Vol 19, No 3 (2023)
Case report
Published online: 2023-03-28

open access

Page views 1289
Article views/downloads 255
Get Citation

Connect on Social Media

Connect on Social Media

Bisphosphonate treatment as a safe choice for treating lung metastases of recurrent giant cell tumor of bone

Hans Kristian Nugraha1, Putu Bihan Surya Kinanta1, I Gede Eka Wiratnaya1
Oncol Clin Pract 2023;19(3):178-183.

Abstract

Giant cell tumor (GCT) accounts for 5% of all primary bone tumors and 20% of benign skeletal tumors. This case report presents the case of a 17-year-old female with a recurrent giant cell tumor and lung metastases. The patient received bisphosphonate therapy instead of surgery. The use of zoledronic acid for lung metastases from GCT may have conservatively improved clinical symptoms and radiological assessments can be achieved. 

CASE REPORT

Oncology in Clinical Practice

DOI: 10.5603/OCP.2023.0007

Copyright © 2023 Via Medica

ISSN 2450–1654

e-ISSN 2450–6478

Bisphosphonate treatment as a safe choice for treating lung metastases of recurrent giant cell tumor of bone

Hans Kristian NugrahaPutu Bihan Surya KinantaI Gede Eka Wiratnaya
Department of Orthopedic and Traumatology, Faculty of Medicine Udayana University/Prof. IGNG Ngoerah General Hospital, Bali, Indonesia

Address for correspondence:

Dr. Hans Kristian Nugraha, Sp.OT

Department of Orthopedic and Traumatology,

Faculty of Medicine Udayana University/

/Prof. IGNG Ngoerah General Hospital

1 Kesehatan Street, Denpasar, Bali 80113,

Indonesia

e-mail: hans.nugraha@yahoo.com

Received: 25.12.2022 Accepted: 13.02.2023 Early publication date: 28.03.2023

ABSTRACT

Giant cell tumor (GCT) accounts for 5% of all primary bone tumors and 20% of benign skeletal tumors. This case report presents the case of a 17-year-old female with a recurrent giant cell tumor and lung metastases. The patient received bisphosphonate therapy instead of surgery. The use of zoledronic acid for lung metastases from GCT may have conservatively improved clinical symptoms and radiological assessments can be achieved.

Key words: bisphosphonate, giant cell tumor, recurrence

Oncol Clin Pract 2023; 19, 3: 178183

Introduction

Giant cell tumor (GCT) accounts for 5% of all primary bone tumors and 20% of benign skeletal tumors. It is common in young adults aged between 20 and 40 years, with a slightly higher incidence in females. GCT metastases to the lung, lymph nodes, liver, soft tissues, brain, mediastinum, scalp, or kidney are fairly rare. The recurrence rate is only about 3%. Inappropriate surgical treatment may lead to increased osteolysis and destruction of the joints adjacent to the primary site. The currently available treatment options for these metastases are metastasectomy, chemotherapy, denosumab, interferon, or bisphosphonates [1, 2]

In this case report, we aimed to evaluate outcomes for a GCT patient with metastases to the lung, who received long-term oral bisphosphonate. The purpose of this study is to show that bisphosphonate is a safe and viable option to achieve good outcomes.

Case presentation

A 17-year-old female presented to the Orthopaedic Clinic of Sanglah General Hospital Denpasar Bali. The patient reported a painful lump on her ankle that she had first noticed 8 months earlier. This issue started with a small lump on the left ankle which gradually grew. At the same time, the pain gradually worsened especially in the preceding 5 months (Fig. 1). At the same time, she suffered from weight loss. She presented with swelling, local tenderness, and a 6 x 6 cm mass with an irregular margin at her distal left tibia. Radiological investigation using plain X-ray and magnetic resonance imagining (MRI) of the ankle was then performed, revealing lytic lesion and cortical destruction on the epi metaphysis of the distal tibia (Fig. 1, 2) without any metastases to the lung (Fig. 3) suggesting Enneking stage 3 or Campanacci grade III giant cell tumor of the distal tibia.

Figure 1. Clinical picture and radiography examination of the left ankle
Figure 2. Magnetic resonance imaging of the ankle showed cortical destruction of the distal left tibia with minimum soft tissue involvement
Figure 3. Chest X-ray

The patient was then admitted for inpatient care and first underwent an open biopsy and frozen section. The histopathology analysis found dense proliferation of spindle mononuclear cells, which confirmed the suspicion of GCT. After this diagnosis, we performed extensive resection followed by fibula and ankle arthrodesis tibial reading as a curative treatment for the lesion (Fig. 4). The post-operative X-ray is shown in Figure 5. The patient also underwent bisphosphonate treatment for 18 months after the resection procedure to prevent any local recurrence and metastases.

Figure 4. Clinical picture of the surgery showing; A. Pre-operative planning; B. The resected tumor with a 2 cm margin of healthy soft tissue; C. Clinical condition after fixation with autologous strut graft from the fibula
Figure 5. Post-operative X-ray

Two years after the surgery, the patient returned to the hospital with a new complaint of shortness of breath aggravated by activity and slightly reduced after rest. A chest X-ray and computed tomography (CT) scan were performed to assess whether any lung metastases had occurred. The chest X-ray showed coin lesions with suspected embolism or metastasis while the CT-scan of the chest revealed multiple enhanced solid nodules in the perihilar segment of the lung. An X-ray of the left ankle also showed lytic lesions at the distal region indicating recurrence (Fig. 6). Cardiothoracic surgeons were consulted for any possible metastasectomy procedure, but there was a considerable risk. Therefore, the patient opted for conservative treatment for the lung metastases, with further 5 months of bisphosphonate therapy. For the primary tumor, the patient underwent a curettage procedure with highspeed burr and phenol followed by bone cement filling to repair the defect (Fig. 6, 7). She then received 4 mg of zoledronic acid in 6 cycles and was able to walk pain-free with no crutches after 6 months.

Figure 6. Chest and ankle X-rays taken 2 years after the first surgery, showing recurrence at the initial primary site with metastases to the lung despite receiving 6 months of bisphosphonate treatment
Figure 7. Chest computed tomography scan after 2 years after surgery, showing metastatic nodules at almost all lobes of the lung

The patient underwent bisphosphonate therapy that consisted of a monthly dose of 4 mg zoledronic acid for 6 consecutive months following the metastasis discovery. Five months follow-up after initiation of bisphosphonate therapy showed a favorable outcome based on clinical and radiological evaluations. The patient had no complaints about shortness of breath and has been able to do daily activities without any difficulty. A chest X-ray and CT scan showed significant differences after zoledronic acid therapy (Fig. 8, 9).

Figure 8. Chest and ankle X-Ray post-surgical bone graft and bisphosphonate therapy
Figure 9. Chest CT scan after bisphosphonate therapy

Discussion

Local recurrence of GCT is rather common, ranging from 10 to 26.9%, with extra-compartmental (soft tissue) extension and tumor grade considered the most significant risk factors [3]. With regards to metastases, the lungs are the m ost common site where GCT metastases frequently occur. Its incidence is estimated to be as much as 5% of bone GCT, especially in younger patients with grade 3 Enneking disease [4–6].

In this case, a CT scan identified pulmonary emboli which were visible as multiple enhanced solid nodules in almost all segments of the lung. This patient was placed under the joint care of thoracic and vascular surgeons. Following discussions with the patient, we decided to treat the metastases with conservative treatment instead of a surgical procedure. Follow-up conducted 5 months after the initiation of conservative bisphosphonate zoledronic acid therapy found significant improvement of the lung lesions. This is in line with previous findings by Zekri et al. [7], which showed that zoledronic acid’s antitumor effect is mediated through inhibition of tumor cells proliferation, induction of apoptosis, synergistic/additive to the inhibitory effect of cytotoxic agents, inhibition of angiogenesis, decrease of tumor cells adhesion to the bone, decrease of tumor cells invasion and migration, disorganization of cell cytoskeleton and activation of a specific cellular antitumor immune response.

Bisphosphonates are stable analogs of inorganic pyrophosphate in which the oxygen atom of the P-O-P bond is replaced with a non-hydrolyzable P-C-P bond. Bisphosphonates inhibit osteoclast activity by several mechanisms which depend largely on their chemical structure. Bisphosphonates have been shown to induce apoptosis of tumor cells and inhibit tumor cell growth of a variety of tumor cell types [8].

Zoledronic acid has a high affinity for mineralized bone accumulating rapidly after intravenous administration and localizing preferentially at sites of high bone turnover. It is thought to be internalized during bone resorption via the endocytic activity of osteoclasts and inhibits bone resorption by inhibiting farnesyl pyrophosphate synthase (FPPS) and preventing protein prenylation. The binding affinity of zoledronic acid for hydroxyapatite was higher than that of other bisphosphonates (binding affinity constants of 3.47 9 10-6 mol/L vs. 2.94, 2.36, 2.19, 1.19 and 0.72 9 10-6 mol/L for alendronic acid, ibandronic acid, risedronic acid, etidronic acid, and clodronic acid, respectively) [9]. Zoledronic acid has also been considered a reasonable, effective treatment for unresectable lesions [7, 10].

Unlike bisphosphonate, the optimal duration, long-term safety, maintenance dose, and optimum indications of denosumab in GCT treatment remain to be elucidated. A recent in-depth review by Li et al. [11] warns that denosumab therapy of GCT of the bone (GCTB) should be applied with caution. Furthermore, denosumab is also still associated with a probable increase of local recurrence in patients treated with curettage [11].

In this study, we conducted bisphosphonate therapy using zoledronic acid in a patient who had lung emboli due to metastases of GCT. Bisphosphonate has shown a promising result in treating metastases of GCT. The anti-osteoclast effect of bisphosphonates and their ability to prevent bone resorption make bisphosphonates a potential treatment for GCT, and several studies have confirmed its efficacy [10]. However, in this study the patient had a recurring case of GCT in the left ankle based on clinical symptoms and radiographic examination. The study conducted by Xu et al. [12] showed that the recurrence rate of GCT was 2.1%, and the mean interval time was 11.3 ± 4.1 months with a range from 517 months.

In a previous study reported by Balke et al. [13], the authors examined clinical and radiological outcomes of bisphosphonate treatment in 25 cases of aggressive primary, recurrent, and metastatic giant cell tumors from 4 European centers. They reported no signs of progression or increase in the size or number of lung metastases in GCT patients who were treated with bisphosphonates. The use of bisphosphonate to treat pulmonary metastases in GCT has also been reported by Dubey et al. in 2019 [14]. They reported that the usage of bisphosphonates successfully reduced chest pain and controlled tumor growth, as soon as 3 months after therapy.

In our case, bisphosphonate therapy has been successful in controlling the lung metastases of the GCT. Even though this finding is based only on observation, we argue that it is still a viable safe first-line method of managing patients with lung metastases from GCBT [14, 15], We propose that surgical metastasectomy could be delayed for such metastases and reserved for cases that are resistant to bisphosphonate therapy.

Conclusion

Improvement in clinical symptoms and control of tumoral growth in the case of lung metastases of GCT could be achieved conservatively by using zoledronic acid.

Consent

Written informed consent was obtained from the patient for being included in the study and its publication.

Ethics statement

All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2008.

Author contributions

N.H.K.: study concept and design, performed surgery, final editing and publication; K.P.B.S.: data collection and drafting; W.I.G.E.: performed surgery.

Funding

This report has not received any specific grant from any funding agency in the government, commercial or non-profit.

Acknowledgments

The authors would like to thank I Made Sunaria for providing the technical illustration of this case.

Conflict of interest

Authors declare no conflict of interest.

References

  1. Tsukamoto S, Tanaka Y, Mavrogenis AF, et al. Is Treatment with Denosumab Associated with Local Recurrence in Patients with Giant Cell Tumor of Bone Treated with Curettage? A Systematic Review. Clin Orthop Relat Res. 2020; 478(5): 10761085, doi: 10.1097/CORR.0000000000001074, indexed in Pubmed: 31794487.
  2. Muheremu A, Niu X. Pulmonary metastasis of giant cell tumor of bones. World J Surg Oncol. 2014; 12: 261, doi: 10.1186/1477-7819-12-261, indexed in Pubmed: 25139054.
  3. Wiratnaya IG, Subawa IW, Astawa P, et al. Arthroscopic Management of Giant Cell Tumor of the Calcaneus. Foot Ankle Spec. 2022; 15(3): 266271, doi: 10.1177/19386400211029120, indexed in Pubmed: 34259061.
  4. Dominkus M, Ruggieri P, Bertoni F, et al. Histologically verified lung metastases in benign giant cell tumours-14 cases from a single institution. Int Orthop. 2006; 30(6): 499504, doi: 10.1007/s00264-006-0204-x, indexed in Pubmed: 16909252.
  5. Tubbs WS, Brown LR, Beabout JW, et al. Benign giant-cell tumor of bone with pulmonary metastases: clinical findings and radiologic appearance of metastases in 13 cases . Ajr. 1992; 158(2): 331334, doi: 10.2214/ajr.158.2.1729794, indexed in Pubmed: 1729794.
  6. Karras NA, Polgreen LE, Ogilvie C, et al. Denosumab treatment of metastatic giant-cell tumor of bone in a 10-year-old girl. J Clin Oncol. 2013; 31(12): e200e202, doi: 10.1200/JCO.2012.46.4255, indexed in Pubmed: 23509309.
  7. Zekri J, Mansour M, Karim SM. The anti-tumour effects of zoledronic acid. J Bone Oncol. 2014; 3(1): 2535, doi: 10.1016/j.jbo.2013.12.001, indexed in Pubmed: 26909294.
  8. Dubey S, Rastogi S, Sampath V, et al. Role of intravenous zoledronic acid in management of giant cell tumor of bone- A prospective, randomized, clinical, radiological and electron microscopic analysis. J Clin Orthop Trauma. 2019; 10(6): 10211026, doi: 10.1016/j.jcot.2019.09.011, indexed in Pubmed: 31736608.
  9. Dhillon S. Zoledronic Acid (Reclast, Aclasta): A Review in Osteoporosis. Drugs. 2016; 76(17): 16831697, doi: 10.1007/s40265-016-0662-4, indexed in Pubmed: 27864686.
  10. Yue J, Sun W, Li S. Denosumab versus zoledronic acid in cases of surgically unsalvageable giant cell tumor of bone: A randomized clinical trial. J Bone Oncol. 2022; 35: 100441, doi: 10.1016/j.jbo.2022.100441, indexed in Pubmed: 35800292.
  11. Li H, Gao J, Gao Y, et al. Denosumab in Giant Cell Tumor of Bone: Current Status and Pitfalls. Front Oncol. 2020; 10: 580605, doi: 10.3389/fonc.2020.580605, indexed in Pubmed: 33123484.
  12. Xu L, Jin J, Hu A, et al. Soft tissue recurrence of giant cell tumor of the bone: Prevalence and radiographic features. J Bone Oncol. 2017; 9: 1014, doi: 10.1016/j.jbo.2017.09.002, indexed in Pubmed: 29018768.
  13. Balke M, Campanacci L, Gebert C, et al. Bisphosphonate treatment of aggressive primary, recurrent and metastatic Giant Cell Tumour of Bone. BMC Cancer. 2010; 10: 462, doi: 10.1186/1471-2407-10-462, indexed in Pubmed: 20799989.
  14. Dubey S, Rastogi S, Sampath V, et al. Role of intravenous zoledronic acid in management of giant cell tumor of bone- A prospective, randomized, clinical, radiological and electron microscopic analysis. J Clin Orthop Trauma. 2019; 10(6): 10211026, doi: 10.1016/j.jcot.2019.09.011, indexed in Pubmed: 31736608.
  15. Tsukamoto S, Ciani G, Mavrogenis AF, et al. Outcome of lung metastases due to bone giant cell tumor initially managed with observation. J Orthop Surg Res. 2020; 15(1): 510, doi: 10.1186/s13018-020-02038-1, indexed in Pubmed: 33160367.