(From the May 2013 Issue of PediatricsOnline)
Aneurysmal bone cyst is a highly destructive lesion in bone, representing 1 to 6 percent of all solid bone tumors. The term “aneurysmal” refers to the explosive, expansile nature of the bone containing the aneurysmal bone cyst, similar to dilation and expansion seen with aortic aneurysms.
Simulation of percutaneous drug delivery to tibial aneurysmal bone cyst.
Approximately 70 percent of aneurysmal bone cysts are primary lesions, with the remaining 30 percent occurring coincidentally with other bone lesions, such as giant cell tumor, osteoblastoma, chondroblastoma, hemangioma, fibrous dysplasia and telangiectatic osteosarcoma. These tumors most often present in the first two decades of life, with the most common locations including the humerus, tibia, fibula, skull, femur and spine. Approximately 8 to 30 percent are encountered in the spine, most often involving the posterior elements of the spine. Previously considered to be an idiopathic bone cyst consisting of multiple honeycomb blood-filled locules, it is now known to represent a clonal benign neoplastic tumor of bone. Most often, it is the result of translocations of the #16 and #17 chromosomes, resulting in the formation of a highly destructive oncogene. The aneurysmal bone cyst oncogene upregulates the development of destructive solid fibroproliferative stroma, giant cell-like osteoclasts and vascular spaces. In addition, the oncogene upregulates expression of matrix metalloproteinase that attacks and destroys the underlying collagenous matrix of bone. Furthermore, the translocation oncogene upregulates the expression of Vascular Endothelial Growth Factor (VEGF) that recruits blood supply for this destructive tumor, similar to the pattern of bone destruction seen with metastatic breast and prostate cancer.
The majority of aneurysmal bone cysts present as a large network of blood-filled cystic spaces. However, 3 to 7.5 percent of aneurysmal bone cysts are predominantly solid tumors with small vascular spaces. Traditionally, the treatment for these cysts relied on surgical curettage of the bone cysts with bone graft placement, and gross-total excision or amputation if there is recurrence after curettage. Aneurysmal bone cysts present unique surgical challenges, often with large amounts of blood loss during surgery, and recurrence following surgical management in 12 to 71 percent of cases (71 percent in children under age 5 years). These therapeutic challenges led to the development of pioneering diagnostic and treatment solutions in the Department of Radiology at Nationwide Children’s, in conjunction with the Department of Orthopedic Oncology in The Ohio State University Wexner Medical Center.
Precise Diagnostic Imaging and Targeted Percutaneous Biopsy
Diagnostic imaging has traditionally relied on a combination of plain radiographs, CT scan, nuclear medicine bone scan and MRI. Of all these modalities, MRI is the imaging modality of choice for global assessment of the extent of the aneurysmal bone cyst, especially in the spine, to determine the extent of spinal cord and nerve compression. MRI routinely detects the multiple blood-filled locules and intercommunicating septa. Studies at Nationwide Children’s demonstrate, for the first time, the value of gadolinium contrast enhancement of the solid tumor cells lining these cysts. Furthermore, the Department of Radiology at Nationwide Children’s has pioneered the use of sonography as a highly specific imaging modality for localization of solid tumor nodules in the aneurysmal bone cysts for targeted core needle biopsy. This clear ultrasound visualization also allows for precise treatment mapping for targeted percutaneous (minimally-invasive, needle access) tumor ablation. Research investigations confirmed with pathologic proof that the septa (seen on ultrasound and MRI) separating the cystic locules indeed represent “solid” elements of the destructive tumor requiring treatment (in addition to the sonographically visible solid tumor nodules). Given this constellation of diagnostic findings, precise biopsy and therapeutic regimens are designed at Nationwide Children’s to specifically target the “solid” tumor elements of the aneurysmal bone cyst. These have resulted in cures not previously reported in the medical literature.
In the past, radiologists relied on fine needle aspiration of the blood filling these cystic locules for attempted biopsy. This biopsy technique resulted in pathologic reports documenting “blood products and occasional hemosiderin-laden macrophages” as the common report. There would be no mention of definitive tissue yield of fibroproliferative stroma (with vascular spaces) and giant cell-like osteoclasts (three definitive histologic features of aneurysmal bone cyst). Fine needle aspiration for biopsies produced a documented zero percent yield of “three definitive histologic feature” biopsies. Since introducing integrated contrast-enhanced MRI and sonographic imaging and pre-planning, the diagnostic yield of “three definitive histologic feature” biopsies is now 86 percent for all aneurysmal bone cysts (cyst walls and nodules), along with 94 percent for those with core biopsies of solid tumor nodules.
When aneurysmal bone cyst was considered to be either an idiopathic cyst, or a form of bone venous malformation, alternatives to surgical treatment involved percutaneous sclerotherapy of the cysts attempted with alcohol solution of zein and polidocanol, with success rates ranging from 58 percent to 94 percent, and complications including pulmonary embolism, skin necrosis, pain, swelling and fever. Prior to therapeutic discoveries at Nationwide Children’s, there was no percutaneous therapeutic regimen consistently delivering outcomes of 90 percent or greater success, without the above-described complications.
When designing therapy for aneurysmal bone cysts, radiologists at Nationwide Children’s took the following into consideration. The ideal therapy would kill the fibroproliferative stromal cells, inhibit or kill the giant cell-like osteoclasts, inhibit angiogenesis (VEGF activity), inhibit matrix metalloproteinase cell destruction and trigger the body to reabsorb the dead tumor cells and heal the bony location of the tumor destruction. The therapeutic regimen would ideally be performed as an outpatient procedure with minimal recovery time and should relieve the bone pain produced by these cysts, all without a significant risk of infectious complications. If treatment would involve injection of a drug into the cysts and solid nodules, the drug should be able to be clearly visualized with image-guided techniques, to include fluoroscopy, CT and ultrasound guidance, Ideally, the drug would be inexpensive, readily available and injected in a sustained-released form that prolong the therapeutic effect of treatment and prevents rapid washout of the ablation drug in the aneurysmal bone cysts vascular spaces.
Radiology investigators at Nationwide Children’s have developed a highly successful percutaneous drug delivery system that meets all of the above mentioned criteria for successful treatment. Researchers discovered that doxycycline (a readily available, inexpensive antibiotic) has chemotherapeutic properties that specifically target and cause necrosis of the fibroproliferative aneurysmal bone cyst stromal cells. Other investigators discovered that doxycycline causes apoptosis (programmed cell death) of the giant cell-like osteoclasts in these cysts. Doxycycline inhibits angiogenesis and matrix metalloproteinase. Researchers have documented relief of aneurysmal bone cyst pain, most often following one treatment session. Doxycycline is an anti-staphylococcal antibiotic, providing excellent protection from skin-related staphylococcus infections (none reported in more than 230 treatment sessions). To date, all 60 patients treated with doxycycline have responded with tumor necrosis and bony healing.
All children with aneurysmal bone cysts adjacent to their growth plates have demonstrated healing of the cysts and normal growth of adjacent bone, with no injury to the bone growth plate. Doxycycline is known to stimulate bone healing cells (osteoblasts), and all 60 patients have demonstrated new bone healing, with 71 percent demonstrating return of the bones to their normal size and shape. Nationwide Children’s researchers have developed a novel doxycycline drug delivery system that produces a stable protein foam that results in a sustained release doxycycline delivery for prolonged tumor killing action of the aneurysmal bone cysts and prevention of rapid drug washout from the cysts. None of the 60 patients (some treated after surgical recurrence) have required surgery for further treatment, and specifically for those with cysts in the spine. None have had spinal fusion with resultant limitation of motion or activity.
Diagnostic and treatment breakthroughs at Nationwide Children’s have converted clinical expectations for patients from those of frustration and uncertainty to precision planning and execution with predictable healing and healthy outcomes. Thorough understanding of aneurysmal bone cyst pathology, innovative drug design and delivery, and commitment to clinical excellence combine to offer aneurysmal bone cyst patients new options, new treatments and new hope for cures.
Case Study: Female Teen
A teenage girl, who was succeeding in high school both socially and academically, began suffering with frequent neck pain and headaches. She was able to push through her pain until it became increasingly worse when she tilted her head to the left. A CT scan demonstrated an aneurysmal bone cyst with complete destruction of the left half of her second cervical vertebra, and no bony protection over the spinal cord in this dangerous location. A neurosurgeon described the most optimistic surgical option, which included extensive surgery, to remove the diseased bony segment in this highly sensitive location, and permanent spinal fusion, with hope for no recurrence. The neurosurgeon recommended a second opinion consultation at Nationwide Children’s. After considering the interventional radiology plan for definitive biopsy and treatment, and evaluating prior results that Dr. Shiels and his team at Nationwide Children’s had provided, the neurosurgeon, patient and her parents elected to proceed with the minimally-invasive interventional radiology biopsy and treatment.
Two years following a series of outpatient treatments, the patient’s neck has fully healed with strong bone fully protecting her spinal cord. She has full mobility and use of her neck.
William E. Shiels II, DO, is chairman of the Department of Radiology at Nationwide Children’s and president of the The Children’s Radiological Institute. Dr. Shiels is a clinical professor of Radiology, Pediatrics, and Biomedical Engineering at the Ohio State University College of Medicine. Dr. Shiels is the clinical professor of Radiology at The University of Toledo Medical College and Visiting Scientist at the American Institute of Radiologic Pathology, Washington, DC. Additional references for this article are available upon request.
Recent Presentations Related to This Topic:
Percutaneous Biopsy and Treatment of Aneurysmal Bone Cysts
AOCR Annual Conference
Palm Beach, FL
11-15 April, 2011
Musculoskeletal Interventional Techniques Guided by Ultrasound
Rio de Janeiro, Brazil
4-7 September, 2011
Pediatric Musculoskeletal Invasive Sonography: New Opportunities for Care
Central Ohio Ultrasound Society Meeting
10 September, 2011
Therapeutic Challenges and Successes in Pediatric Interventional Radiology
Grand Rounds – University of British Columbia
Vancouver, BC, Canada
28 September 2011