General orthopedic surgeons frequently encounter patients with conditions affecting multiple bones. It is important to recognize common polyostotic diseases. This article describes five polyostotic conditions: Multipe Enchondromatosis (Ollier Disease and Maffucci syndrome), Multiple Hereditary Exostosis (Diaphyseal Aclasis), Fibrous Dysplasia (McCune-Albright syndrome and Mazabraud syndrome), Paget’s Disease of bone (Osteitis Deformans), and Skeletal Metastases. This is a survey of the clinical, pathologic and radiographic features that assist in diagnosing these conditions. Also, an overview of the laboratory findings, treatment, follow-up, and prognosis is presented. Recognizing these diseases will aid in prompt and accurate diagnosis and appropriate referral and therapy.
Key points
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In history and physical examination, similar lesions should always be looked for in other parts of the musculoskeletal system and additional pertinent findings should be analyzed in review of systems, which might offer clue to the diagnosis.
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Most patients with these diseases are asymptomatic and do not require treatment other than regular clinical and radiographic follow-up. Symptomatic lesions may necessitate further laboratory and radiographic investigation that in rare cases may require biopsy.
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A sudden increase in pain or appearance of swelling may herald pathologic fracture or malignant change. Patients with select conditions should be warned of these rare potential risks and told to seek immediate consultation in the event of worrisome symptoms.
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Skeletal metastasis in the differential in older patients with unexplained bone pain, swelling, and pathologic fracture, especially with a previous cancer history, should always be considered.
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Patients with suspected malignancy should be referred early for further evaluation, biopsy, and expert management.
Multiple enchondromatosis (Ollier disease and Maffucci syndrome)
Enchondroma is a common benign tumor that consists of mature hyaline cartilage. It can be solitary or multiple. Solitary enchondromas are usually diagnosed incidentally and are commonly observed in the long bones of the hand and extremities. Multiple enchondromatosis (Ollier disease) is rare. Multiple enchondromata associated with soft tissue hemangiomata (Maffucci syndrome) is rarer still. There is no gender predominance for these conditions. Most enchondromata involve the metaphysis and diaphysis, whereas only 10% are epiphyseal. Enchondromata associated with Ollier disease are commonly found in the femur, tibia, and ilium, followed by phalanges, metacarpals, and metatarsals. Maffucci syndrome is the most severe of all and most commonly involves the hand. Both Ollier disease and Maffucci syndrome are congenital.
Pathology
The cause is unknown, but Ollier disease and Maffucci syndrome are thought to arise from small rests of physeal cartilage entrapped in the metaphysis of growing bones. These “cartilage rests” grow until skeletal maturity and frequently reside in the metaphysis or diaphysis and over time mineralize in varying degrees. Most cases of enchondromatosis are sporadic, but families with multiple affected members have been reported, possibly suggesting autosomal-dominant (AD) inheritance. There is a controversial and iterative role of one or more mutations in PTHR1 (parathyroid hormone receptor 1). Grossly, the lesions are lobular with a bluish color and microscopically composed of lobules of hyaline cartilage that are relatively hypocellular and matrix-rich. In the hands and feet, enchondromata can appear radiographically aggressive. Microscopically, they are hypercellular with atypical cells but still are considered benign. Also, lesions in young children associated with Ollier disease and Maffucci syndrome are more cellular than solitary enchondromas in adults. Although these features are interpreted as benign in the small bones, similar findings in axial and appendicular long bones in adults could be interpreted as low-grade chondrosarcoma. There is a great deal of variability among pathologists in the interpretation and diagnosis of malignant change in enchondromata. These lesions are variously named as atypical enchondroma, aggressive enchondroma, sarcoma in situ, and grade I chondrosarcoma.
Clinical Features
Most solitary enchondromata diagnosed in adults are asymptomatic and discovered incidentally. Rarely, patients present with pain due to pathologic fracture. Pain in the absence of fracture in patients with a solitary enchondroma suggests another unrelated cause, or rarely, transformation to an active or overtly malignant disease process. The involved bone may also be slightly enlarged. Patients with Ollier disease may be asymptomatic but may present with growth disturbances, enlargement, shortening, and deformity of the affected bones as well as scoliosis. Most patients with Ollier disease have bilateral involvement but may only exhibit unilateral or single limb predominance. This disease is usually diagnosed in younger patients. Maffucci syndrome is characterized by multiple enchondromata with soft tissue lesions, most commonly, cavernous hemangiomas in the subcutaneous tissues, usually affecting the same extremity. The hemangiomas are present at birth in only 25% of affected patients. Most are diagnosed in childhood.
The risk of malignancy is high in tumors that are large and in proximal locations like the pelvis, proximal femur, and proximal humerus. Although malignant transformation in solitary enchondroma is rare, the risk of developing a chondrosarcoma in the setting of multiple enchondromata is high. Malignant change is heralded by progressive pain and the appearance of swelling.
Imaging
Laboratory tests are normal and radiographs are usually diagnostic. On radiographs, enchondromata are centrally located, intramedullary, metaphyseal, or metadiphyseal-based radiolucent lesions with matrix mineralization. Most (95%) demonstrate mineralization variously described as dots, punctuate, stippled, speckled, annular rings, arcs, whorls, flocculent, and popcorn mineralization. The lesions may be completely radiolucent especially in children and in short tubular bones. They may be associated with thinning and expansion of cortex as well as endosteal scalloping, but cortical disruption and periosteal reaction are unusual without pathologic fracture or malignant transformation. In the phalanges, enchondromata may extend to the ends of bones. In hands and feet, these lesions may appear more aggressive radiologically but are generally considered benign. In the long bones, radiolucent streaks or fan-like septations extending from the growth plate into the diaphysis and asymmetric enlargement and flaring of the metaphyses may be present in patients with multiple enchondroma ( Fig. 1 ). In the pelvis, and particularly in the iliac bones, these fan-like linear changes are characteristic of Ollier disease. Maffucci syndrome may display phleboliths on radiographs ( Fig. 2 ).
On magnetic resonance (MR), the lesions appear as low to intermediate intensity on T1-weighted and high intensity on T2-weighted images with sharp margins. The mineralization appears as punctate or globular dark areas on both T1 and T2 pulse sequences. MR also shows the lobular nature of the tumor (on T2), size, and the intramedullary extent. Computed tomography (CT) is better for identifying the matrix, endosteal scalloping, cortical destruction, and periosteal reaction. Aggressive lesions generally display increased scintigraphic uptake on bone scan but children may also have active lesions that show active and intense uptake. Bone scan or skeletal survey is used to localize the lesions in other bones.
The radiological features suggestive of aggressive behavior are larger lesions, longer than 4 cm, medullary fill of greater than 90%, large unmineralized areas, or faint, amorphous calcification, lysis within a previously mineralized area, a wide zone of transition from normal to abnormal, localized thickening of the cortex, deep endosteal scalloping (greater than two-thirds of cortex), longitudinal scalloping throughout the length of the lesion, cortical disruption, periosteal reaction, and a soft tissue mass. A heterogeneous and increased scintigraphic uptake (greater than the corresponding anterior superior iliac spine) on bone scan is also suggestive of malignant change.
Biopsy can be challenging because it is difficult to differentiate low-grade chondrosarcoma from enchondroma by histology alone; therefore, clinical, radiologic, and pathologic correlation are essential to arrive at a correct diagnosis.
Treatment
Most lesions are asymptomatic and, other than routine radiographic surveillance, surgery is not necessary. For benign symptomatic lesions or for impending pathologic fracture, curetting and bone grafting with or without physical adjuvants can be considered. Internal fixation may be necessary. If a pathologic fracture occurs, the fracture should be allowed to heal before curetting and bone grafting. More aggressive lesions in pelvis and long bones require wide resection. Treatment of patients with enchondromatosis due to Ollier disease and Maffucci syndrome may necessitate correction of deformities and leg-length discrepancy in addition to careful surveillance, genetic counseling, prompt biopsy, and intervention for suspected malignant transformation.
Prognosis and Follow-Up
In solitary enchondromas, the risk of malignant transformation to chondrosarcoma is less than 1% and is even rarer before skeletal maturity. The risk of malignant transformation of an enchondroma in Ollier disease spirals upward to 25% to 30% and in Maffucci syndrome is up to 56%. Patients with Maffucci syndrome also have the risk of developing acute lymphocytic leukemia, astrocytoma, and gastrointestinal and ovarian malignancies. The risk of skeletal or nonskeletal malignancy in Maffucci syndrome is probably almost certain if patients are followed long enough.
Multiple enchondromatosis (Ollier disease and Maffucci syndrome)
Enchondroma is a common benign tumor that consists of mature hyaline cartilage. It can be solitary or multiple. Solitary enchondromas are usually diagnosed incidentally and are commonly observed in the long bones of the hand and extremities. Multiple enchondromatosis (Ollier disease) is rare. Multiple enchondromata associated with soft tissue hemangiomata (Maffucci syndrome) is rarer still. There is no gender predominance for these conditions. Most enchondromata involve the metaphysis and diaphysis, whereas only 10% are epiphyseal. Enchondromata associated with Ollier disease are commonly found in the femur, tibia, and ilium, followed by phalanges, metacarpals, and metatarsals. Maffucci syndrome is the most severe of all and most commonly involves the hand. Both Ollier disease and Maffucci syndrome are congenital.
Pathology
The cause is unknown, but Ollier disease and Maffucci syndrome are thought to arise from small rests of physeal cartilage entrapped in the metaphysis of growing bones. These “cartilage rests” grow until skeletal maturity and frequently reside in the metaphysis or diaphysis and over time mineralize in varying degrees. Most cases of enchondromatosis are sporadic, but families with multiple affected members have been reported, possibly suggesting autosomal-dominant (AD) inheritance. There is a controversial and iterative role of one or more mutations in PTHR1 (parathyroid hormone receptor 1). Grossly, the lesions are lobular with a bluish color and microscopically composed of lobules of hyaline cartilage that are relatively hypocellular and matrix-rich. In the hands and feet, enchondromata can appear radiographically aggressive. Microscopically, they are hypercellular with atypical cells but still are considered benign. Also, lesions in young children associated with Ollier disease and Maffucci syndrome are more cellular than solitary enchondromas in adults. Although these features are interpreted as benign in the small bones, similar findings in axial and appendicular long bones in adults could be interpreted as low-grade chondrosarcoma. There is a great deal of variability among pathologists in the interpretation and diagnosis of malignant change in enchondromata. These lesions are variously named as atypical enchondroma, aggressive enchondroma, sarcoma in situ, and grade I chondrosarcoma.
Clinical Features
Most solitary enchondromata diagnosed in adults are asymptomatic and discovered incidentally. Rarely, patients present with pain due to pathologic fracture. Pain in the absence of fracture in patients with a solitary enchondroma suggests another unrelated cause, or rarely, transformation to an active or overtly malignant disease process. The involved bone may also be slightly enlarged. Patients with Ollier disease may be asymptomatic but may present with growth disturbances, enlargement, shortening, and deformity of the affected bones as well as scoliosis. Most patients with Ollier disease have bilateral involvement but may only exhibit unilateral or single limb predominance. This disease is usually diagnosed in younger patients. Maffucci syndrome is characterized by multiple enchondromata with soft tissue lesions, most commonly, cavernous hemangiomas in the subcutaneous tissues, usually affecting the same extremity. The hemangiomas are present at birth in only 25% of affected patients. Most are diagnosed in childhood.
The risk of malignancy is high in tumors that are large and in proximal locations like the pelvis, proximal femur, and proximal humerus. Although malignant transformation in solitary enchondroma is rare, the risk of developing a chondrosarcoma in the setting of multiple enchondromata is high. Malignant change is heralded by progressive pain and the appearance of swelling.
Imaging
Laboratory tests are normal and radiographs are usually diagnostic. On radiographs, enchondromata are centrally located, intramedullary, metaphyseal, or metadiphyseal-based radiolucent lesions with matrix mineralization. Most (95%) demonstrate mineralization variously described as dots, punctuate, stippled, speckled, annular rings, arcs, whorls, flocculent, and popcorn mineralization. The lesions may be completely radiolucent especially in children and in short tubular bones. They may be associated with thinning and expansion of cortex as well as endosteal scalloping, but cortical disruption and periosteal reaction are unusual without pathologic fracture or malignant transformation. In the phalanges, enchondromata may extend to the ends of bones. In hands and feet, these lesions may appear more aggressive radiologically but are generally considered benign. In the long bones, radiolucent streaks or fan-like septations extending from the growth plate into the diaphysis and asymmetric enlargement and flaring of the metaphyses may be present in patients with multiple enchondroma ( Fig. 1 ). In the pelvis, and particularly in the iliac bones, these fan-like linear changes are characteristic of Ollier disease. Maffucci syndrome may display phleboliths on radiographs ( Fig. 2 ).
On magnetic resonance (MR), the lesions appear as low to intermediate intensity on T1-weighted and high intensity on T2-weighted images with sharp margins. The mineralization appears as punctate or globular dark areas on both T1 and T2 pulse sequences. MR also shows the lobular nature of the tumor (on T2), size, and the intramedullary extent. Computed tomography (CT) is better for identifying the matrix, endosteal scalloping, cortical destruction, and periosteal reaction. Aggressive lesions generally display increased scintigraphic uptake on bone scan but children may also have active lesions that show active and intense uptake. Bone scan or skeletal survey is used to localize the lesions in other bones.
The radiological features suggestive of aggressive behavior are larger lesions, longer than 4 cm, medullary fill of greater than 90%, large unmineralized areas, or faint, amorphous calcification, lysis within a previously mineralized area, a wide zone of transition from normal to abnormal, localized thickening of the cortex, deep endosteal scalloping (greater than two-thirds of cortex), longitudinal scalloping throughout the length of the lesion, cortical disruption, periosteal reaction, and a soft tissue mass. A heterogeneous and increased scintigraphic uptake (greater than the corresponding anterior superior iliac spine) on bone scan is also suggestive of malignant change.
Biopsy can be challenging because it is difficult to differentiate low-grade chondrosarcoma from enchondroma by histology alone; therefore, clinical, radiologic, and pathologic correlation are essential to arrive at a correct diagnosis.
Treatment
Most lesions are asymptomatic and, other than routine radiographic surveillance, surgery is not necessary. For benign symptomatic lesions or for impending pathologic fracture, curetting and bone grafting with or without physical adjuvants can be considered. Internal fixation may be necessary. If a pathologic fracture occurs, the fracture should be allowed to heal before curetting and bone grafting. More aggressive lesions in pelvis and long bones require wide resection. Treatment of patients with enchondromatosis due to Ollier disease and Maffucci syndrome may necessitate correction of deformities and leg-length discrepancy in addition to careful surveillance, genetic counseling, prompt biopsy, and intervention for suspected malignant transformation.
Prognosis and Follow-Up
In solitary enchondromas, the risk of malignant transformation to chondrosarcoma is less than 1% and is even rarer before skeletal maturity. The risk of malignant transformation of an enchondroma in Ollier disease spirals upward to 25% to 30% and in Maffucci syndrome is up to 56%. Patients with Maffucci syndrome also have the risk of developing acute lymphocytic leukemia, astrocytoma, and gastrointestinal and ovarian malignancies. The risk of skeletal or nonskeletal malignancy in Maffucci syndrome is probably almost certain if patients are followed long enough.
Multiple hereditary exostosis (diaphyseal aclasiS)
Osteochondroma (osteochondral exostosis) is the most common skeletal tumor, comprising 20% to 50% of benign bone tumors and 10% to 15% of all bone tumors. They occur as either solitary or multiple tumors with a slight male predominance. The solitary exostosis (SE) is much more common than the multiple variant (multiple hereditary exostosis or MHE). Solitary exostoses are generally diagnosed in older individuals (before age 30) and MHE patients are diagnosed before age 10. Both SE and MHE occur in metaphyseal bone and morphologically can exhibit a stalk (pedunculated) or a broad base (sessile). Pedunculated lesions are more often encountered in patients with SE, whereas the sessile morphology is more common in patients with MHE. Solitary exostoses occur around the knee (50%) in the distal femur and proximal tibia followed by proximal humerus. Axial involvement (ie, the flat bones including the scapula, ilium, and clavicle) is much less common. In patients with MHE, the knees, hips, ankles, and shoulders are most commonly involved. Some MHE patients have associated multiple enchondromata, a condition known as metachondromatosis. Although both diseases are transmitted in an AD fashion, they are the result of different mutations.
Pathology
SEs occur sporadically and some are associated with chemotherapy and radiotherapy. Around 90% of the MHE are inherited as AD with 96% to 100% penetrance. Approximately 10% have no family history and represent new, sporadic mutations. The AD variant is associated with tumor-suppressor exostosin genes, EXT I, EXT II, and EXT III, in chromosomes 8, 11, and 19, respectively. The pathogenesis of these lesions is not clear but growth from aberrant ectopic physeal foci is suggested. The growth of individual osteochondromata parallels that of the “normal” growth plate and ceases with skeletal maturity. These lesions have a “cauliflower appearance” with an irregular osseous surface covered by a cartilage cap of varying thicknesses. The cartilage cap resembles physeal hyaline cartilage histologically. The cap is 2 or 3 cm thick in children and usually less than 1 cm thick after skeletal maturity. The stalk is composed of cortical bone with a marrow cavity that is continuous with the underlying native bone. The cartilage cap may mineralize, especially if the tissue undergoes osteonecrosis. A delicate, fibrous membrane known as perichondrium, representing a continuation of the periosteum of the adjacent cortex, overlies the cartilaginous cap.
Clinical Features
Most lesions, in both SE and MHE, are asymptomatic and often found incidentally. Pain and a bump are the most common presenting symptoms. Pedunculated lesions are more symptomatic than corresponding sessile tumors. Pain can result from mechanical irritation of soft tissues, nerve impingement, bursa formation, osteonecrosis, fracture of the stalk, and malignant transformation. Pseudoaneurysm is a rare but known complication of large osteochondral exostoses in the popliteal fossa. Patients with MHE tend to be of short stature and have valgus deformities of the elbows and knees as well as ulnar deviation of the wrists. Patients may also develop joint subluxation if deformities involve the paired bones in the forearm or leg. Lesions in the spine can be associated with neurologic dysfunction.
Malignant change should be suspected in patients with increasing pain, and unexplained growth after skeletal maturity. Malignant transformation is extraordinarily rare in children and quite rare in patients with solitary lesions. Patients with MHE, however, have substantial risk (3%–25%) that requires self-awareness as well as examination and clinical surveillance. Sessile lesions in axial locations (pelvis, hips, shoulders, scapula, and proximal femur) have a greater risk of malignant change than those in distal acral locations. Also, the overlying bursae may develop synovial chondromatosis that mimics malignant change on imaging.
Imaging
The radiographic features are characteristic and diagnostic, revealing pedunculated or sessile lesions arising from metaphysis and growing away from the joint with corticomedullary continuity. In MHE, 90% of the exostoses are sessile and only 10% are pedunculated. A constant radiographic feature is the presence of corticomeduallary continuity in contradistinction to entities, such as parosteal osteosarcoma or periosteal myositis ossificans, where the cortex is abutted by the lesion but intact and not in continuity with the medullary canal. The overlying radiolucent cartilaginous cap may be mineralized, a phenomenon that increases with age with corresponding thinning of the cartilage. In MHE, the affected bones are relatively short, whereas the metaphyses are enlarged ( Fig. 3 ). There is generalized cortical thinning throughout the body, not only in the regions involved by exostoses. These features contribute to affected patients having a “stocky” appearance with innumerable small bumps. In most individuals with MHE, the femoral neck is short and broad with multiple osseous excrescences, another diagnostic feature of this disease.
