastasis (TNM) guidelines.[16]

Histopathologically, punctate calcifications of the chondroid matrix define the appearance of enchondromas. On examination, the typical enchondroma is smaller than 3 centimeters. The enchondroma is composed of well-circumscribed nodules of benign hyaline cartilage. There is limited engulfment seen of the adjacent lamellar and cortical bone. The nuclei of the chondrocytes are small and uniformly round with condensed chromatin. Rarely binucleate forms are present. Foci of endochondral ossification may be present in heavily calcified enchondromas. Syndromes characterized by multiple enchondromas, Ollier’s disease, and Maffucci syndrome exhibit more cellularity and atypia than classic, single enchondromas.[17] 

The increased cellularity and atypia make distinguishing enchondroma from chondrosarcoma more difficult. The distinction between benign cartilaginous lesions and atypical cartilaginous tumor/chondrosarcoma grade 1 (ACT/CS1) is difficult. The cartilaginous lesions are typically hypocellular, while ACT/CS1 has a hypercellular appearance. The chondrosarcomas have a higher number of binucleated chondrocytes. Also, they exhibit pleomorphism, cortical destruction, engulfment of the host bone, and irregular cellular distribution.

History and Physical

The symptoms of enchondroma are often nonspecific and found as a result of a pathologic fracture/trauma or localized versus radiating pain. The most common presenting symptoms are pain, swelling, and deformity. Pathologic fractures can be seen in 40-60% of patients at presentation.[3][18] However, many are ultimately found incidentally on radiographic imaging.[19] 

Nail plate deformity may also be seen in distal phalangeal enchondromas.[4] Enchondromas may present at any age, although the classic presentation is in the second to third decade of life: 15 to 35 years of age. Enchondromatosis syndromes present earlier in life, typically before age 10.[20] Enchondromas are the most common benign tumor to present in the hand. The classic location of the lesions is in the proximal metaphysis of the proximal phalanx with a predilection for the ulnar side of the bone.[21] 

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. Specifically, the functions of the flexor and the extensor tendons need to be assessed, as the distal phalangeal tumors can cause avulsion of the flexor tendons. [4]

Evaluation

Radiographically, enchondromas have varied appearances based on location and extent of calcification, and they may resemble medullary bone infarcts. Enchondromas typically appear as well-defined solitary defects in the metaphyseal region of bones, especially in the long bones. Their appearance depends heavily on the location and extent of the calcification of the tumor. Centrally located lesions usually appear as well-circumscribed areas of rarefaction, most frequently diaphyseal, with an expanded cortex around it. Juxtacortical lesions are eccentric and beneath the periosteum in well-defined cortical defects. Small, flocculent foci of calcification are visible within the tumor.[22]

Radiographically visible calcifications appear as fine, punctate stipplings and, if pronounced, may suggest a bone infarct. The calcifications can range in size from punctate to rings. Larger lesions can cause endosteal scalloping along with expansion and thinning of the cortex. Heavily calcified lesions may resemble bone infarct or bone islands, while an unclassified lesion may appear lytic. The appearance of cortical thinning, expansion, or breach of the cortex or soft tissue involvement signifies either advanced lesions or chondrosarcoma.[23] X-rays of the hand- posteroanterior, lateral, and oblique views should be done to evaluate the hand enchondromas.[4]

Computed tomography (CT) is useful for detecting matrix mineralization and cortex integrity, while Magnetic resonance imaging (MRI) adds insight into the aggressive and destructive features of the tumor. Indicators of potential malignancy include large size, a large unmineralized component, significant thinning of the adjacent cortex, and bone scan activity greater than that of the anterior superior iliac spine (ASIS). Progressive destruction of the chondrite matrix by an expanding, non-mineralized component, an enlarging lesion associated with pain, or an expansile soft tissue mass is strongly associated with the malignant transformation of an enchondroma.[24] 

On MRI, enchondroma, and chondrosarcoma often appear similarly on first pass analysis. Both exhibit low signal intensities on T1 with reciprocal high-intensity changes on the T2-weighted images with a lobular growth pattern. Both show enhancement with gadolinium contrast in peripheral and spatial areas. Neither dynamic contrast-enhanced MRI nor advanced techniques such as diffusion-weighted imaging and hydrogen proton spectroscopy have proved effective in differentiating enchondroma from chondrosarcoma. To differentiate the two, peritumoral edema must be assessed. Although this finding has not undergone prospective examination, case series have revealed consistency. In the case series analysis, no peritumoral edema was noted with enchondromatous lesions, while chondrosarcoma lesions showed the edema. Both CT and MRI can easily distinguish bone infarct from enchondroma.[6]

Only two known biomarkers distinguish enchondroma from chondrosarcoma: periostin and alpha-methylacyl-CoA racemase (AMACR). Periostin, a stromal-related protein, is reportedly absent in enchondroma but is present in low-grade chondrosarcoma.[25] AMCR, a mitochondrial and peroxisomal enzyme, is expressed in most enchondromas. Conversely, AMCR is present in a minority of chondrosarcomas.[26] Further investigation is needed to further validate and confirm these biomarkers as reliable entities. 

Treatment / Management

Management of symptomatic enchondroma lesions typically involves surgical management in the form of simple curettage with bone grafting. The bone graft used may be allogeneic bone, autogenous, or synthetic bone substitutes. The impact of the type of graft on healing, recurrence, complications, and malignant transformation is unknown. Currently, no standardized algorithm for surgical treatment of enchondroma exists. Also, the necessity of curettage with grafting remains unproven. Asymptomatic enchondromas can be observed.[4] Also, it is not necessary to ask for routine radiographic follow-up for asymptomatic lesions. For symptomatic lesions and those with pathologic fractures, surgical management improves outcomes and helps establish a definitive diagnosis. However, the timing of surgical intervention has also not been shown to have significant benefits. Early and delayed surgical intervention was shown to have similar functional outcomes.[21] 

During surgical management, one needs to stick to the principles of tumor surgery to prevent tumor dissemination. The surgery is performed under tourniquet control without exsanguination using an esmarch bandage. After the curettage, various adjuncts can be used that supposedly kill the residual tumor cells and help reduce recurrence. They include phenol, liquid nitrogen, cryotherapy, polymethyl methacrylate, and electrocautery.[27][28] However, there is no data to suggest which adjunct is superior among the various treatment options. A frozen section is not recommended in these surgeries.[4](B2)

After the curettage, the bone void can be filled using either autograft, allograft, bone substitute, or bone cement. Some studies have described leaving the void without filling it with grafts/ cement with equivalent functional outcomes. The proponents of the latter theory suggest that it saves surgical time, prevent donor site morbidity, and prevents complications related to the introduction of foreign materials (in the case of allografts and bone cement).[18](A1)

Prophylactic intervention aiming to prevent impending fracture via internal fixation methods is unknown and controversial. Retrospective studies have formed a basis to guide the indications, but the limits of these guidelines are 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 the risks of fracture pertaining to bone neoplasms. These criteria consider the location, pain, lesion type, and lesion size.[29]

A score greater than 8 dictates a significant fracture risk and a need for a prophylactic internal fixation. A bone tumor with a score less than seven can undergo observation according to these criteria. In applying these criteria, the defined fracture risk uses the load-bearing requirement of the bone divided by its load-bearing capacity. The parameters for load-bearing requirement and capacity were also stipulated and analyzed. The patient's age, weight, activity level, and ability to protect the site dictate the load-bearing requirement. The load-bearing capacity depends on the amount of bone loss, modulus of the remaining bone, and location of the defect with respect to the type of load applied. 

Differential Diagnosis

When considering a lesion to be an enchondroma, the clinician must also consider bone infarction on the differential as both may have a similar radiographic appearance. Tuberculous dactylitis and low-grade chondrosarcoma are also considerations in patients with enchondroma who have pain without the presence of fracture at their index presentation.[30] The other differential diagnosis includes tumor-like conditions, including giant cell reparative granuloma and other benign tumors like giant cell tumor and chondroblastoma.[31]

Staging

Takigawa proposed a radiographic classification for enchondromas, which has five categories. They include central, eccentric, polycentric, associated, and giant form categories.[23]

Prognosis

Solitary enchondromatous lesions are typically self-limited. Recurrence is rare following curettage and bone grafting; however, higher recurrence risks are associated with enchondroma lesions involving long bones.[7] Also, the recurrence rates and chances of malignant transformation increase with enchondromatosis, including Ollier disease and Maffucci syndrome.

Complications

As these tumors arise in the medullary portion of the bone, their expansile properties may ultimately result in pathologic fracture as the cartilaginous tumor encroaches on the cortical bone. If surgery is delayed until fraction union has occurred, the patient may be exposed to extended periods of immobilization. Hospital costs are also higher for patients treated with primary surgery for their pathologic fracture. Patients treated with primary surgery of the pathologic fracture had a shorter time to return to work than the delayed surgical candidates whose procedure was held until fracture union.[21] Stiffness, joint deformities, and contractures can be seen following surgeries, especially in the hands.[3]

Malignant transformation to chondrosarcoma usually occurs following skeletal maturity. Transformation of a singular enchondromatous lesion is rare, less than 1%.[32] Malignant transformation risk increased with Ollier disease and Maffucci syndrome.[33][34]  These two syndromes are also associated with non-sarcomatous, extraosseous neoplasms, including brain tumors.[35]