Successful treatment of a C2 aneurysmal bone cyst with hydroxyapatite and calcium sulfate synthetic bone void filler injection: a case report

Introduction

Aneurysmal bone cyst (ABC) is a destructive, expansile and benign neoplasm of the bone, composed of multiloculated blood-filled cystic spaces (1). These lesions can be classified as primary or secondary, with the latter defined as arising from other primary bone tumors such as giant cell tumors (GCTs), chondroblastomas, osteoblastomas, or telangiectatic osteosarcomas. They represent approximately 1% of all primary bone tumors, with female and patients younger than 20 years mostly affected (2). According to the Enneking staging system, most ABCs appear as locally aggressive tumors, with the majority falling into grade 2 or 3 (3). Macroscopically, they appear as “blood-soaked sponge”-like expansile lesions. Histologically, they comprise endothelium-lined, blood-filled cysts surrounded by fibrous tissue containing histiofibroblasts, giant multinucleated cells, capillary vessels, and immature bone trabeculae. Treatment strategies for ABCs encompass various approaches, with en bloc excision as the surgical treatment with the lower rate of tumor relapse while selective arterial embolization (SAE) as the most effective non-surgical treatment (2). Of all ABCs, 10–30% originate in the mobile spine, accounting for 1.5% of primary spine tumors. Upper cervical spine ABCs present unique challenges due to the peculiar anatomy surrounding the lesion: deep shunts with vertebral arteries, proximity to vital spinal cord nuclei, involvement of the spine’s most mobile joint (C1–C2). Due to their extension at both posterior and anterior column, surgical access is intricate and often necessitates a two-stage approach, possibly including the transoral route (4). Craniovertebral junction ABCs resection can jeopardize spinal stability, necessitating upper-cervical or craniocervical fixation to maintain stability. This case illustration focuses on a 25-year-old woman treated at our institution for a C2 ABC. We explore the reasons for avoiding surgical removal of the lesion, discussing the failure of conservative pharmacological, endovascular and direct intracystic treatments. We also highlight the role of bone void fillers in the treatment of ABCs, especially at the craniocervical junction. We present this case in accordance with the CARE reporting checklist (available at https://jss.amegroups.com/article/view/10.21037/jss-24-16/rc).

Case presentation

Clinical history

A 25-year-old female patient, without relevant previous medical history, presented to the outpatient clinic with complaints of axial mechanical cervicalgia and dysesthesias on the left side of her neck and left mandibula from 2 months. Reduced cervical axial rotatory range of motion and a palpable mass on the left part of the neck were documented during the visit.

Imaging examination

Diagnostic imaging, including magnetic resonance image (MRI) and computed tomography (CT) scans (Figure 1), revealed an osteolytic mass centered at the posterior arch of C2 which involved spinous process, lamina bilaterally, left pedicle and left vertebral body. An angio-MRI with TOF sequences revealed intratumoral arterial blood supply from the left vertebral artery (VA) which was almost surrounded by the tumor. Standard MRI scans demonstrated an isointense lesion in T1-weighted images, patchy hyperintensity in T2-weighted images, multiple fluid-fluid levels, and patchy enhancement following contrast administration. The Spinal Instability Neoplastic Score (SINS) was 9, Enneking stage 3 and Weinstein-Boriani-Biagini (WBB) 6-11/B. A percutaneous biopsy confirmed the diagnosis of primary ABC. Considered lack of instability (SINS 9) and neurological deficits, a multidisciplinary consultation involving neuroradiologists, oncologists, radiotherapists, and interventional radiologists guided the decision to pursue non-surgical treatments.

Figure 1 Preoperative MRI and CT-scan. (A) Contrast enhancement sagittal T1-weighted MRI which shows patchy enhancement. (B) TOF axial sequence shows left VA subtotal encasement without invasion. (C) Coronal bone CT-scan shows involvement of left lateral mass without invasion of the C1–C2 capsule or displacement of the normal C1–C2 articulation. (D) Axial bone CT-scan shows an osteolytic lesion characterized by a thin bone layer delimiting the lesion. MRI, magnetic resonance image; CT, computed tomography; TOF, time-of-flight; VA, vertebral artery.

Management

Despite considered the non-surgical gold standard (5), transarterial embolization was not initially performed due to the presence of multiple anastomoses between both deep cervical artery, the main feeder of the lesion, and the VA, resulting in a high risk of posterior cerebral circulation embolism.

Following some successful cases described in literature (6,7), we decided to start denosumab administration. Therefore, the patient received a standard cycle of subcutaneous Denosumab injections, with a dosage of 120 mg administered on days 1, 8, 15, and 29, followed by injections once every 4 weeks. Nevertheless, a 6-month CT-scan showed increased dimensions of the lesion and unchanged osteolytic appearance (Figure 2).

Figure 2 CT-scan after denosumab administration shows an interval change. (A) Pre-denosumab sagittal bone CT-scan passing through the body. (B) Post-denosumab sagittal bone CT-scan. (C) Pre-denosumab axial bone CT-scan. (D) Post-denosumab axial bone CT-scan. CT, computed tomography.

Despite high risk of ischemic complications, it was decided to proceed with transarterial embolization using EVOH copolymers (ethylene vinyl alcohol, non-adhesive permanent embolic material). Given the angioarchitecture of the neoplasm (Figure 3), Squid 12 was used, as its increased fluidity was believed to facilitate better penetration of the liquid inside the lesion. A total volume of 4.5 mL of squid was injected into the arterial feeders using balloon catheters to minimize potential reflux; uncontrollable anastomoses with the vertebrobasilar circulation were occluded by coils (Figure 4). Due to the numerous anastomoses between the primary arterial feeders and the ipsilateral VA (Figure 3C,3D), achieving complete occlusion of the lesion was considered impractical. A satisfactory yet incomplete occlusion of the arterial feeders supplying the lesion was achieved (Figure 4B-4D). Follow-up MRI and CT scans at 1-, 6- and 18-month intervals documented the dimensional stability of the lesion, with minimal sclerotization in the left part of the vertebral body and the caudal-posterior part of the lesion (Figure 5).

Figure 3 Selective angiography. (A) Left VA coronal selective angiography shows vascularization to the mesial and left part of the lesion. (B) Right VA coronal selective angiography shows vascularization to the right and mesial part of the lesion. (C) Left deep cervical artery sagittal selective angiography shows anastomosis with ipsilateral VA. (D) Right deep cervical artery sagittal selective angiography shows anastomosis with ipsilateral VA. VA, vertebral artery.

Figure 4 SAE of VA and ascending cervical artery. (A) Coils were placed to exclude the main anastomosing vessel between right VA and right deep cervical artery to prevent SQUID12 backflow. (B) Digital unsubtracted angiography shows SQUID12 in the right and mesial part of the lesion. (C,D) Sagittal and coronal plane balloon microcatheter in the left deep cervical artery to occlude the residual anastomosis with VA, to inject SQUID12 and to prevent reflux. SAE, selective angiography embolization; VA, vertebral artery.

Figure 5 Follow-up MRI and CT-scan showed stable tumor dimension and morphology after SAE. (A) 6-month sagittal CE T1-weighted MRI. (B) 6-month sagittal bone CT-scan. (C) 18-month bone sagittal CT-scan. (D) 18-month bone axial CT-scan. Red arrows pointing at the lesion. MRI, magnetic resonance image; CT, computed tomography; SAE, selective angiography embolization; CE, contrast-enhanced.

Given SAE ineffectiveness, following some positive reports in the literature (8), we decided to proceed with experimental intralesional administration of centrifugated iliac crest bone marrow (mesenchymal stem cells-Stem-G2, Novagenit, Mezzolombardo, Italy). This involved four procedures, each spaced 2 months apart, conducted using CT-guided (Medtronic O-arm, S8 stealth) needles to ensure access to the most left anterior portion of the lesion (Figure 6). Nevertheless, a follow-up CT-scan (Figure 7) conducted at the end of the fourth injection did not reveal any dimensional differences or variation in bone mineralization. A second angiography procedure, performed 2 years after the initial one, did not indicate revascularization of the lesion and the small remaining hypervascular component appeared to be vascularized only by muscular branches of the vertebral arteries. Therefore, no further endovascular treatment was undertaken due to the high procedural risk.

Figure 6 Centrifugated bone marrow harvest and injection. (A) Bone marrow harvesting. (B-D) The needle was connected to a navigated probe and matched to the reference. (E) Centrifugated bone marrow navigated injection. (F,G) CT-navigation allowed centrifugated bone marrow injection in the deeper part of the lesion. CT, computed tomography.

Figure 7 O-ARM axial CT-scan at last centrifugated bone marrow injection revealed stable dimension and morphology of the lesion. (A) Axial bone CT-scan at the level of C2 body. (B) Axial bone CT-scan at the caudal part of the lesion corresponding to C3 body. Red arrows pointing at the lesion. O-ARM, (O-arm O2, Medtronic, Inc., Minneapolis, MN, USA); CT, computed tomography.

Finally, the patient underwent an experimental injection of a small amount (5 mL) of biphasic bone void filler to promote internal ossification of the lesion. The rationale for employing it was the young age of the patient, the surgical risks, known bioactive properties which could lead to bone reformation, restoration of spine support and pain relief (9). Injection of Hydroxyapatite and Calcium Sulfate Synthetic Bone Void Filler (CERAMENT^® BONE VOID FILLER-BONESUPPORT AB, Lund, Sweden) was performed. Surgical team included a senior neurosurgeon and a senior interventional radiologist. The procedure was performed under sedation, with rotational images acquired using angiography and the use of a 13G needle biopsy to inject 5 mL of the biphasic bone void filler onto the safest routes of the aneurysmatic cavity (i.e., pedicles and lamina, away from the vertebral canal), which uneventfully occurred. Follow-up CT-scans, performed 6 months and 1 year after the procedure, documented nearly complete remineralization of the lesion, characterized by a ground-glass morphology [Neer score I (10)]. There was reformation of cortical bone, which limited the spinal canal without causing compression on the spinal cord and the BCBS injected, in line with its biochemical properties, left no radiographic artifacts (Figure 8). Upon completion of the therapeutic process, the patient exhibited no focal sensory-motor deficits with resolution of mechanical cervicalgia/neck dysesthesias. She reported psychological relief from the successful conclusion of the long-onset medical condition (almost 4 years) which did not require surgery.

Figure 8 Vertebroplasty follow-up CT-scan. (A,B) Sagittal and axial multiplanar reconstruction of rotational-DSA at the end of BCBS injection. (C,D) Sagittal and axial bone CT-scan at 6 months showing near complete bone remineralization and the absence of artifact due to BCBS. CT, computed tomography; DSA, digital subtraction angiography; BCBS, biphasic ceramic bone substitute.

All procedures performed in this study were in accordance with the ethical standards of the Institutional and/or National Research Committee(s) and with the Helsinki Declaration (as revised in 2013). Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Discussion

ABCs are benign yet locally aggressive bone tumors, accounting for 10–30% of tumor cases in the mobile spine. Of those, 22–42% occur in the cervical spine, while rarely at the cranio-cervical junction. Managing ABCs in the upper cervical spine presents significant challenges due to the complexities associated with treatments and the risks of recurrence.

Observations

This article illustrates the case of a young adult woman with a C2 ABC. Despite various non-surgical approaches that were initially unsuccessfully attempted, a novel off-label vertebroplasty utilizing a bone void filler ultimately proved effective. En bloc marginal resection is considered the gold standard for ABC treatment, as it offers the lowest risk of recurrence (2). This approach necessitates the removal of the entire cyst and the surrounding pathological tissue. While technically feasible, this task is particularly challenging when dealing with ABCs in the cranio-cervical junction due to the risks of neurological complications, cerebrospinal fluid leakage, oral cavity fistulas, infections and damage to major vessels. As they often affect both the anterior and posterior vertebral elements, a combined anterior (i.e., transoral route) and posterior surgical approach with stabilization is often necessary to achieve complete tumor resection, which may result in a significant reduction in cervical range of motion.

Less invasive surgical strategies, such as intralesional excisions, are associated with an increased recurrence risk ranging from 6% to 22% (11). Given the variability of ABC presentations, the optimal treatment approach should be tailored to individual patients and should consider patient’s opinion.

Factors to consider include tumor location, patient age, neurological deficits, associated deformities, the presence of pathological fractures, and instability resulting from tumor erosion or postoperative complications.

Surgical intervention is mandatorily reserved for cases with neurological compromise, pathological fractures, anticipated postoperative instability, or preoperative instability (12,13), or when managing cases with a history of previous treatment failure marked by the onset of instability, neurological symptoms, or an increase in tumor volume (14).

Preoperative instability should be determined with SINS (15). In cases where none of these conditions are present, there is a growing preference in the literature for non-surgical management.

Despite the similar expression of RANKL, Denosumab has been recommended by the AOSpine Knowledge Forum Tumor and has been approved by FDA as a standalone or adjuvant treatment for GCTs but not for ABCs (16). As a result, many authors have advocated its experimental use (17,18). Literature lacks consensus regarding the optimal treatment duration, suggesting at least 12 months for pediatric patients (13). Following the criteria established by Kurucu et al. (7), we defined Denosumab inefficacy as an increase in tumor volume observed on 6-month CT-scan.

Regarding SAE, Boriani et al. consider it the best non-surgical ABCs treatment (2). While three out of four patients achieved healing without additional treatments, the fourth experienced a 12-month local recurrence. Moreover, the same authors do not recommend SAE when the ABC feeding-arteries have branches leading to the spinal cord or when there are anastomoses with the VA or ascending cervical arteries or when anterior spinal artery originates from the same or nearby vascular pedicle as the tumor-feeding arteries. Moreover, repeated SAE has been reported as less effective than anticipated, with 26% of patients eventually requiring surgery (14).

Ehlers et al. documented a C2 ABC with complex connections to the VA via branches from the deep cervical and ascending cervical arteries, increasing the risk of post-procedural ischemia (19). Thus, SAE is limited in certain anatomical locations, such as high cervical and dorso-lumbar spine levels, because of anastomosis with critical arteries. In line with those evidences, SAE in the present case was meticulously attempted to avoid EVOH copolymer reflux. Given the lack of ossification at follow-up CT-scans and the impossibility to obtain complete embolization without posing significant risk of reflux, we aborted further procedures.

An emerging approach involves the use of autologous bone marrow concentrate (BMC) which is rich in mesenchymal stem cells and demonstrated regenerative and osteoinductive capabilities in other bone cystic lesions (20). A case-series involving 46 ABCs located in the pelvis and long bone metaphysis has shown promising results. Only one patient required surgical treatment, with more than 50% achieving full recovery after a single injection (21).

Similarly to our case, Barbanti-Brodano et al. reported two pediatric cases of C2 ABC treated with autologous bone marrow injections. Ossification of the lesions was observed at 27 months, and patients reported relief from symptoms (8). Despite similarities to our case, we did not achieve the same result even after multiple injections of autologous centrifugated bone marrow and dubbed this treatment, among the abovementioned others, ineffective in our case.

Therefore, we explored alternative experimental strategies aimed at bone remodeling, structural support restoration, and pain relief. Recent studies have examined the use of biphasic ceramic bone substitute (BCBS) powders, composed of hydroxyapatite (HA) and calcium sulfate hemihydrate, in the treatment of cystic bone lesions, demonstrating a low recurrence rate and minimal complications (10,22). The product is now FDA and CE approved for bone void filling. Calcium sulfate acts as an osteoinductive, resorbable carrier for HA, which has a slow resorption rate and promotes bone in-growth, providing long-term structural support. Its porosity allows for cell, fluid, and growth factor penetration, leading to bone formation and, ultimately, to spinal column support and pain relief.

An 18 patients-case series from Döring et al. reports BCBS percutaneous injection into cystic bone tumors, including 3 long-bone ABCs (9). A 2-month CT scan revealed subcortical bone reformation around the cysts, with recalcification inside the cysts evident at the 6-month scan. This resulted in bone reformation, nearly normal vertebral body height restoration, fracture healing, and pain relief. BCBS has shown some degree of unsuccess. In this case-series 6 patients were observed to have BCBS leakage; however, because of material property, it fully reabsorbed without consequences. One patient had major septic complication that needed BCBS removal and curettage. Two ABCs patients needed reoperation because of relapse, at 4 and 9 months, respectively. Also, Horstmann et al. documented 2 cases of ABCs relapse necessitating further treatments (10). However, in the case we presented here, follow-up is 1 year to-date and no relapse has been observed. Both Döring et al. and Horstmann et al. reported postoperative soft-tissue inflammation around the surgical site the most common complication which spontaneously disappeared after few days.

Notably, Döring et al. used BCBS to fill bone defects resulting from curettage (9), while we used it as a standalone procedure. To our knowledge, the only previously documented case of an ABC successfully treated with a stand-alone injection of BCBS has been reported by Guarnieri et al. (23).

To date, the utilization of BCBS in the treatment of ABCs has shown few complications, rendering it a safe treatment option.

Patient perspective

I received the diagnosis of a C2 ABC back in November 2019 when I complained about neck pain, in particular on the left side of my neck. Radiological examination and neurosurgical visit confirmed the lesion which implicated to consider that my neck was unstable, so I started wearing a cervical collar to prevent any form of aggravation.

It is hard to describe any emotions of those years, but I’m pretty sure about one thing: I entrusted the surgical and neuroradiological team for the treatments and the agreed approaches. During the following 4 years, I went through several interventional procedures under general anesthesia and pharmacological treatments with subcutaneous injection of an experimental medicament. Each post-anesthesia awakening was filled with sadness and hope. Nonetheless, after the first several attempts and after numerous “hospital trips”, radiological follow-up did not show any sign of remission, on the contrary it showed a slow progression of the disease.

At a certain point, I thought I would have to live with it for a long time and that there was no solution. During these years I drastically changed my routine: from being hyperactive, I became extremely calm and careful with every movement. I started to be afraid even of the possibility that a hug might hurt me. I asked myself: why do I have to change my life for something that has no solution? My family and friends’ support was crucial: with irony, love and encouragement I relieved the severity of the situation.

Despite everything, I continued to hope and trust in the team’s choices. I supported their decisions about any treatments.

Finally, the latest procedure executed (an experimental cementification of the vertebra) showed the ossification of the cyst and I felt like this pain was going to end. I know that I have to keep doing with follow-up visits and CT-scans, but I finally removed the collar, I don’t feel neck pain anymore and I returned to my hyperactive life, also playing sports again. Four years is a long time; years of my life which cannot be back: it costs me sacrifice, pain and patience. Now I feel good and happy, although the thought of eventual regression doesn’t leave me.

I’m sure that my case will help the resolution of all subsequent eventual patients.

Thanks for everything!

Limitations

Despite our success, given the study design, the result of our case can’t be generalized, but further studies aimed at exploring the role of BCBS and validating its use in ABCs are encouraged. Besides, although radiological findings during the previous 2 years FU dubbed the former procedures ineffective, a possible adjunctive role of SAE, denosumab and centrifugated bone marrow injection to the BCBS administration cannot be excluded. Although a median time-to-relapse of 9 months in the case series by Döring et al. (9), follow-up length is this case is limited at 1 year and still ongoing.

Conclusions

Unlike previous reports, our case represents the first instance of employing BCBS for the treatment of an ABC at the craniocervical junction. While repeated SAE is reported to be the most effective non-surgical option for managing ABCs, it poses a high risk when dealing with upper cervical spine due to the intricate connections to vertebral arteries, ASA, or ascending cervical arteries, which can lead to ischemia and neurological deficits. Among experimental treatments, such as denosumab administration or centrifugated bone marrow injections, vertebroplasty using BCBS shows distinctive advantages. It requires only a single session to achieve the desired therapeutic effect. Furthermore, the resorbable nature of calcium sulfate eliminates artifacts in follow-up CT scans or MRIs, ensuring clear identification of potential disease relapse. Additionally, it allows for the restoration of bone structure, including a cortical layer that defines the spinal canal, making it a feasible option for ABC with pathological fractures. Consequently, vertebroplasty with BCBS can broaden the scope of non-invasive treatment options for managing ABCs. Considering these benefits, we propose vertebroplasty with BCBS as a primary alternative to SAE for managing ABCs that are not suitable for gross-total resection.

Acknowledgments

Funding: None.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://jss.amegroups.com/article/view/10.21037/jss-24-16/rc

Peer Review File: Available at https://jss.amegroups.com/article/view/10.21037/jss-24-16/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jss.amegroups.com/article/view/10.21037/jss-24-16/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the Institutional and/or National Research Committee(s) and with the Helsinki Declaration (as revised in 2013). Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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