The ABCs of Aneurysmal Bone Cysts: Is there a Role for Radiation Therapy?

1. Introduction

Aneurysmal bone cyst (ABC) is a benign, expanding, osteolytic lesion comprised of varisized blood-filled spaces separated by connective tissue septae containing trabeculae, osteoid tissue, and osteoclast-like giant cells (1- 4). This distinct clinical entity derived its name from its initial description by Jaffe and Lichtenstein in 1942. They named these “peculiar blood-containing cysts of large size” as “aneurysmal bone cysts”- using “aneurysmal” to emphasize the “blown-out”, distended contour of the affected bone; and “bone cyst” to describe how the lesion appears as a blood-filled cavity when entered through a thin shell of bone (5-6). This is now known to be a misnomer, as ABCs are neither true vascular aneurysms, nor true cysts.

2. Pathophysiology

The exact nature nor pathophysiology of the ABC, to date, remain elusive. Dabska and Buraczewski in 1969 were the first to describe its natural history, which they divided into four phases. The initial phase entails osteolysis of the marginal part of the bone with the elevation of the periosteum. The growth phase involves progressive destruction of bone. This is then followed by the stabilization phase which gives rise to the classic appearance of ABC as an expansile lesion with a distinct bony shell and osseous septations. Finally, the healing phase gives rise to progressive ossification of the lesion, thus giving rise to an irregular, bony mass (7).

Historically, Lichtenstein posited that the ABC is not a true neoplasm but, rather, a reactive lesion wherein the vascular disturbances in bone lead to increased intraosseous pressure, which subsequently causes local destruction and distention of the bone (6). This is supported by the findings of a later study by Camapanacci et al. which proposed that ABCs are secondary to an initial insult which in turn produces intraosseous bleeding which, subsequently, leads to the formation of a cyst. The cyst walls may contain capillaries that hemorrhage into the cavity, producing osteolytic and fibrotic tissue that would ultimately explain the lesion’s characteristic histopathology (8).

Many cases of ABC, however, are without history of any- at least recalled- trauma. Indeed, emerging evidence has seen genetics to be implicated in the pathogenesis of ABC, furthering the hypothesis that, rather than being a reactive lesion, it is in fact a true neoplasm. In a histopathologic study, Oliveira et al. found that 69% of primary ABCs (i.e., ABCs not associated with a preexisting bone lesion) were associated with translocations in chromosomes 16 and 17 causing the juxtaposition of CDH11 and USP6. No such translocations were observed in secondary ABCs (9). Given these findings, up to 70% of ABCs are considered primary lesions, and 30% believed to be secondary to a different primary tumor which triggered the initial vascular insult (10).

3. Epidemiology and Presentation

ABCs are rare, with incidence rates ranging from 1.4 to 3.2 per million individuals (9,11-12). These lesions have been reported from ages ranging from 1 to 59 years old; however, up to 80% occur in patients less than 20 years of age (13). Males are slightly more often affected than females, with ratios up to 1.8:1.0. (11-12). Majority of ABCs- 50 to 60% arise in the metaphysis of long bones, particularly the tibia and fibula. The second most common location is in the bony spine and sacrum.

The most common presenting symptoms of ABCs are pain, soft-tissue swelling, and/or a palpable expansile mass. (15). Because ABC is a benign disease, systemic symptoms such as fever, weight loss, malaise, nausea, and/or vomiting are uncommon (16).

On computed tomography (CT) imaging, ABCs appear as well-demarcated, multiloculated, expansile, osteolytic lesions. MRI delineates these features more exquisitely, in addition to the internal septations as well as the lesion margin. ABCs are heterogeneously enhancing with a surrounding rim of low T1 signal. (1,13,16-17).

Figure 1. CT scan of an 8-year-old male with aneurysmal bone cyst of the left ischium. Coronal view shows a large, expansile, lucent bone lesion in the left inferior pubic ramus and ischium with internal septations. Margins are well-defined and measures approximately 4.5 x 2.9 x 8.3 cm. Image courtesy of Dr. David Cuete. https://radiopaedia.org/cases/aneurysmal-bone-cyst-of-ischium?lang=us

Figure 2. MRI of a 10-year-old female with aneurysmal bone cyst of the left proximal ulna. Sagittal T2-weighted image shows an expansile lesion in the proximal ulnar metadiaphysis with extension to the epiphysis. The lesion displays multiple cysts with fluid/fluid leveling. Image courtesy of Dr. Ahmed Abdrabou. https://radiopaedia.org/cases/aneurysmal-bone-cyst-8?lang=us

4. Treatment Modalities: Old and New

The preferred treatment modality for ABCs is surgery via intralesional curettage and bone grafting. The performed curettage can range from either the creation of a small fenestration to a large cortical window in the cyst to complete saucerization (16). A retrospective review by Gibbs et al. (1999) of ABCs of the extremities found that 4 of 34 ABC patients (12%) who underwent simple curettage had a local recurrence, whereas no patient who underwent complete cyst excision had a recurrence. (24).

Emerging minimally invasive treatment approaches include cryotherapy, sclerotherapy, and arterial embolization. Cryotherapy- the localized application of low temperatures to ablate or destroy the tissue in question- has been found to reduce the recurrence rate of ABCs. Peeters et al. (2009) reviewed 80 cases of ABCs located in various sites treated with cryotherapy and, at an average follow-up of 55 months, found an overall local recurrence rate of only 5% (25). Similarly, a single-institution review by Schreuder et al. (1997) found, among 27 ABC patients, a local recurrence rate of only 3.7% (26).

Sclerotherapy capitalizes on the theory that ABCs arise as vascular malformations. A retrospective review by Rastogi et al. (2006) of 72 patients with ABC treated with percutaneous sclerotherapy with polidocanol found a clinical response rate of 84.5% (27). In a similar vein, Varshney et al. (2010) reviewed 94 ABC patients treated either with curettage and bone grafting or sclerotherapy. With an average follow-up of 4.4 years, patients treated with curettage and bone grafting had an 84.8% healing rate compared to 93.3% among those treated with sclerotherapy. Recurrence rates were the same; however, the sclerotherapy group reported better functional outcomes with fewer complications (28).

Selective arterial embolization is likewise emerging as an alternative and novel therapeutic modality. A retrospective review by Rossi et al. (2010) of 36 patients with ABCs treated with arterial embolization noted complete clinical and radiologic response in 94% of patients. However, of these, 14 required more than one session of embolization. Furthermore, two cases of skin necrosis- one necessitating flap coverage- were reported (29).

5. The Role of Radiation Therapy: Emerging Evidence and Unanswered Questions

The role of radiation therapy (RT) in the management of ABCs is less well-defined and still emerging. RT has been used either in the definitive (as an alternative to surgery) or adjuvant setting for recurrent, aggressive, medically inoperable, or unresectable cases. A retrospective review was conducted by Zhu, Hitchcock, and Mendenhall (2015) of 12 patients with ABC who received curative-intent RT with or without prior surgical interventions at the University of Florida from February 1964 to June 2011. Eight (66.7%) of these patients were treated with definitive RT alone without prior surgeries and/or chemotherapy.

The total prescribed doses ranged from 20 to 60 Gy (median of 30.15 Gy) delivered via a variety of beam energies including 2-, 6-, 8-, 17-, 20-MV photons; and Cobalt-60. Interestingly, intensity modulated radiation therapy (IMRT) was used only for one patient, reflecting the fact that this RT modality still was unavailable prior to the 1990s. All but one patient were treated once per day, 5 days per week consecutively. 83.3% of patients received between 1.5 to 2.0 Gy per fraction. The radiation fields were targeted at the volume indicated by radiographs with a margin ranging from 1-3 cm.

With a follow-up duration spanning 3-36 years (median of 20.5 years)- to date the longest among studies exploring the role of RT in ABCs-RT was found to be well-tolerated in all 12 patients. 41.7% experienced only mild RT-related side effects: mild skin reaction in 16.7%, nausea and vomiting in 16.7%, and mild edema in 8.3%. All of such symptoms resolved upon completion of RT. Remarkably, pain relief was achieved for all patients 2-4 weeks upon completion of RT; 16.7%, in fact, even reported pain relief even before the RT course had concluded.

Resolution of the ABC cavity begins with gradual ossification of the soft tissue component. Post-RT radiographs revealed that the soft tissues inside the cystic cavity undergo ossification immediately after RT and may continue for up to 2 years post-RT. The ABC cavity in 16.7% of patients decreased to less than half of the original size; the sizes remained stable for the rest of the patients. This retrospective review, therefore, reported a 100% local control rate for RT, used either alone as definitive treatment or adjuvantly (18).

The outcomes reported in Zhu, Hitchcock, and Mendenhall’s retrospective review are consistent with those of other older studies and case series. Bisecker et al. (1970) reported 4 cases of ABC treated with RT alone and 7 cases treated with RT for post-curettage recurrence. The reported 4-year local control rate from RT was 90.9% compared with 55% for surgery (19).

Marcove et al. (1995) reported a case series of 11 ABCs treated with primary RT alone. A local control rate of 90.9% was reported for RT and only 63.2% for surgery. However, one patient developed radiation-induced sarcoma. (20). A later case series by Boriani et al. (2001) explored 18 patients treated with RT, either alone or postsurgery) found a 0% rate of recurrence after at least 2 years of follow-up. However, 9 incidences of bony deformity were noted.

Indeed, the surveyed literature shows that RT offered outcomes that were just as good as, if not better than, surgery. Despite these promising data, however, there remains hesitation in using RT for ABCs, most especially for the pediatric population among whom majority of ABCs arise, because of the aforementioned isolated cases of chronic late effects and second malignancies. Retrospective series of pediatric patients treated with older radiotherapy machines and modalities two to three decades prior report a cumulative incidence of secondary radiation-induced malignancies ranging from 9.3 to 19% at 30 years postradiation (30-32). However, Feigenberg et al. (2001) and Marks et al. (1976) assert that such incidences are likely due to the suboptimal radiation treatment received by these patients, precluded by the now-obsolete radiation equipment and techniques reported in these studies. (21-22)

5. Conclusion

The potential role of radiation therapy for aneurysmal bone cysts (ABCs) – whether in the definitive or adjuvant setting- remains an active area of research. To date, there remains a dearth of literature on ABCs treated with radiation; what little data is available is largely derived from case reports and series. Nonetheless, this data is promising- revealing satisfactory local control rates with acceptable toxicities for ABCs treated with radiation. This is despite the fact that these reports were largely crafted in the pre-IMRT era. Since then, the field of Radiation Oncology has expanded exponentially. Radiation doses have become more conformal, treatment delivery has become more precise and reproducible, and knowledge of normal tissue constraints and toxicities has become more refined. Hence, more data in the present era- even in the form of case reports or serieswould doubtless shed more light and define the yet-emerging role of radiation therapy in the treatment of ABCs.

Abbreviations:

ABC – Aneurysmal bone cyst

CT – Computed tomography

Gy – Gray

IMRT – Intensity-modulated radiation therapy

MRI – Magnetic resonance imaging

MV – Megavoltage

RT – Radiation therapy

Statements:

Author’s contributions: JHZ, KSY, and APC conceived of the discussed topic; JHZ drafted the initial paper; KSY and APC made the final revisions to the final paper.

Consent for publication: As the corresponding author, I confirm that the manuscript has been read by and approved for submission by all authors.

Funding: This study did not receive any specific grant from the funding agencies in the public, commercial, or not-for-profit sector.

Conflicts of Interest: The authors declare no conflict of interest.

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