1 Introduction

A Giant Cell Tumor (GCT) is a benign intramedullary tumor of the bone that accounts for approximately 5% of all primary bone tumors in adults.¹ While most GCTs occur at the ends of long bones, 6% occur in the sacrum.² By the time a diagnosis is made, sacral tumors are often large and can be entangled in local structures. Surgical treatments that are successfully utilized in long bones, such as intralesional curettage or complete or partial resections, are therefore complicated in the pelvis as they often threaten neurological and vascular structures. Because of this, optimal treatment of sacral GCTs, remains unclear.³ Denosumab is a monoclonal antibody that inhibits the interaction between RANK and RANKL, preventing osteoclast differentiation. The recent use of Denosumab in treating GCTs has provided a means for reducing tumor volume in cases where surgery is not a viable option. Denosumab has been shown to be an effective treatment both in a neoadjuvant setting and as a sole treatment course when resection is not a possibility.⁴ In a study administering continuous bimonthly Denosumab treatment, 66% of patients remained stable after 10 months of follow-up.⁵ As a long-term therapy, however, the ideal doses and duration to manage the tumor while minimizing potential side effects is still unknown.⁴ In GCTs with extensive involvement of the pelvic bone, in situ image guided cryoablation offers an alternative approach that is minimally invasive and has proven to be effective both in tumor ablation and for palliative care.⁶ A previous study on image guided cryoablation in spinal osteoid osteomas and osteoblastomas demonstrated the potential for customized 3D printed intraoperative instruments (i.e., jigs) to further enhance this treatment.⁷ In complicated procedures where the risk of injury to adjacent structures is high, 3D planning optimizes the treatment approach, elevating the safety and efficacy of the procedure. Here we report on the application of a novel workflow in which a 3D printed customized jig is used in the pre-operative planning and the execution of in situ image guided cryoablation in a 27-year-old female suffering from GCT of the sacrum.

2 Case description

I.M was a 23-year-old female who had been experiencing two years of ongoing back pain. The pain began in her first pregnancy and resolved with the use of painkillers. However, over the course of her second pregnancy, during which she had lost 20 kg, the pain returned. For four more months she suffered from lower back and pelvic pain as well as right drop foot and left leg weakness. At this point the patient was hospitalized at a local hospital and underwent a CT guided biopsy where she was diagnosed with Giant Cell Tumor of the sacral bone with a secondary aneurismal bone cyst (Fig. 1). The patient was then transferred to Tel Aviv Sourasky Medical Center (Tel Aviv, Israel) for further treatment. At this time, it was decided that the patient was not a suitable candidate for surgical intervention. Due to the size and characteristics of her tumor, wide resection of the tumor to avoid local recurrence would have led to a total sacrectomy. Because the morbidity and mortality associated with this procedure was too great, she was instead treated with Denosumab. For six years, from the time of her diagnosis in 2012 until her procedure in 2018, the patient was admitted to the hospital over forty times, most of the time in order to receive her treatment. Every 2–3 months, the patient returned to the hospital for 125 mg of Denosumab treatment. The patient responded well to the Denosumab and no side effects from this treatment were noted. In 2015 the patient underwent a debulking surgery and afterwards she was also admitted due to recurrent infection exacerbations that occurred at the surgical site on her right pelvis as well as for exacerbations in her pain and certain falls. These infections were treated with surgery to wash out the wound site along with antibiotic treatment. Over the course of this time, treatment was complicated due to lack of patient compliance however during this period the patient's tumor remained stable.

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Fig. 1 An axial CT showing a 144.3*125.3 mm GCT tumor with a volume of 1092.93 cm^3 located in the sacrum from 2012.

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In March of 2018 the patient presented to the hospital with intensifying pain in her leg and discharge from a wound in her lower back as well as a fever. Due to low compliance for her Denosumab therapy, the patient's tumor had progressed in the pelvis and now included nerve roots S1-3 on both the right and left side. At this point it became clear that her Denosumab treatment was no longer sufficient. She received pain killers and the decision was made to perform an in situ cryoablation procedure with 3D planning. Additionally, the patient received a psychosocial workup to assess her emotional state due to the fact that she was suffering from chronic pain that accompanied her illness. At the time she was on antidepressants and anti-anxiolytics. Three months later, the procedure was performed.

3 Methods

3.1

3.1 Preparation of the navigation jig

Initially, the surgeon S.D provided a medical engineer with a computerized tomographic (CT) scan of the pelvis at 0.5–1 mm thickness. The 2D images were imported into an FDA-approved image-processing software (Mimics®, Materialise, N.V. Leuven, Belgium, or Intellispace Portal V9 and V11, Philips Healthcare, Best, Netherlands). The images were merged and segmented to produce a 3D digital model that contained the precise bone anatomy and tumor borders. The PSI mainly covered the spinous process at levels S2–S4 and the bilateral laminas of S3 (see Figs. 2 and 3). Following the segmentation, the model was exported as an STL file into an FDA approved CAD software (3-matic®, Materialise N.V.). A navigating jig was designed based upon the desired cryoablation needles (Fig. 2). After the engineer completed the virtual planning, it was reevaluated and approved by the surgeon S.D, and then the cutting jig was printed from biocompatible, high-strength and thermal-resistant material (ULTEM™ 1010 resin) by a Fused Deposition Modeling (FDM) printer (Fortus 450 mc, Stratasys, Eden Prairie, Minnesota; Rehovot, Israel). Finally, the jigs were washed, double-packed, and underwent a standard autoclave sterilization process before being brought into the surgical theater. In addition, a precise anatomical model was printed to physically evaluate the tumor and for advanced surgical planning (Fig. 3).

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Fig. 2 A digital 3D anatomical model and needle navigation plan.

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Fig. 3 3D physical anatomical model of the pelvis, GCT and needle navigation plan.

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4 Procedure

In situ CRA– In this procedure damage to the cell membrane incites apoptosis causing cell death by an “ice ball” coverage of all tumor surfaces. To begin, six ice rod needles (Galil Medical Ltd. Yokneam Israel) were placed according to the planned trajectory into the center of the tumor through the jig openings. The location of the needles were then confirmed using intraoperative Cone-beam navigation system (o-arm® scanner Medtronic Sofamor, Danek Memphis, TN, USA). Throughout the procedure, intraoperative CT using the O arm scanner as well as intraoperative fluoroscopy was used to validate the needle location and monitor the “ice-ball” in real time. Additionally, during the procedure the sacral nerve roots were observed under nerve monitoring every 2–3 min. Once the needles were in place and validated, the ablation protocol was performed (Fig. 4). This included 10 min of freezing, 5 min of active thawing for the entire 5 min, followed by ten more minutes of freezing. During the freezing interval, temperatures were kept below minus 40° Celsius creating an ice ball surrounding the entire tumor (Fig. 5). It is considered a relatively safe procedure with minimal damage to the tumor's collagenous structures. Following the procedure, the patient was hospitalized for one week after which she was released to go home. She underwent follow-up every two months and continued her Denosumab regiment. There were no early complications from the treatment. At her first follow-up the patient experienced intermittent pain however two months later the patient was in excellent condition. She was in no pain and had no open wounds. At her six-month follow-up the patient displayed further improvement and showed no issues with incontinence. Three months later she was able to move completely independently. To date, over three years after the procedure, I.M is ambulating with no pain or limping, she has no other symptoms (Fig. 6). In her most recent CT from 2020, there was no significant change in tumor size compared to her post-operative imaging performed in 2018 and there were no noted functional changes for the patient. Overall, we achieved stabilization of the disease since the cryoablation procedure.

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Fig. 4 A. An axial CT showing GCT tumor prior to the procedure in May 2018. Tumor was 89.0*88.8 mm GCT tumor and had a volume of 339.899 cm^3 B. An axial CT showing GCT tumor after the procedure in August 2018. Tumor was 65.5*72.4 mm and had a volume of 183.379 cm. CT showed increased contrast enhancement prior to the surgery and a reduction in contrast enhancement after the surgery. Additionally, the CT displayed increased calcium deposition indicative of necrosis after the surgery.

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Fig. 5 Sacrum during the cryoablation procedure.

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Fig. 6 An axial CT showing 77.1*76.3 mm GCT tumor of the sacrum with a volume of 208.26 cm^3 from 2020.

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5 Discussion

In their initial stage of development, GCTs tend to be clinically silent. By the time a diagnosis is made, GCTs are often large, and the patient commonly presents with pain and neurological deficits in the affected area.^8,9 While complete resection is the optimal treatment to minimize recurrence, the risk for neurological complications and intraoperative bleeding makes this procedure in the sacrum costly.² In patients with extensive tumors, complete resection often requires a total sacrectomy, a procedure where the morbidity and mortality are great. Beyond the bleeding and neurological risks, total sacrectomy produces vertical and rotational instability as well as an enormous osseous and soft tissue defect that requires reconstruction in order to re-establish stability. Additionally, after surgery the patient is highly susceptible to infection and due to the complexity of the region a multistage operation might be necessary.^1,10 Intralesional curettage, another surgical approach to GCTs of the long bone, is both less effective in reducing the rate of recurrence and still bears the risks of an invasive procedure in the sacrum.

Other non-surgical treatments options include arterial embolization and the use of Denosumab.² Denosumab is a monoclonal antibody that more recently has been approved for patients with Giant Cell Tumor of the bone. The drug works to reversibly block the progression of bone reabsorption and osteolytic tumor expansion by inhibiting the interaction between RANKL, continuously expressed by the tumor stromal cells, and its receptor (RANK) on the osteoclasts. Currently, use of Denosumab is indicated in patients with Giant Cell Tumors of the bone whose tumors are too difficult to resect and in cases where surgical procedure would lead to severe morbidity.¹¹

In this patient, though Denosumab kept tumor progression stable for some time, treatment ultimately failed to adequately control the progression of the disease and an alternative approach to treat this tumor became necessary. In situ cryoablation is a minimally invasive method that offers a more practical approach for treatment of sacral GCTs. In addition to exhibiting lower morbidly and mortality, cryoablation has unique characteristics that enhance care including a shorter recovery time and intrinsic analgesic properties.¹² While more involved surgical procedures are demanding on the patient, the nature of cryoablation also allows for the possibility of repeated treatments with disease progression or tumor recurrence.⁶ Additionally, cryoablation offers better control over ablation margins compared to other modalities such as radiofrequency ablation (RFA) and microwave ablation. In this procedure imaging can be used to monitor the ablation zone intraoperatively and multiple inserted probes can carefully tailor the targeted area while avoiding other local structures.¹³ Three-dimensional modeling is an effective tool to enhance the precision and preparedness for in situ cryoablation treatment. With this technology it is possible to plan both a safe route to access the zone of ablation as well as simulate the necessary probe orientation to optimize an approach that encases the entire theoretical zone.⁷

Ultimately, for our patient, cryoablation offered the most effective treatment to address her pain and neurological symptoms while minimizing the risks associated with more invasive procedures. The treatment was successful in alleviating pain, and she maintained her mobility. The patient has been followed-up since and in her most recent CT in 2020 there were no significant change in tumor size compared to her post-operative imaging performed in 2018. The plan was to continue follow up and to assess the possibility for another cytoablative procedure for further treatment.

6 Conclusion

With the use of 3D modeling, cryoablation was successful in reducing the burden of disease in our patient. Additionally, this method minimizes many of the risks that accompany other common treatment modalities, making cryoablation a favorable treatment method for sacral GCTS.

Funding

None declared.

Ethical approval

Paper was approved by the Tel Aviv Sourasky Medical Center Ethics committee.

Authors contribution

Avital Elias was the main author of the manuscript. Amit Benady and Eran Golden helped plan and prepare the procedure. Ortal Segal and Solomon Dadia were the surgeons performing the procedure and conceived the original idea. All authors critically read and approved the final manuscript.