➢ Polyostotic skeletal lesions represent a multitude of non-neoplastic, benign, and malignant conditions.
➢ In children, adolescents, and young adults, chronic recurrent multifocal osteomyelitis, Langerhans cell histiocytosis, polyostotic fibrous dysplasia, and enchondromatosis can present as multifocal skeletal lesions.
➢ In adults, skeletal metastases, multiple myeloma, osteitis fibrosa cystica, and Paget disease can present as multifocal skeletal lesions.
➢ The evaluation of such patients must begin with a comprehensive history, physical examination, and radiographs.
➢ When there is concern regarding polyostotic disease, a bone scan is often of great utility for the identification of all sites of skeletal disease and for monitoring disease progression or regression.
The approach to skeletal lesions has been well described1-3. Nevertheless, these lesions remain intimidating to both clinicians and patients. This is particularly true in the setting of polyostotic lesions, which can represent a metastatic process. Although it is imperative to consider this diagnosis, especially in adults, multicentric skeletal lesions can be the manifestation of a plethora of processes, ranging from non-neoplastic and benign conditions to more devastating malignant lesions and metastatic disease (Table I). In order to ensure accurate diagnosis and treatment, orthopaedic surgeons must be familiar with these conditions and the necessary workup. This article presents the approach to polyostotic disease while also reviewing some of the more common conditions presenting as multicentric skeletal lesions.
Presentation and Evaluation
There are many ways in which patients with polyostotic lesions present to orthopaedic surgeons. Some patients already will have had imaging studies performed, whereas others are being seen for the first time. Regardless, a thorough history and physical examination must be performed as it is only with the combination of a history, physical examination, and imaging that a differential diagnosis can be appropriately formulated.
Once a lesion is identified, a bone scan is useful for identifying the extent of skeletal involvement. Although a multitude of other imaging studies can be performed (e.g., magnetic resonance imaging [MRI], computerized tomography [CT]), they are not always indicated. Laboratory workup, in addition to biopsy of the lesion, can at times provide additional insight into a disease but also may be unnecessary.
The examination and radiographic findings, the indications for advanced imaging, and the need for other diagnostic adjuncts are often disease-specific. They will be discussed within each of the upcoming sections.
Osteitis Fibrosa Cystica
Osteitis fibrosa cystica is a rare consequence of severe, untreated primary or secondary hyperparathyroidism, which leads to uncontrolled osteoclast activation and subsequent bone resorption4. Although hyperparathyroidism is most commonly due to a parathyroid gland adenoma (seen in 80% to 85% of patients), hereditary factors, renal osteodystrophy, and carcinoma are other known causes5. Osteitis fibrosa cystica is rare in developed countries as early diagnosis and effective treatments limit the adverse sequelae of hyperparathyroidism6.
Females are more commonly affected than males, with symptoms most often manifesting during the fifth and sixth decades of life7. Generalized symptoms of hyperparathyroidism include obtundation, nausea, constipation, fatigue, and weakness. As with many polyostotic conditions, the musculoskeletal symptoms of osteitis fibrosa cystica are nonspecific and include extremity pain, tenderness, swelling, and/or the inability to bear weight. With axial skeleton involvement, localized or radicular pain may be evident7.
On radiographs, hyperparathyroidism presents as diffuse osteopenia with multiple, poorly defined metaphyseal lytic lesions. Classic findings include erosion of the radial aspects of the phalanges (Fig. 1) and resorption of the symphysis pubis, distal part of the clavicle, and vertebral bodies8. Advanced imaging is not required for diagnosis but may be performed as part of the general evaluation of an adult patient with lytic skeletal lesions.
Laboratory studies can help to confirm the diagnosis. Along with the increased level of parathyroid hormone, the levels of serum calcium, phosphate, and alkaline phosphatase are elevated. In equivocal cases, biopsy is indicated and can assist with diagnosis.
Treatment of osteitis fibrosa cystica is focused on addressing the underlying etiology of the hyperparathyroidism. Tumors typically resolve with control of the metabolic disease7.
Paget disease is a disorder of skeletal remodeling that is due to increased osteoclastic resorption and an associated compensatory increase in bone formation9. The axial skeleton and the long bones of the lower extremities are most often affected. Although Paget disease is a non-neoplastic process, Paget sarcoma is a rare but malignant sequela that occurs in <1% of cases, most frequently in the femur, pelvis, humerus, and craniofacial bones10.
Paget disease is rarely diagnosed in individuals who are less than fifty-five years old, with men being more commonly affected than women9,11. A familial predisposition also has been observed, with a four-times greater risk among those with an affected first-degree family member12.
Patients are usually asymptomatic, with the diagnosis typically based on incidental radiographic findings. Symptomatic patients have pain at involved sites. In joints associated with pagetic bone, degenerative arthritis occurs as a result of the accelerated remodeling of the affected bone. Patients with spine involvement may have a radiculopathy or, in the most severe cases, cauda equina syndrome13. Any acute onset or exacerbation of underlying pain can be indicative of fracture or malignant transformation. Also concerning for malignant transformation is the presence of a soft-tissue mass in the vicinity of a skeletal lesion. The extraskeletal manifestations of Paget disease are numerous and include hearing loss, congestive heart failure, gout, and loosening of teeth. Metabolic complications can be seen in patients with polyostotic Paget disease and include hypercalciuria and hypercalcemia14.
The radiographic features of early Paget disease include osteolytic metaphyseal lesions, whereas the features of late disease include the more traditional sclerotic lesions, trabecular coarsening, and cortical thickening (Fig. 2, A). With advanced disease, lesions progress and are evident in diaphyseal bone as well. Secondary osteosarcoma is associated with cortical destruction and/or the presence of a soft-tissue mass on radiographs. A bone scan should be made when there is concern about Paget disease and is effective for determining the extent of disease (Fig. 2, B)9,15.
Patients with active Paget disease exhibit increased alkaline phosphatase levels and otherwise normal laboratory findings. The alkaline phosphatase levels correlate with the extent of skeletal involvement and the stage of disease as indicated on bone scans. Diagnosis is based on clinical, radiographic, and laboratory assessments. Biopsy is only indicated in unclear cases or cases in which malignant transformation is suspected.
Bisphosphonates are the first-line treatment for symptomatic Paget disease as they suppress the increased bone turnover seen in association with active disease15. Severe side effects are uncommon but include renal injury, uveitis, rash, atrial fibrillation, osteonecrosis of the jaw, and atypical femoral fractures. Alternatively, calcitonin can be employed as it inhibits bone turnover and has been shown to be effective for relieving the bone pain and neurologic sequelae of Paget disease16. Operative treatment may be indicated for patients with end-stage osteoarthritis, pathologic and impending fractures, and severe spinal stenosis. Impaired fracture-healing has been observed in patients with Paget disease, resulting in delayed union and nonunion15.
Chronic Recurrent Multifocal Osteomyelitis
Chronic recurrent multifocal osteomyelitis is an inflammatory bone disease of unclear etiology that is associated with recurring episodes of an aseptic process that resembles osteomyelitis both clinically and radiographically. Chronic recurrent multifocal osteomyelitis can occur in conjunction with other autoimmune diseases, such as psoriasis and inflammatory bowel disease, and also may have a hereditary predisposition17. It typically affects children between the ages of four and fourteen years, but cases in adults have been reported18.
The classic presentation involves a healthy child with complaints of insidious bone pain that is worse at night. Fevers and other constitutional symptoms are variable. Although swelling and warmth can occur over affected areas, objective findings are rarely observed on examination. Involvement of as many as twenty sites at a time has been observed, with the metaphyseal regions of the long bones, clavicles, and vertebral bodies most frequently involved19-21.
The child with suspected chronic recurrent multifocal osteomyelitis should be evaluated with radiographs of all symptomatic sites. The traditional findings resemble infectious osteomyelitis and include metaphyseal lytic lesions abutting the physes in the early phase and more reactive lesions with surrounding sclerosis and periosteal reaction in the late phase (Fig. 3, A and B). The involved sites also should be evaluated with MRI, which is the most sensitive modality for determining the extent of bone and soft-tissue involvement, both during the diagnostic workup and at the time of follow-up22. As a surveillance tool in the setting of presumed chronic recurrent multifocal osteomyelitis, MRI can help in the identification of lesion progression and the need for biopsy. Admittedly, MRI is at times misleading and can make nontumorous processes, such as chronic recurrent multifocal osteomyelitis, appear more aggressive and even malignant in nature.
Laboratory studies reveal variable elevations in the white blood-cell count and inflammatory markers. Blood and bone cultures are negative. The diagnosis is ultimately made after the exclusion of infection.
The treatment of chronic recurrent multifocal osteomyelitis is empiric. Although nonsteroidal anti-inflammatory drugs (NSAIDs) are effective in the majority of cases, patients with vertebral involvement and/or radiographic evidence of arthritis at the time of presentation are typically less responsive to this intervention20. As a second line, short courses of oral corticosteroids, methotrexate, sulfasalazine, colchicine, and azithromycin may be used. Bisphosphonates and biologic agents (tumor necrosis factor and interleukin-1 [IL-1] inhibitors) are increasingly being used in refractory cases22. For each of the aforementioned pharmacologic interventions, treatment success is based on the relief of symptoms.
Benign Neoplastic Conditions
Polyostotic Fibrous Dysplasia
Fibrous dysplasia is thought to develop during skeletal formation. It is caused by both a disruption in the remodeling process in which primitive bone becomes mature bone and a failure of bone to realign in response to mechanical stress. The result is a collection of immature and isolated trabeculae encased in dysplastic fibrous tissue that never completely remodels23,24. Its etiology has also been associated with a mutation in the Gsα gene, the product of which serves various roles in cell signaling. Although a benign condition, malignant transformation occurs with an estimated prevalence of 0.4% to 4%25.
Fibrous dysplasia manifests in children and adolescents as either a monostotic or polyostotic process, with the monostotic type being more common24. Monostotic lesions expand in proportion to skeletal growth and cease to enlarge at skeletal maturity. The polyostotic type, albeit less common, produces more severe deformities via lesions that may continue to enlarge after skeletal maturity. Polyostotic lesions are most frequently found in the femur, tibia, pelvis, and foot25.
Unlike monostotic disease, polyostotic fibrous dysplasia is often symptomatic, with complaints of localized bone pain, deformity, and/or pathologic fracture being reported by adolescence. Of note, female patients may complain of increased pain during pregnancy and while menstruating as estrogen receptors have been shown to play a role in fibrous dysplasia26.
Polyostotic fibrous dysplasia can present as part of McCune-Albright and Mazabraud syndromes. In McCune-Albright syndrome, patients undergo precocious puberty, have café au lait spots on the trunk and proximal aspects of the limbs, and have polyostotic lesions that are larger and more symptomatic than those in patients without the disease. Mazabraud syndrome is a rare disorder in which the lesions of fibrous dysplasia are seen in conjunction with intramuscular myxomas25.
Radiographs show intramedullary metaphyseal and diaphyseal lesions with a ground-glass appearance and sclerotic border. Involved bones also may exhibit cortical expansion and endosteal scalloping and resorption (Fig. 4, A). Coxa vara is a classic radiographic finding in patients with fibrous dysplasia and manifests as a so-called shepherd crook deformity on radiographs. For patients with newly diagnosed cases, a bone scan should be done to assess for polyostotic disease (Fig. 4, B). When radiographic findings are characteristic of fibrous dysplasia, biopsy is unnecessary. However, in equivocal cases, biopsy has diagnostic utility.
Treatment depends on disease severity and symptoms. Asymptomatic patients are often observed with surveillance radiographs every six months to assess lesion progression. Surgical intervention is indicated for deformity correction (Fig. 4, A), prevention of pathologic fracture, stabilization of fracture, and/or eradication of symptomatic lesions. Lesion curettage and bone-grafting is an effective means of preventing fracture and decreasing pain due to symptomatic lesions. Cortical grafts should be used as they persist much longer than cancellous grafts, which are replaced by the dysplastic bone characteristic of fibrous dysplasia27.
In patients with polyostotic disease, the lesions are often too numerous to treat with curettage and bone-grafting. In such cases, bisphosphonates have been shown to successfully decrease the radiographic size of lesions, pain, and the rate of pathologic fractures28. When severe deformity and/or a high risk of fracture is present, surgical intervention is indicated (Fig. 4, A).
Langerhans Cell Histiocytosis
Langerhans cell histiocytosis is a rare condition that primarily affects pediatric patients, with most new diagnoses in children between the ages of one and fifteen years29. Langerhans cell histiocytosis is known by several different eponyms that vary on the basis of disease severity. Specifically, eosinophilic granuloma involves a solitary lesion; Hand-Schüller-Christian disease is defined by the triad of skull lesions, diabetes insipidus, and exophthalmos; and Letterer-Siwe disease is a fatal disease of infancy in which disseminated lesions lead to multisystem organ failure.
Langerhans cell histiocytosis has a highly variable presentation. However, the skeleton is the most commonly affected part of the body29. The vertebral bodies, cranium, ribs, mandible, and long bones are frequently implicated30. Asymptomatic lesions are often found incidentally, whereas painful lesions prompt patients to seek care. The extraskeletal manifestations are common and are associated with integumentary, pulmonary, and endocrine system involvement.
On radiographs, the radiolucent lesions of Langerhans cell histiocytosis manifest in many ways; some are more permeative in nature, whereas others are more sharply defined (Fig. 5). Advanced imaging modalities such as MRI are therefore of great utility as they provide more detailed depictions of lesions. This added detail is of great benefit to the clinician with regard to focusing an otherwise broad differential diagnosis, which may include osteomyelitis, Ewing sarcoma, and osteosarcoma. Following MRI, a bone scan can be performed to evaluate for polyostotic involvement.
Formal diagnosis requires histologic evaluation and should be performed when diagnosis is unclear on the basis of imaging, history, and examination. Microscopically, lesions exhibit accumulations of eosinophils, lymphocytes, and macrophages as well as the presence of the so-named Langerhans cells. Langerhans cells are normally antigen-presenting cells of the skin; their unusual presence in Langerhans cell histiocytosis lesions of other tissues is essential for diagnosis.
The treatment of Langerhans cell histiocytosis is determined by the extent of disease. Skeletal lesions may be treated with observation, surgical curettage, intralesional corticosteroid injection, and/or NSAIDs. For patients with spine involvement, bracing can help to provide short-term relief of symptoms. Chemotherapy, systemic corticosteroids, and bisphosphonates are being employed for patients with more severe cases of multisystem and polyostotic disease31.
Enchondromatosis is a rare condition with an estimated prevalence of one case per 100,000 individuals32. There are two subtypes: traditional enchondromatosis and Ollier disease. The traditional variant affects mostly men, is transmitted in an autosomal dominant fashion, and is characterized by enchondromas located throughout the extremities33. The second subtype, referred to as Ollier disease, affects mostly women, is sporadic, and is characterized by a unilateral distribution of enchondromas. When multiple enchondromas are seen in conjunction with soft-tissue hemangiomas, the condition is referred to as Maffucci syndrome34.
The benign cartilage tumors of enchondromatosis and its various subtypes develop in the metaphyses of long bones. Although a benign condition, malignant transformation of these tumors into secondary chondrosarcomas can occur. This risk is greater in those with Maffucci syndrome as compared with Ollier disease34-37. In one series, six malignancies developed in six of thirty-seven patients with Ollier disease whereas ten malignancies developed in four of seven patients with Maffucci syndrome; the malignancies included chondrosarcoma, osteosarcoma, astrocytoma, and visceral adenocarcinoma36.
The clinical manifestations of enchondromatosis often appear in the first decade of life, with the presence of a palpable osseous mass on a finger or toe or shortening of an extremity with limping being some of the more common presentations. In other instances, enchondromatosis is asymptomatic and is diagnosed incidentally.
Radiographs demonstrate long, oval, and calcified intramedullary lesions. Calcifications are scattered throughout lesions and can appear stippled or ring-like (Fig. 6, A and B). As the lesions evolve, the clinician may notice migration from a metaphyseal to more diaphyseal location. In the most severe cases, deformity such as shortened diaphyses and extreme metaphyseal bending will be evident (Fig. 6, C). Pathologic fractures can also occur. Although solitary enchondromas are most often well-defined, those associated with polyostotic disease can have more dysplastic features, making them difficult to distinguish from their malignant counterparts. The radiographic features worrisome for malignant transformation include cortical erosion, extension of the tumor into soft tissues, ill-defined tumor borders, and the absence of calcification within the lesion.
The diagnosis of enchondromatosis is dependent on clinical and radiographic assessment. Advanced imaging is only indicated for the evaluation and monitoring of lesions that become symptomatic or concerning for malignant transformation. Biopsy is not required for diagnosis. Although biopsy is performed when there is concern regarding malignant transformation, it may be of only limited utility because of the histologic similarities between the benign lesions of enchondromatosis and low-grade chondrosarcoma, both of which demonstrate substantial cellular heterogeneity and chondrocyte diversity34.
Enchondromatosis should be followed with observation. There is no medical treatment. Orthopaedic surgery is indicated when deformity (Fig. 6, C), pathologic fractures, and malignant transformation occur.
Multiple Myeloma and Metastatic Skeletal Disease
Multiple myeloma and metastatic skeletal disease can present as polyostotic processes. Although multiple myeloma is the most common primary malignancy of bone, metastatic disease is the most common reason for multiple destructive, radiolucent bone lesions in patients older than forty years of age3. Metastatic bone disease is most commonly caused by breast, lung, thyroid, renal, and prostate carcinomas. Skip lesions are a less common form of skeletal metastasis that occur in the setting of primary bone tumors (e.g., osteosarcoma). These lesions are defined as synchronous and smaller foci of tumor occurring in the same bone as the primary lesion or on the opposing side of a joint. They are important to distinguish from the more traditional metastatic skeletal disease secondary to the aforementioned extraskeletal malignancies as they are treated differently.
Myeloma and metastatic diseases rarely affect individuals younger than forty years of age. The median age at the time of diagnosis of myeloma is sixty-five years38. The initial presentations of myeloma and metastatic disease are highly variable and range from early detection of localized lesions to late detection of disseminated disease.
Radiographic findings at the time of presentation are common in patients with multiple myeloma39. The typical myeloma lesion is a “punched-out” radiolucent lesion, with a sharp zone of transition and an absence of surrounding reactive bone (Fig. 7)39. Metastatic lesions are also usually lytic and similar in appearance to those of multiple myeloma. However, both myeloma and metastatic disease can also present with more destructive, osteolytic lesions. Blastic metastases also can occur and are seen in patients with prostate and breast cancer.
A multitude of laboratory and imaging studies are used to determine the origin of a skeletal lesion in an adult. Crucial laboratory studies include a complete blood-cell count, inflammatory markers (erythrocyte sedimentation rate, C-reactive protein level), serum and urine protein electrophoresis, comprehensive metabolic panel, thyroid-stimulating hormone, and prostate-specific antigen in men. Radiographs of the entire involved bone; bone scanning; and CT of the chest, abdomen, and pelvis with intravenous and oral contrast medium are performed in search of the primary malignancy and/or additional skeletal lesions.
A myeloma-specific workup, including serum beta-2-microglobulin and immunofixation studies, a skeletal survey, and bone marrow biopsy, must be initiated when electrophoresis is positive. A skeletal survey is necessary because bone scans often fail to identify myeloma-associated lesions40. Negative bone scans in this setting occur because technetium uptake is dependent on an osteoblastic response, which does not occur with multiple myeloma. The bone marrow biopsy is usually performed concurrently with the skeletal survey and is consistent with myeloma when there are ≥10% monoclonal plasma cells in the aspirate41.
In addition to the traditional responsibilities of performing tissue biopsies and treating pathologic and/or impending pathologic fractures, orthopaedic surgeons also provide unique insight into the skeletal lesions affecting patients with presumed malignant skeletal disease. While practitioners of other medical specialties may assume that a polyostotic lesion in a patient with a known history of cancer is metastatic disease, the orthopaedic surgeon understands that metastatic disease is only one of many potential diagnoses, with benign and non-neoplastic conditions also being possibilities. Such unique insight underscores the importance of the orthopaedic surgeon in not only the treatment but also the evaluation of these patients.
Polyostotic lesions transcend all ages and demographic categories and are associated with a plethora of non-neoplastic, benign, and malignant conditions. As such, these lesions can be perplexing to orthopaedic surgeons, posing diagnostic and management dilemmas. A succinct but comprehensive approach is thus crucial. The history, physical examination, and radiographs are of paramount importance as subtle but unique findings are at times present that can help to focus an otherwise broad differential diagnosis. Bone scans are also of great utility and can aid the clinician in the identification of polyostotic involvement. When armed with an understanding of the approach to and a familiarity with the common conditions that manifest as polyostotic disease, orthopaedic surgeons will be positioned to perform the appropriate workup and to facilitate optimal care.
Source of Funding: None of the authors received any funding related to the development and production of this manuscript.
Investigation performed at the Division of Orthopaedic Surgery, Albany Medical College, Albany, New York
Disclosure: None of the authors received payments or services, either directly or indirectly (i.e., via his or her institution), from a third party in support of any aspect of this work. None of the authors, or their institution(s), have had any financial relationship, in the thirty-six months prior to submission of this work, with any entity in the biomedical arena that could be perceived to influence or have the potential to influence what is written in this work. Also, no author has had any other relationships, or has engaged in any other activities, that could be perceived to influence or have the potential to influence what is written in this work. The complete Disclosures of Potential Conflicts of Interest submitted by authors are always provided with the online version of the article.
- Copyright © 2014 by The Journal of Bone and Joint Surgery, Incorporated