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Case Report

Effect of Denosumab in Giant Cell Tumor of Bone

Ramesh Chandra Maharaj, Sibasish Panigrahi, Biplabi Sarangadhar Das
Department of Orthopedics, Shri Ramachandra Bhanj Medical College, Cuttack, Odisha, India

Abstract
Giant cell tumor (GCT) of bone is a benign tumor with locally aggressive nature. The presence of mononuclear stromal cells and multinucleated
giant cells is the microscopic characteristic feature of the GCT. It is an osteoclastic tumor with destruction of tumor is mediated by the receptor
activator of nuclear factor kappa‑B ligand (RANKL). Denosumab, a RANKL inhibitor, may reduce or eliminate tumor giant cells, the relative
content of proliferative, densely cellular tumor stromal cells, replacing with nonproliferative, differentiated woven new bone. We report a case
of GCT of the right distal femur in a 20‑year‑old female, treated with 6 cycles of denosumab as neoadjuvant therapy, which shows consolidation
of the lesion and became amenable for extended curettage with phenol cauterization and cementing without going for any radical surgery
shown to have very good functional outcome.

Keywords: Denosumab, giant cell tumor, receptor activator of nuclear factor kappa‑B

Introduction normal. Frontal and lateral radiograph of the right knee

showed a well‑defined eccentric expansile meta‑epiphyseal
Giant cell tumor  (GCT) of bone is a locally aggressive
lytic lesion involving lateral condyle of the right distal femur
destructive benign tumor usually involving the ends of
measuring approximately 4 cm × 6 cm [Figure 1a]. There is
long bones. The most common age group of presentation is
cortical thinning with few foci of cortical breach on lateral
20–40 years with a female predominance and it accounts for
and anterior aspect. The lesion has irregular margins with
approximately 20% of all benign bone tumors.[1] Most common
relatively broad zone of transition in superior aspect. There
sites of presentation for the GCT in decreasing order are distal
is no obvious extension into knee joint cavity. There is no
femur, proximal tibia, and distal radius. Traditionally, surgery
matrix calcification or associated soft‑tissue mass. Magnetic
is the mainstay of treatment in GCT. However, the disease
resonance imaging (MRI) revealed 4.5 cm × 4.3 cm × 5.9 cm
can recur even with the optimal procedure. Understanding
multiloculated lytic mass on the distal right lateral femoral
role of the receptor activator of nuclear factor kappa‑B
condyle with extension to the surrounding soft tissue but
(RANK)/RANK‑ligand (RANKL) pathway in the pathogenesis
without involvement of the joint. Needle biopsy from the lesion
of the GCT has led to the development of the monoclonal
showed the presence of several multinucleated osteoclast‑like
antibody denosumab against RANKL.[2] Here, we reported
giant cells in the background of stromal cells confirming
one such case of GCT of distal femur treated with preoperative
the diagnosis of GCT  [Figure  1b]. Further investigations
6 cycles of denosumab and followed by extended curettage,
showed no distant metastasis. Considering clinical picture,
phenol cauterization, and cementing.
imaging, and biopsy, the patient was treated with neoadjuvant
subcutaneous injection of denosumab 120 mg subcutaneous
Case Report every 28 days up to 6 cycles and with additional 120 mg on
A 20‑year‑old female presented with a history of pain and the 8th and 15th day of the first cycle of therapy. The patient
swelling over the right knee for 4‑month duration. There was
no history of trauma or fever. On the local examination, three Address for correspondence: Dr. Biplabi Sarangadhar Das,
was a firm, nontender, well‑defined swelling arising from the Department of Orthopedics, Shri Ramachandra Bhanj Medical College,
lateral aspect of the right distal femur. There was no crepitus Cuttack, Odisha, India.
and tenderness, and the range of movement at the knee was E‑mail: d.biplabi@gmail.com

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DOI:
10.4103/oji.oji_15_17 How to cite this article: Maharaj RC, Panigrahi S, Das BS. Effect of
denosumab in giant cell tumor of bone. Oncol J India 2017;1:34-6.

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Maharaj, et al.: Denosumab in giant cell tumor

was followed up every month. After completion of six doses of

denosumab, X‑ray and MRI of the lesion showed consolidation
of the lesion with reduction of size, sclerosis, and healing of the
cortical breaks [Figure 2a]. The patient treated with extensive
curettage with a cortical window with high‑speed burr,
cauterization of the wall of the cavity with phenol, and filling
the resulting cavity with 80  mg of polymethylmethacrylate
bone cement [Figure 2b]. Sample was sent for histopathology
study and revealed a significant decrease in the number of giant
cells as well as stromal cells with areas of fibrosis indicating
response to denosumab  [Figure  3]. There was no evidence a b
of wound infection in postoperative period. The patient was Figure 1: (a) X‑ray of the right knee (frontal and lateral view) showing a
discharged after suture removal. The patient could comfortably well‑defined expansile lytic lesion involving lateral condyle of the distal
bear weight on the 2nd  postoperative day; she resumed her femur measuring approximately 4 cm × 6 cm with cortical thinning and
routine physical activity after discharge. few foci of cortical breach, and (b) microsection (H and E, ×100) showing
presence of multinucleated giant cells with stromal cells

Discussion
RANKL is the ligand for endogenous protein osteoprotegerin
expressing on the surface of osteoblasts and released into
the microenvironment where it binds to and activates its
receptor RANK on the immature osteoclast. The activation of
RANK‑RANKL is necessary for the formation, survival, and
function of osteoclast, and hence, blocking interaction between
RANK‑RANKL will limit the osteoclastogenesis.
In GCT, osteoclastic giant cells are uniformly distributed in
a b
a background consisting of mononuclear rounded cells and
spindle‑shaped stromal cells with high levels of RANKL Figure 2: X‑ray of the right knee showing (a) consolidation of the lesion
expression.[3] Aggressively lytic behavior is the hallmark of and reduction in the tumor size to approximately 2.5 cm × 4.5 cm after
denosumab therapy, and (b) tumor replaced by polymethylmethacrylate
the GCT. This osteoclast‑like tumor giant cell is responsible
bone cement
for this lytic process, and RANKL potentiates this osteoclast
differentiation of monocytes leading to the process.
Denosumab is a human monoclonal antibody that binds to
RANKL with high affinity, preventing its interaction with
RANK on the osteoclast surface and inhibits normal or
tumor‑associated osteolysis disrupting the cycle of bone
destruction.[3,4] The dose schedule of the denosumab also
varies, and it may consist of three loading doses of 120 mg at
7 days apart followed by one dose every 4 weeks or consists of
120 mg monthly dose without any loading dose.[5,6] Published
data showed that denosumab suppresses bone destruction in
patients with osteolytic bone disease such as bone metastases
in breast and prostate cancer and other solid tumors.[3]
Denosumab has the ability to prevent tumor progression,
induce primary tumor reduction, increase bone formation, and
reduce pain in GCT.[7] A phase II study showed the benefit of
treatment with denosumab in altering the osteolytic effect of Figure 3: Microsection (H and E, ×100) showing areas of fibrosis with
GCT of bone.[8] A study on histologic comparison of baseline significant reduction in giant cells and stromal cells
and after treatment with denosumab for the GCT of bone
showed a response in classical architecture, changing from giant cells.[3] It indicates the differentiation of tumor cell
proliferative densely cellular stromal cells, RANK‑positive component toward a nonproliferative osteoblastic phenotype
mononuclear cells, and tumor giant cells to nonproliferative with a marked reduction in osteolysis. The possible mechanism
osteoid matrix, wove bone, and new bone with only focal of such response may be indirectly by eliminating factors
areas of proliferative RANKL‑positive stromal cells and associated with tumor giant cells or by direct action on the
mononuclear cells and with greatly reduced number of tumor tumor stromal cells to form bone.

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Maharaj, et al.: Denosumab in giant cell tumor
Denosumab delayed disease progression, prolonged time to
surgery, and downgraded the tumor that reduces the need for
mutilating surgery in patients with GCTB. However, many
questions are remain unsolved including the optimal timing
for excision of tumor in a patient receiving neoadjuvant
denosumab as well as the optimal duration of treatment in
unresectable tumor and also the need for adjuvant therapy
with denosumab to prevent relapse. Furthermore, the
exact proportion of relapse patients receiving neoadjuvant
denosumab is unclear. Prospective randomized trial studies
with larger sample size are necessary to know the different
stages of treatment, optimal dose, its side effect, and
pattern of disease progression after discontinuation of the
denosumab.
Declaration of patient consent
The authors certify that they have obtained all appropriate
patient consent forms. In the form the patient(s) has/have
given his/her/their consent for his/her/their images and other
clinical information to be reported in the journal. The patients
understand that their names and initials will not be published
and due efforts will be made to conceal their identity, but
anonymity cannot be guaranteed.
Financial support and sponsorship
Nil.
36
Conflicts of interest
There are no conflicts of interest.
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Oncology Journal of India  ¦  Volume 1  ¦  Issue 2  ¦  October-December 2017