Rapid Recurrence of Giant Cell Tumour of C2 Vertebra After Long-Term Denosumab Following Surgical Resection

A 25-year-old man presented with symptoms of cervical myelopathy for 10 days. Imaging revealed an expansile, lytic lesion involving the C2 vertebra completely and compressing the spinal cord, suggestive of giant cell tumor (GCT). Tumor resection and posterior stabilization from C1-C4 were done. Histopathology confirmed the diagnosis of GCT. The patient was kept on adjuvant Denosumab (D-ab) for two years with no signs of recurrence. However, discontinuation of D-ab therapy led to recurrence of the tumor within three months, which was managed with repeated surgical resection and anterior instrumentation followed by radiotherapy. To the best of our knowledge, this is the first reported case of GCT involving the upper cervical spine with rapid recurrence following the stoppage of D-ab therapy.


Introduction
A giant cell tumor (GCT) is a locally aggressive tumor. When involving the upper cervical spine, its proximity with critical neurovascular structures complicates surgical resection and increases the requirement of adjuvant therapy like Denosumab (D-ab). Although D-ab is increasingly being utilized in cases of GCT, rapid recurrence following its discontinuation has been previously reported [1]. We report a case of GCT of the C2 vertebra that was managed with surgical resection and long-term D-ab therapy. However, discontinuation of D-ab led to rapid recurrence of the tumor, which required a second surgery followed by radiotherapy. To the best of our knowledge, this is the first reported case of GCT involving the upper cervical spine with rapid recurrence following the stoppage of D-ab therapy.

Case Presentation
A 25-year-old man presented with gait disturbance, urinary retention, and difficulty in fine finger movements for 10 days. This was associated with neck pain and radiculopathy for three months. There was no history of fever, weight loss, or trauma. Local examination revealed tenderness at the upper cervical spine with poor neck holding. Neurological examination revealed the power of grade 4/5 (Medical Research Council, MRC) in bilateral upper and lower limbs. Sensations were reduced below the C4 dermatomal level. Signs of hypertonia (ankle clonus, extensor plantar response, hyperreflexia) were seen in all extremities.
Plain radiographs and computerized tomography (CT) revealed an expansile, lytic lesion involving the C2 vertebral body with mild instability on flexion and extension ( Figure 1). Magnetic Resonance Imaging (MRI) revealed that the lesion involved the C2 vertebra completely, appeared isointense to muscle on T1-weighted and hyperintense on T2-weighted images, and caused mild spinal cord compression at the corresponding level, suggestive of GCT, whereas metastasis generally shows multilevel involvement ( Figure 2). Triple phase whole-body nuclear bone scan performed with Technetium 99m-methylene diphosphonate (99mTc MDP) showed a warm spot at the C2 vertebra, and no other high activity lesions were noted in the spine, ruling out the possibility of metastases.

Discussion
Although GCT is mostly seen in long bones, it can also involve the spine. Primary GCT of the cervical spine accounts for 2%-3% of spine tumors, and GCT in the axial vertebra (C2) is rare [2]. Although regarded as a benign tumor, 5%-10% of GCTs are malignant and aggressive, commonly metastasizing to the lungs [3]. However, when the tumor involves an anatomically complex region, like the C2 vertebra in our case, local aggressiveness poses a higher risk for mortality than distant metastasis.
Patients with spinal GCT generally present with pain, instability, or neural deficits. Treatment options include en-bloc wide resection, intralesional curettage or excision with or without adjuvant techniques, and radiation therapy. The goals of surgery are to preserve function, alleviate pain and prevent local recurrence.
Owing to the peculiarity and complexity of the upper cervical spine anatomy, it is challenging to get an adequate tumor-free margin without damaging critical neurovascular structures. Due to hesitant resection, upper cervical GCTs show a higher rate of recurrence. Depending on the tumor's location, a radical resection procedure such as pan-vertebrectomy may be required, which is associated with significant morbidity [4]. In addition, GCT is a soft and friable tumor; hence en-bloc resection is demanding and less effective due to the risk of tumor cell leakage and seeding. Accuracy of implants and restoration of spinal alignment is also vital to prevent mechanical complications. Although adequate tumor resection and surgical stabilization followed by adjuvant therapy have become the preferred treatment, there is still no consensus regarding the ideal treatment of cervical spine GCT [5].
To prevent recurrence of GCT in the upper cervical spine due to limited resection, adjuvant therapies are required. Potential adjuvant treatments include radiation therapy, embolization, cryosurgery, bisphosphonates, phenol, and D-ab. Radiation can control local growth but is associated with secondary malignant transformation [6]. Long-term responses with phenol are unreliable [7]. D-ab, on the other hand, has been approved by the Food and Drug Administration (FDA) and is being extensively used as adjuvant and neoadjuvant chemotherapy for GCT when the tumor is unresectable or surgical resection has considerable side effects. Table 1 summarizes the previous studies on the utilization of D-ab in the management of cervical GCT [6,[8][9][10][11][12][13][14][15].  The major components of GCT are multinucleate giant cells (osteoclasts) and mononuclear stromal cells.
Osteoclasts express receptor activator of nuclear factor-kappa B (RANK), and mononuclear stromal cells express RANK ligand (RANKL). Binding of RANKL to RANK leads to osteoclast activation. D-ab specifically inhibits RANKL and prevents its pairing with RANK and the resultant osteolysis and hence, has utilization in the management of GCT. However, it has little effect on the RANKL producing stromal cells, causing chances of recurrence as high as 15% after discontinuation of D-ab therapy [16]. Rapid recurrence of GCT after discontinuation of D-ab has been previously reported in the literature [1]. However, to the best of our knowledge, this is the first such case concerning the upper cervical spine.
Although D-ab is increasingly being used as an adjuvant therapy for GCT, future research surrounding its utilization is required. The current literature does not define any endpoint in terms of duration for the use of D-ab while treating GCT. Tartrate-resistant acid phosphatase (TRACP) 5b, a bone resorption marker, is typically high in patients with GCT and has been shown to decrease drastically post-denosumab administration [17]. It might prove to be a good screening tool to check for recurrence after cessation of D-ab therapy. It is also not clear whether a re-administration of D-ab in case of recurrence can achieve the desired response due to the rapid progression of the tumor mass and symptoms. Possible association of prolonged use of D-ab with hypercalcemia, osteonecrosis of the jaw, and sarcoma also needs to be studied.