Eur opean Rev iew for Med ical and Pharmacol ogical Sci ences 2016; 20: 3692-3695 Denosumab: non-surgical treatment option for selective arterial embolization resistant aneurysmal bone cyst of the spine and sacrum. Case report

R. GHERMANDI, S. TERZI, A. GASBARRINI, S. BORIANI

Department of Oncological and Degenerative Spine Surgery, Istituto Ortopedico Rizzoli, Bologna, Italy

Abstract. – OBJECTIVE: Aneurysmal Bone Primary ABC is a rare disease (about 1% of Cyst (ABC) is a cystic lesion of bone, occurring primary tumours of bone). Considered for sever - in 70% of cases as a primary lesion. Even if the al years a pseudotumoral lesion of uncertain ori - metaphyseal region of long bones is more fre - quently involved, vertebral localization is not gin it is now proven that it is a real benign prima - rare: ABC represents 15% of all primary spine ry tumor, associated with a specific pattern of ge - and sacral tumours. Selective arterial emboliza - netic alterations that result in the activation of the tion (SAE) represents the first treatment option gene USP6 located on 17p13 2. for vertebral ABC. However, in few cases, mul - Imaging is typical and shows an expansive, tiple SAEs are not possible. The aim of this osteolytic lesion, which swells and sometimes work is to report two cases of vertebral ABC unresponsive to SAE positively treated with destroys bone. Aggressive osteolytic area on CT Denosumab. scan and multiple fluid/fluid levels on MRI are PATIENTS AND METHODS: Two patients af - characteristics. fected by ABC of the lumbar spine were treated Histologically it is composed of large gaps filled by SAE without any response. Thus, the pa - with blood, separated by thin fibrous septa of con - tients were submitted to an off-label treatment nective tissue, that contain several cellular ele - with Denosumab, following the same protocol ments, often including multinucleated giant cells. already used in case of Giant Cell Tumour 3 (GCT): 120 mg once a week for 4 weeks con - According to Enneking, ABC ranges stage 1 to 3 . secutively, then once every 40 days. Even if the metaphyseal region of long bones RESULTS: In both cases, patients resulted to is more frequently involved, vertebral localiza - be pain-free after 11-13 Denosumab administra - tion is not rare: ABC represents 15% of all pri - tions and CT scan showed almost complete os - mary spine and sacral tumors. Compared to other sification of the lesions. skeletal locations, vertebral involvement presents CONCLUSIONS: The two cases reported here are not conclusive but they may support the clinical and treatment peculiarities. project of a prospective study to confirm the ef - Enneking stage 3 lesions (benign aggressive) can fectiveness of Denosumab in ABC treatment as provoke nerve roots, spinal cord or cauda equina an alternative to SAE. compression with a wide range of symptoms. Rarely, a pathological fracture may occur and Key Words: Aneurysmal bone cyst, Spine, Selective arterial em - in this case an acute paraplegia or a cauda equine bolization (SAE), Denosumab. syndrome is possible. Different surgical (intralesional curettage with or without instrumentation or en bloc resection) and non-surgical (selective arterial embolization Introduction (SAE), direct intralesional injection, radiation therapy) options have been proposed for the Aneurysmal bone cyst (ABC) is a cystic lesion treatment of primary ABC. The treatment of sec - of bone, consisting of blood lacunae separated by ondary ABC is that of the primary tumour. connective septa; in 30% of cases is found inside Surgical curettage must be carefully consid - other bone diseases (giant cell tumour, osteoblas - ered due to the high risk of profuse intraoperative toma, chondroblastoma, telangiectatic osteosar - bleeding and late local recurrence. En bloc resec - coma), while in 70% of cases it occurs as a pri - tion, related to high morbidity rate, represents an mary lesion 1. overtreatment for a benign lesion as ABC. Radia -

3692 Corresponding Author: Riccardo Ghermandi, MD; e-mail: [email protected] Denosumab in ABC treatment as an alternative to SAE tion therapy is nowadays reserved only for very According to the protocol approved by our In - selected local recurrence cases considering the stitution for non-surgical treatment of GCTB, proven risk of secondary malignancy. Denosumab was administered off-label as fol - The good results obtained in a previous pub - low: 120 mg once a week for 4 weeks consecu - lished study 4 convinced us that selective arterial tively, then once every 40 days. embolization represents the first treatment option Patients evaluation at follow-up included for vertebral ABC. MRI, CT scan and clinical and radiographical Despite this, it must be underlined that, in few teeth and mouth examination. cases, multiple SAEs are not possible, due to the The aim of this work is to report two cases of close connection of tumour vascularity with cord vertebral ABC unresponsive to SAE positively feeding arteries, they do not achieve the expected treated with Denosumab. result or they are contraindicated considering ra - diation exposure. For this reason, a therapeutic alternative must be found. Case Report Denosumab is a fully human monoclonal anti - body that inhibits RANKL (receptor activator of Case 1: 42-year-old healthy man with a 2 nuclear factor kappa-B ligand), the main osteo - years story of lumbar back pain (Figure 1) clastogenic cytokine; its effect is to drastically At the onset of symptoms an MRI was per - reduce bone resorption. FDA approved it for the formed and showed an L5-S1 giant cystic lesion treatment of osteoporosis and bone metastases. with fluid-fluid levels suspected to be ABC. In addition, following the publication of trials Treated elsewhere, a biopsy was not performed that have demonstrated its efficacy, it is spread - and the patient underwent selective arterial em - ing for medical treatment of giant cell tumour of bolization with partial pain relief. Six months lat - bone (GCTB) 5. er symptoms recurred, with worsening both low - Histomorphological characteristics similar in er limbs radicular pain. GCTB and ABC is the prerequisite that justifies When admitted to our Institute, clinical exami - the use of the antibody in selected ABC cases. nation revealed a scoliotic attitude of the lumbar

Figure 1 . Imaging history of Case 1, reporting CT scan and MRI performed before ABC treatment, after embolization and af - ter treatment with Denosumab.

3693 R. Ghermandi, S. Terzi, A. Gasbarrini, S. Boriani

Figure 2 . Imaging history of Case 2, reporting CT scan and MRI performed before ABC treatment, after embolization and af - ter treatment with Denosumab. spine, stretched back muscles, and right L5 and At each admission, CT and MRI were per - S1 nerve root paresis; hypoesthesia was present formed and showed progressive ossification of too. CT scan confirmed the hypothesis of a wide the lesion. Patient was symptoms free after 6 ad - aggressive L5-S1 ABC showing a ballooning, ministration of Denosumab (2 months follow-up). multilocular lytic lesion with a blown-out thin After a total number of 13 Denosumab admin - layer of cortical bone with significant ex - istrations, at the final follow-up (35 months after traosseous extension. MRI showed a large “soap- diagnosis), the patient was pain-free and CT scan bubble” lesion with right posterolateral extension shows almost complete ossification of the lesion. causing L5-S1 nerve roots compression. A consecutive SAEs treatment program was Case 2: 16-year-old healthy boy with four started and performed monthly 6 times. Despite months back pain and sciatic right leg pain this, a slowly progressive worsening of the lesion (Figure 2) was observed: MRI showed mild growth of the When admitted to our Institute, 3/5 strength mass and increase of typical levels; the patient weakness at right quadriceps and right L5 nerve reported an aggravation of back and leg pain roots hypoesthesia were recorded. with unchanged paresis. The treatment was X-Rays and CT-scan revealed a L5 osteolytic stopped and a CT guided trocar biopsy was per - lesion involving pedicle, lamina and spinous formed; final histological report confirmed the process with extraosseous extension. MRI imag - previous hypothesis of aggressive ABC, in this ing showed a multicystic mass with fluid-fluid case unresponsive to SAE. levels with an intermediate signal on T1-weight - Avoiding surgery, related to high risk of se - ed images and increased signal uptake on T2 im - vere neurological consequences and intraopera - ages, consistent with blood or fluid. A biopsy tive bleeding, and considering literature 6, the pa - was performed first and final histological report tient was submitted to an off-label treatment with confirmed the hypothesis of ABC. Denosumab. The same protocol already used in A consecutive SAEs treatment program was case of giant cell tumour (GCT) was followed: started and performed monthly 5 times but without weekly 120 mg injections of Denosumab were any evidence of efficacy due to pathologic vascu - performed first for 1 month, then monthly. larity every time developing after embolization.

3694 Denosumab in ABC treatment as an alternative to SAE

After 6 months of treatment, an untreatable Conclusions right sciatalgia required a hospitalization. CT tro - car biopsy was performed again, and the histo - Two cases are not conclusive but they may logical result confirmed the diagnosis of ABC, support the project of a prospective study to con - unresponsive to SAE. firm the effectiveness of Denosumab also in The patient was submitted to an off-label treat - ABC and standardize the treatment protocol. ment with Denosumab following the same proto - col already used in case of giant cell tumor (GCT). Progressive neurological and clinical improve - ––––––––––––––––– –– Acknowledgements ment occurred since the 1st month of treatment; CT and MRI imaging have showed a gradual The Authors thank Mr. Carlo Piovani for his helpful collab - mass reduction and progressive ossification since oration in patients’ images storage and editing and Dr. Cris - tiana Griffoni for collaboration in manuscript editing. the 3rd month of administration. A total number of 11 Denosumab administra - –––––––––––––––– –-– –– tions were performed; at the final follow-up (33 Conflict of Interest months after diagnosis) the patient is completely The Authors declare that they have no conflict of interests. pain-free, back to normal daily activities and sport practice. References

Discussion 1) CAMPANACCI M. Aneurysmal bone cyst. In: Bone and soft tissue tumors. New York, NY: Springer- Verlag Wien, 1990; pp. 813-840. Treatment of spinal and sacrum ABC resistant 2) PAULI C, F UCHS B, P FIRMANN C, B RIDGE JA, H OFER S, to SAE is challenging. BODE B. Response of an aggressive periosteal Surgical treatment is not recommended con - aneurismal bone cyst (ABC) of the radius to sidering the danger of intraoperative bleeding, denosumab therapy. World J Surgl Oncol 2014; neurological post-operative deficit and late local 12: 17. recurrence in case of intralesional curettage and 3) ENNEKING WF. Muscoloskeletal tumor surgery. the high rate of possible complications in case of Churchill Livingstone, Edinburgh-London, 1983. en bloc resection. 4) AMENDOLA L, S IMONETTI L, S IMOES CE, B ANDIERA S, D E IURE F, B ORIANI S. Moreover, radiation therapy is related to the Aneurysmal bone cyst of the mo - bile spine: the therapeutic role of embolization. risk of malignant evolution of the tumor. Eur Spine J 2013; 22: 533-541. Denosumab binds and inhibits RANK-L, the 5) CHAWLA R, H ENSHAW L, S EEGER E, C HOY JY, B LAY S, most important osteoclastogenic cytokine; it was FERRARI J, K ROEP R, G RIMER P, R EICHARDT P, R UTKOWSKI initially used for the treatment of osteoporosis S, S CHUETZE K, S KUBITZ D, T HOMAS Y, Q IAN I. Jacobs. and bone metastases. Safety and efficacy of denosumab for adult and Its use was then extended to the treatment of skeletally mature adolescent with giant cell tumor of bone: interim analysis of an open-label, paral - GCT once discovered that RANK-L role is the lel-group, phase 2 study. Lancet Oncol 2013; 14: key to understand giant cell tumor growth. 901-908. Clinical trials have shown that Denosumab is 6) LANGE T, S TEHLING C, F RÖHLICH B, K LINGENHÖFER M, effective in reducing tumor mass dimension in the KUNKEL P, S CHNEPPENHEIM R, E SCHERICH G, G OSHEGER case of refractory, recurrent or inoperable GCT 7. G, H ARDES J, J ÜRGENS H, S CHULTE TL . Denosumab: a Even if different from a clinical, histological potential new and innovative treatment option for aneurysmal bone cysts. Eur Spine J 2013; 22: and radiological point of view, GCT and ABC 1417-1422. share histomorphological characteristics; Pelle et THOMAS D, H ENSHAW R, S KUBITZ K, C HAWLA S, S TAD - 8 7) al demonstrated that RANK-L, following the DON A, B LAY JY, R OUDIER M, S MITH J, Y E Z, S OHN W, same pattern as in GCT, is basic for primary DANSEY R, J UN S. Denosumab in patients with gi - ABC growth too and, for this reason, the non- ant-cell tumour of bone: an open-label, phase 2 surgical treatment with the use of Denosumab is study. Lancet Oncol 2010; 11: 275-280. justified in case of ABC. 8) PELLE DW, R INGLER JW, P EACOCK JD, K AMPFSCHULTE K, Literature in this field is still poor and small, SCHOLTEN DJ 2 ND , D AVIS MM, M ITCHELL DS, S TEENSMA MR . Targeting receptor-activator of nuclear kap - and non-homogenous patients’ series are not in - paB ligand in aneurysmal bone cysts: verification dicated to evaluate efficacy and safety of the use of target and therapeutic response. Transl Res of Denosumab for the treatment of ABC. 2014; 164: 139-148.

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