Continuing Education Activity

A simple bone cyst is a solitary, benign, fluid-filled, cyst that may be a single chamber or septated. The most common sites are the proximal humerus and proximal femur. An aneurysmal bone cyst is a locally destructive, rare, blood-filled, benign cystic bone tumor that involves the metaphysis of long bones in children and young adults. Although they can involve any bone, the most common sites are the distal femur, proximal humerus, proximal tibia, and spine. Most cases present with mild to moderate pain. The rapid growth of lesion may mimic malignancy. This activity outlines the evaluation and treatment of bone cysts and highlights the role of the interprofessional team in caring for these patients.

Objectives:

• Describe the pathophysiology of bone cysts.

• Review the evaluation of a patient with a bone cyst.

• Summarize the treatment options for bone cyst.

• Outline the importance of collaboration and communication among the interprofessional team in distinguishing bone cysts on clinical and radiological presentations, which will lead to better patient outcomes.

Introduction

Bone cysts are often asymptomatic and found incidentally on radiographs (see Image. Tuberculosis Benign Bone Cyst, Radius, Ulnar). Sometimes, they may present with pain due to repeated hemorrhages or pathological fracture. Bone cysts are inclusive of but not limited to the simple/unicameral bone cyst (SBC/UBC) and aneurysmal bone cyst (ABC). 

A simple bone cyst is a solitary fluid-filled; a benign bone cyst which may be unicameral (single chamber) or septated. It can involve any bone of extremities, the most common site being proximal humerus and proximal femur (see Image. Bone Cyst in Proximal Femur).[1] In adults, the ilium and calcaneus are common locations. These lesions are most active during growth spurts and are known to heal spontaneously after bone maturity. Two-thirds of UBCs present with a fracture. UBCs in flat bones are often asymptomatic unless detected incidentally on imaging. 

An aneurysmal bone cyst is a rare, locally destructive, blood-filled, benign cystic bone tumor. It involves the metaphysis of long bones in children and young adults.[2] They can involve any bone, but the most common sites are the distal femur, proximal tibia, proximal humerus, and spine. Most cases present with mild to moderate pain. The rapid growth of lesion may mimic malignancy. Spinal lesions may cause radicular pain or neurologic deficits. They often involve posterior elements of the vertebral bodies. Exceptionally, ABC can also arise in soft tissue. See Image. Ankle Radiograph, Aneurysmal Bone Cyst (ABC).

Etiology

UBC seems to be a reactive bone lesion rather than a true bone tumor. It forms secondary to venous stasis in cancellous bone. Bone resorption occurs secondary to venous stasis, a buildup of pressure and increased inflammatory mediators in cyst fluid.[1]

ABC is a locally aggressive indeterminate tumor. It was thought to be caused by intraosseous hemorrhage because of venous stasis and bone resorption due to the activation of osteoclasts. However, this is no longer the accepted theory for primary ABC. Approximately 70% of primary ABC lesions are associated with recurrent chromosomal translocations causing gene fusions between ubiquitin specific peptidase 6 (USP6) and multiple genes.[3] Secondary ABC has correlations with a plethora of benign and malignant primary bone lesions like chondroblastoma, osteosarcoma, simple bone cyst, giant cell tumor, and telangiectatic osteosarcoma. These secondary ABC lesions lack chromosomal translocations.[4]

Epidemiology

UBC is a common lesion. Most commonly, these lesions occur during the second decade of life (approximately 85%), with a male to female ratio of 2 to 1.

ABC is rarer, at 1.4 per 10000 population per year, and accounts for 9.1% of all bone tumors.[5] There is a female preponderance, and 80% of these lesions occur in the second decade. Most occur in patients younger than 20 years. It is rare after 30 years of age.

Pathophysiology

Unicameral bone cyst: Typically, these lesions arise near the physis. As the years progress, it gradually grows away from the physis, and may remain as a static bone defect in diaphysis, or may resolve completely with time. Blockage of venous flow is the most favored hypothesis for cyst formation, which occurs in rapidly growing and remodeling bone. There are reports of a reduced partial pressure of oxygen in bone cyst as compared to arterial and venous blood which further supports the hypothesis of venous stasis.[6]

Aneurysmal bone cyst: ABC can show three different forms of evolutivity; quiescent, active, and aggressive. In some cases, ABC may undergo spontaneous resolution while in others they may become more aggressive mimicking fears of malignancy.

Primary: Comprising 70% of cases, ABC arises de-novo.

Secondary: In the other 30% of cases, ABC occurs in underlying bone tumors like giant cell tumor, simple bone cyst, chondroblastomas, osteoblastomas, fibrous dysplasia, nonossifying fibroma, and chondromyxoid fibromas.[1]

The classification and staging of ABC are according to morphological characteristics and behavior of lesions.

Enneking staging for benign bone tumors according to the behavior of lesion[7]:

• Inactive form: most benign, expansion is rare, minimal inflammation
• Active: Expansile lesion with cortical thinning, reactive bone formation, mild pain clinically
• Aggressive: Rapidly expansile, destructive, severely symptomatic

Capanna morphologic types of aneurysmal bone cyst[8]:

• Type 1: Central well contained a metaphyseal lesion
• Type 2: Lesion involving an entire segment of bone with cortical expansion and thinning
• Type 3: Eccentric metaphyseal lesion with no or minimal cortical expansion
• Type 4: Subperiosteal reaction with no or minimal cortical erosion
• Type 5: Periosteum displaced with the erosion of cortex and extension into cancellous bone

Histopathology

UBC: Grossly, cyst fluid appears clear yellow and serous unless there is a pathological fracture causing bleeding. Cyst fluid contains inflammatory mediators like prostaglandin, free radicals, interleukins, metalloproteins, and cytokines. The cyst wall lacks epithelial lining and forms from the fibrovascular stroma. Deep to this membrane lie fragments of immature bone, osteoclast giant cells, and mesenchymal cells. Fracture thickens the cyst wall with fibroblast, hemosiderin and reactive woven bone. Calcified cementum-like material in the cyst wall is found to be immature bone on immunohistochemistry.[9]

ABC: Grossly ABC is blood filled cavitary lesion with septations surrounded by a thin layer of cortical bone. Microscopically, it shows hemorrhagic tissue with cavernous spaces and cellular stroma. Lining consists of compressed fibroblast and histiocytes. The fluid contains chronic inflammatory cells, prostaglandins, and giant cells. A solid variant of ABC, called giant cell reparative granuloma, is also known.

History and Physical

UBC is often asymptomatic. Incidentally detected UBC in the femur or humerus is common. On occasions, pain can arise due to spontaneous fracture through the cyst.

ABC: Long bones and spine are mostly involved. Mild to moderate pain, present for weeks to months is the most common symptom which brings patients to the clinic.[10] Spinal lesion presents with back pain, scoliosis or torticollis. Soft tissue swelling may be present. Sometimes the patient presents with a fracture.

Physical examination shows tenderness, local swelling, and torticollis/scoliosis or neurological deficits in case of a spine cyst.

Evaluation

UBC:

Plain Radiograph: Well marginated, metaphyseal, juxtaepiphyseal, central cystic, purely lytic, moderately expansile lesion along the long axis of the long bone are usually diagnostic of UBC. The cyst never causes a cortical breach; prominent inner wall cortical ridges may give it the multiloculated appearance. There is no periosteal reaction. In case of fracture, there may be a small cortical fragment on the floor of cyst called a fallen fragment sign, which is considered pathognomonic of UBC with a fracture. UBC starts as a metaphyseal lesion, abutting the epiphysis in children. With time it moves into diaphysis. The lesion is considered as active when it is within 1 cm of the physis, and stable when closer to the diaphysis.

CT: shows thick-walled cysts with pseudoseptations. It is useful in assessing the fracture risk of cysts and imaging of adjacent involved structures.

MRI: shows T2 hyperintense cysts and gadolinium enhancement of cyst wall and septa.

Bone scintigraphy and positron emission tomography are inconclusive.

Cystography: is done to study venous drainage within the cyst.

ABC:

Primary Diagnosis: Suspect ABC on clinical examination and imaging:

Imaging characteristics: Radiograph reveals an expansile lytic, eccentric metaphyseal lesion, that remains contained by a thin cortical wall. The cyst can be well-marginated or mildly permeative mimicking malignancy. A smooth periosteal reaction usually covers the cyst. Bone scan shows peripheral tracer uptake and a central area of decreased uptake called "doughnut sign."

CT and MRI further help in delineating cyst characteristics, soft tissue involvement, and aggressiveness of a tumor. CT is particularly useful in delineating cysts in areas like spine and pelvis. When differentiating UBC and ABC on MRI, the presence of the double density fluid and intralesional septations indicates ABC. Imaging further helps in planning surgical management.

Diagnosis: Biopsy should take place in all cases for confirmation[2]. An optimal biopsy specimen is necessary for diagnosis. However, fine needle aspiration cytology is performed at some facilities by radiologists which are often inconclusive. Indication for biopsy is high clinical and radiological suspicion for ABC. Uncorrected coagulopathy disorders are relative contraindications.

Treatment / Management

UBC: Nonoperative management is the choice for mild symptoms. 

Small asymptomatic lesions in upper extremities are usually followed up with serial plain radiographs. Larger lesions at risk for fracture, symptomatic lesions,  and lower extremity lesions typically receive treatment with curettage or aspiration and injection (corticosteroids, bone marrow aspirates, bone matrix, and other materials). Pathological fractures in the upper extremity generally have conservative treatment. The priority of therapy is to treat the fracture first, typically by immobilization for 4 to 6 weeks. However, unstable fracture or fracture in weight-bearing areas like in the lower extremity, treatment involves both fracture fixation and treatment of the bone cyst.[11]

Treatment of all the other lesions is via non-aggressive options; techniques associated with preventive osteosynthesis. Injection of corticosteroid is one such option. The cyst is punctured with two needles and its contents aspirated with one needle, and radiological contrast is injected with the another, which is followed by injection with methylprednisone after emptying the contents. This also helps to differentiate from ABC. Cryptographic assessment showing the absence of venous drainage in the cyst rather than the presence of rapid venous outflow is a good prognostic indicator for treatment outcome with former showing better cyst healing.[12] This technique works by either its antiprostaglandin effect or by decreasing intracystic pressure. It demonstrates a success rate of more than 90%. 

Bone marrow aspirate and demineralized bone matrix injection avoids open bone curettage and grafting in 78% of cases with proximal humerus UBC, can be considered as an adjuvant to curettage.[13]

Elastic stable intramedullary nailing in case of long bones of children has shown promising results for the treatment of UBC.[14]

Current treatment concepts include a combination of decompressions, cyst wall disruption, injection with corticosteroid/demineralized bone matrix/bone marrow aspirate, and internal fixation in the weight-bearing region.[15]

Diagnosis is either incidental or prompted by a fracture. In both scenarios, ABC and underlying malignancy must be ruled before further management.

ABC: Treatment goal for ABC is the eradication of disease, prevention of recurrence and reduction of pain/ functional impairment. Surgical curettage and bone grafting with or without adjuvant therapy was classically the primary mode of treatment. However need for wide resection, disability, cost of rehabilitation post surgery and the benign nature of cyst has prompted to look for less aggressive treatment options.

Several minimally invasive treatments have emerged as an alternative to curettage including sclerotherapy with polidocanol, selective embolization of feeding vessel to the cyst and medical therapy with denosumab. Radionuclide ablation is also an option.[16][17] Preoperative embolizations also help to minimize surgical bleeding for lesions involving the spine and pelvis. When curettage is not possible due to difficult anatomy,  arterial embolization can be an option. Low dose radiation can cause rapid ossification of the lesion. However, it is less popular due to the risk of malignant transformation. However, it is sometimes used in surgically inaccessible recurrent spinal tumors.

Percutaneous injection of calcitonin and steroids under CT guidance has shown positive results. Repeated recurrences or development of any suspicious findings on imaging necessitate a more aggressive treatment.[18] Injection with an alcoholic solution of zein (corn protein), which possesses thrombogenic and fibrogenic properties, is a simple alternative; it makes open surgical treatment unnecessary by stopping the cyst growth and inducing new bone formation along the inner endosteal layer of the cyst.[19] Absolute alcohol also shows comparable treatment efficacy with a low complication rate. It may require repeated injections.

Differential Diagnosis

1. UBC and ABC affect the same age group, similar sites, and are fluid-filled cystic lesions making diagnosis difficult. However, ABC is more eccentric, aggressive, and shows increased trabeculations which help differentiate from UBC. Even so, traumatized UBC can be difficult to diagnose from primary ABC. In this case, a biopsy can be helpful; areas of cement-like substance indicate UBC while calcifying bluish fibrochondroid areas indicate ABC.[20]

2. Telangiectatic Osteosarcoma: These lesions show similar features as ABC radiographically. A biopsy is particularly essential to rule out osteosarcoma. Atypical cells, mitosis, and irregular osteoid matric are features of telangiectatic osteosarcoma. Molecular biology, using fluorescence in situ hybridization (FISH) will show rearrangement of USP6 in primary ABC.[1]

3. Giant Cell Tumor

4. Eosinophilic granuloma, osteoblastoma, malignant tumors

5. Nonossifying fibroma and solid ABC could appear similar

Other cystic bone lesions:

Intraosseous ganglion cyst: These typically occur at the ends of the long bones particularly distal tibia, knee, and shoulder. On x-rays, they appear as well marginated, unilocular or multilocular lytic defects with a thin rim of sclerosis. Treatment involves local excision and curettage.

Epidermoid cyst: These are cystic lesions that are filled with keratinous material and lined with squamous epithelium.

Prognosis

UBC: UBC develops in the metaphysis and gradually grows away from the physis and is known for spontaneous resolution, as evidenced by the fact that UBC is rare in adults.

Active cysts are those that are very near the growth plate while inactive cysts are those that have grown away from growth or not in direct contact with growth plate.[21] High-risk areas are those which may lead to significant disability like femur neck cyst, which if fractured may lead to necrosis and limb length discrepancy. Asymptomatic lesions with low risk for pathological fractures/inactive cyst are usually left alone. Most children present with pain due to pathological fractures through cyst. Growth discrepancy due to cyst pressure into growth plates, as a complication of cyst treatment very near growth plate, or fracture through femoral neck cyst may occur. All these may cause limb length discrepancy and deformities. Hence, the appropriate treatment protocol is crucial for the management of cysts. Curettage and bone grafting with internal fixation are reserved for larger, symptomatic lesions in high-risk areas like the femur. Other lesions are treated with percutaneous injections as described above. Poor prognostic factors for recurrence following percutaneous treatment include large size, multilocation, active lesions, and age younger than 10 years.

ABC: Recurrence rate after curettage of ABC is approximately 10 to 20%. Age younger than 15 years, central location, and incomplete removal of the cystic cavity are known risk factors for recurrence. Complete surgical resection is reserved for more dispensible bones like the clavicle and fibula, where partial bone excision does not cause any significant long term morbidity.

Complications

The following complications may accompany these lesions[1][22][1]:

1. Pathological fracture: The main complication of SBC is a fracture. Pain, younger age of presentation, proximal humeral lesion, change in the size of a cavity with age, distance from growth plate, multiple septations, and early recurrence are signs of an active cyst and increased fracture risk
2. Pain
3. Malignant transformation is rare in UBC. Rare cases of malignancies have been reported several years after the treatment of ABC
4. Arthritis
5. Pressure symptoms
6. Growth disorder: Limb length discrepancy or axial deviation may be induced in children if cysts transgress the physis or involve the epiphysis
7. Recurrence: No treatment guarantees complete cure except for complete surgical resection - the post-treatment recurrence rate in case of UBC is about 10 to 30%; hence, the least aggressive treatment is the initial option
8. Aggressive surgical treatment for femoral neck lesions has generally been advocated given the dreaded complications associated with pathological femur neck fractures (like avascular necrosis, residual coxa vara, etc.).
9. General risks related to management of cysts: Unanticipated residual structural deformity and functional disability,  and injury to adjacent vital structures (e.g., neurovascular) can occur

Deterrence and Patient Education

It is of extreme importance to educate the patients and primary caregivers in case of pediatric patients regarding the benign course of the tumor; and what to expect with regard to deformity, disability, complications, and recurrence following treatment. The parents should also receive counsel regarding different treatment options and the risk and benefits of these treatment modalities. The role of patient counseling and family support in ensuring appropriate health care delivery to these patients cannot be understated.

Pathological fractures: Pathological fracture is present in approximately 75% of cases of UBC at the time of presentation (which is, in fact, the most common cause of pathological fracture in children).[23][24]

Mirel's criteria are used to predict a high risk of pathological fracture among long bones in case of lytic/sclerotic lesions (typically malignant pathologies). It consists of the following components: site, location, matrix, and presence or absence of pain. It has a minimum score of 4 and a maximum score of 12. A score of more than 9 suggests the necessity of prophylactic fixation.[25] Mirel's criteria can be useful to predict fracture risk in the bone cyst and to plan appropriate management by the health care team.

Enhancing Healthcare Team Outcomes

Good knowledge of clinical/radiological presentations of bone cysts; as well as possible distinguishing features from other bone tumors presenting as lytic lesions of the bone is of utmost importance in appropriate medical planning and management of these lesions. Although orthopedic surgeons play a pivotal role in the management of these patients, appropriate inputs from pediatricians, family physicians, radiologists, pathologist, orthopedic surgeons, and physiotherapists are necessary at different stages of management. Nurse practitioners are involved in home care management when pathological fractures are managed conservatively. 

Inter-departmental co-operation and planning of treatment protocols in consultation with patients, physicians, nurses, and social workers enhance team performance and patient care. A majority of our knowledge on this topic has its basis in level IV or V evidence.