GCTB is a benign, but locally aggressive, primary bone neoplasm driven by the overproduction of RANKL, leading to osteoclastogenesis and bone resorption. We report a unique GCTB displaying atypical morphologic features in a patient on two-month treatment with secukinumab for PsA. Histologic analysis showed gross and microscopic characteristics reminiscent of GCTB treated with denosumab.
Secukinumab promotes new bone growth in GCTB
IL-17 mediates bone resorption in inflammatory mediated joint diseases (e.g. PsA and ankylosing spondylitis) [7, 9]. In these conditions, secukinumab is recommended for use to reduce bone resorption and joint erosions [8]. In GCTB, IL-17 signaling increases the expression of MMP9, CathK, and RANKL, thus promoting osteoclastogenesis and local bone destruction [10]. A potential mechanism of IL-17 mediated osteoclastogenesis in GCTB may occur through activation of EGFR. In cultures of peripheral blood mononuclear cells, the addition of EGF with M-CSF increases the number of TRAP+ osteoclast-like giant cells [12]. Also, higher numbers of osteoclasts are reported in EGFR+ GCTB cases [12]. Inhibition of EGFR in GCTB, in-turn, elicits denosumab-like effects [14]. IL-17 may activate EGFR in GCTB similar to what is observed in TNBCs [11]. In these tumors, IL-17 enhances the sensitivity of EGFR to EGF through crosstalk of Src/PYK2, as well as phosphorylating EGFR and inducing nuclear translocation, an integral part in the signaling cascade [11]. We demonstrate an association between inhibition of IL-17 signaling and new bone growth with decreased expression of MMP9, CathK, and RANKL in a denosumab-like manner. These findings suggest secukinumab, an anti-IL-17 monoclonal antibody, likely affects bone turnover modulation in GCTB. Additionally, the ossification was observed after the patient had received only two doses of secukinumab, compared to the five doses of denosumab in the comparison tissue, raising the possibility of a shorter treatment duration to elicit an ossification response.
Therapeutic advantage of Secukinumab in GCTB
A clinical benefit of denosumab exists in patients with advanced or unresectable GCTB [4]. In an open-label, parallel-group, phase 2 trial, 65 of 159 (41%) surgically unsalvageable patients showed an objective tumor response defined as partial or complete after treatment with denosumab [15]. Therefore, denosumab therapy in association with or instead of surgery is recommended for select cases. However, prolonged treatment with denosumab is associated with osteonecrosis of the jaw, peripheral neuropathy, skin rash, hypophosphatemia, and atypical femoral fracture [15]. Furthermore, the use of denosumab is contraindicated in pregnancy [16]. Yet, secukinumab has much milder adverse effects, including nasopharyngitis, headache, nausea, diarrhea, and pyrexia, and is not contraindicated for pregnant patients [17, 18]. Notably, secukinumab has not been associated with untoward bone effects, like osteonecrosis of the jaw or atypical fractures of the femur. A recent, comprehensive literature review of the clinical experience with secukinumab showed a consistent increase in spine and hip bone mineral density and no change in fracture incidence [19]. If secukinumab has a similar therapeutic advantage to that of denosumab, it may be a promising option for patients who experience adverse events or have contraindications to denosumab therapy.
The use of denosumab has been associated with an increased risk of GCTB recurrence after treatment. It is still unknown how denosumab increases recurrence, but it is thought that denosumab principally targets the reactive infiltrating giant cells rather than affecting the neoplastic spindle cells. By increasing ossification, tumor cells can be trapped and sequestered from curettage, contributing to recurrence [20]. Cells left behind may be the source of recurrence or malignant transformation. Whether secukinumab has a similar influence on recurrence risk remains unknown. The atypical findings of bone formation in the setting of inhibition of IL-17, a known modulator of osteoclastogenesis in GCTB, raises the possibility of a therapeutic benefit of secukinumab in GCTB. Due to the uncontrolled nature of this case report, we do not have access to radiographic or pathologic data from this patient’s tumor prior to treatment with secukinumab. Therefore, it is impossible to assign causality definitively or to rule out that his prior treatment with adalimumab was a contributing factor to the ossification in the tumor. Further studies are needed to investigate if there is a role for secukinumab as medical monotherapy or adjuvant therapy for select cases of GCTB.