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Case Records of the Massachusetts General Hospital

Founded by Richard C. Cabot

Eric S. Rosenberg, M.D., Editor Nancy Lee Harris, M.D., Editor
Jo‑Anne O. Shepard, M.D., Associate Editor Alice M. Cort, M.D., Associate Editor
Sally H. Ebeling, Assistant Editor Emily K. McDonald, Assistant Editor

Case 26-2016: A 28-Year-Old Woman with

Back Pain and a Lesion in the Lumbar Spine
Edwin Choy, M.D., Ph.D., Francis J. Hornicek, M.D., Ph.D., Yen‑Lin Chen, M.D.,
Daniel I. Rosenthal, M.D., and Darcy A. Kerr, M.D.​​

Pr e sen tat ion of C a se

Dr. Joseph H. Schwab (Orthopedics): A 28-year-old woman was admitted to this hospital From the Department of Medicine, Divi-
because of back pain and a lesion in the lumbar spine. sion of Hematology–Oncology (E.C.), and
the Departments of Orthopedic Surgery
The patient had been well until approximately 6 months before admission, (F.J.H.), Radiation Oncology (Y.-L.C.), Ra-
when low back pain developed and then worsened and could not be relieved by diology (D.I.R.), and Pathology (D.A.K.),
ibuprofen (at a dose of 800 mg every 6 hours, as needed). Approximately 6 weeks Massachusetts General Hospital, and the
Departments of Medicine (E.C.), Ortho-
before admission, severe pain developed that radiated down her left leg to her pedic Surgery (F.J.H.), Radiation Oncology
ankle. She was seen by her primary care physician, and acetaminophen and hydro- (Y.-L.C.), Radiology (D.I.R.), and Pathol-
codone were prescribed for 2 weeks; her condition did not improve. Approxi- ogy (D.A.K.), Harvard Medical School —
both in Boston.
mately 1 month before admission, she was seen in the emergency department of
another hospital, and prednisone was prescribed for 4 days, with transient im- N Engl J Med 2016;375:779-88.
DOI: 10.1056/NEJMcpc1505482
provement. She returned to her primary care physician’s office when the pain Copyright © 2016 Massachusetts Medical Society.
worsened. Imaging studies of the lumbar spine that had been performed at an-
other hospital reportedly revealed destruction of the fifth lumbar vertebra (L5) and
the presence of a large soft-tissue mass extending into the spinal canal and para-
spinal soft tissues. Neurosurgical consultation was obtained. Ten days before ad-
mission, a biopsy of the lesion in the paravertebral region of the lumbar spine was
performed.
Dr. Darcy A. Kerr: Pathological and cytologic examination of the biopsy specimen
revealed a giant-cell tumor of bone.
Dr. Schwab: The patient was referred to the orthopedic oncology clinic of this
hospital. On evaluation, she reported “excruciating” pain in her back that awak-
ened her from sleep, radiated down her left leg, and was associated with swelling
and numbness of the knee and distal leg but not with perineal numbness. She was
primarily restricted to a wheelchair or bed because of the pain. She had mild con-
stipation that she attributed to pain medications and no incontinence of urine or
stool. She had migraine headaches and had had two previous episodes of transient
lumbar back pain after motor vehicle accidents. Medications were gabapentin,
ibuprofen, and oxycodone for pain, which she reportedly took sparingly. She was
allergic to penicillin, which caused a rash. She had moved to the United States
from the Caribbean as an infant, lived in an urban area with her boyfriend and
child, and worked in retail. She did not smoke tobacco, drink alcohol, or use il-

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 The n e w e ng l a n d j o u r na l
licit drugs. Her parents were living, and some of
her relatives had high blood pressure and hyper-
cholesterolemia.
On examination, the patient was in mild dis-
tress and walked with a limp. The blood pres-
sure was 142/84 mm Hg, and the pulse 105 beats
per minute; the temperature, respiratory rate, and
oxygen saturation were normal. The left ilium
and left lower lumbar spine were tender in re-
sponse to palpation, and there was no palpable
mass. The left foot was slightly cooler than the
right; pedal pulses were present. Strength testing
revealed 5/5 (normal) strength in all muscle
groups on the right side, 4+/5 strength in the
left iliopsoas and hamstrings, and 4/5 strength
on abduction of the left hip. Strength was 5/5 bi-
laterally in the quadriceps, tibialis anterior, exten-
sor hallucis longus, and gastrocnemius and so-
leus complex. The patient’s left leg had decreased
sensation, particularly along the lateral thigh,
medial and lateral calf, and dorsal and plantar
aspects of the foot. The patellar and Achilles re-
flexes were 1+ bilaterally; the Babinski sign was
not present. There was no clonus. Toe and heel
walking were limited because of the pain in her
back and leg. Active and passive straight-leg-
raising tests induced radicular pain in the left
leg. She had minimal pain when she performed
the FABER (flexion, abduction, and external rota-
tion of the hip) maneuver, and femoral nerve
stretch testing was negative.
A complete blood count, white-cell differential
count, and blood levels of electrolytes, calcium,
glucose, urea nitrogen, and creatinine were nor-
mal. The patient was admitted to the hospital,
and narcotic analgesic agents and gabapentin
were administered for pain.
Dr. Daniel I. Rosenthal: Radiographs of the lum-
bosacral spine showed a lytic lesion involving L5.
There was destruction of the left pedicle and
central portions of the vertebral body (Fig. 1A
and 1B). Computed tomography (CT) and mag-
netic resonance imaging (MRI) of the lumbar
spine revealed involvement of the lamina and a
very large, hypervascular paraspinal mass. The
mass extended into and filled the spinal canal
(Fig. 1C through 1F). The next day, CT of the
chest revealed an indeterminate nodule (3 mm
in diameter) in the left upper lobe but was other-
wise normal. A radionuclide bone scan showed
high uptake between L5 and the first sacral
vertebra (S1).
Dr. Schwab: Management decisions were made.
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of m e dic i n e
Discussion of M a nagemen t
Surgical Management
Dr. Francis J. Hornicek: This patient has an unusual
presentation of giant-cell tumor of bone. She has
a locally advanced lesion of the lumbar spine
that produces disabling symptoms due to com-
pression of the spinal nerve roots and adjacent
structures. This presentation poses management
challenges.
Giant-cell tumor of bone occurs most com-
monly around the knee. The axial skeleton is
generally an uncommon location for giant-cell
tumor of bone, although the sacrum is the
fourth most common location for this tumor.
Giant-cell tumor of bone involves the spine in
3 to 7% of cases, and it accounts for up to 4%
of vertebral tumors.1 Approximately 60% of cases
in the mobile spine occur in the vertebral bodies.
In the past, resection with wide surgical mar-
gins was the most common treatment for giant-
cell tumor of bone, and recurrences were un-
common. However, reconstruction after such
procedures was complex and associated with a
high rate of complications. Because giant-cell
tumor is typically benign, the current standard
of care does not include a wide resection unless
the tumor is located in an expendable bone (e.g.,
the clavicle, distal ulna, or proximal fibula) in
which resection produces no clinically significant
effect on function. Intralesional surgical proce-
dures, which involve curettage of the tumor and
débridement of the surface of the healthy bone
with a burr, are the mainstay of therapy in most
other cases. Primary radiotherapy is not rou-
tinely used unless the tumor is located in an
anatomical region in which resection would be
challenging, such as the sacrum.
The local recurrence rates for giant-cell tumor
of bone approach 20% among patients who have
undergone intralesional surgical procedures2;
therefore, new local adjuvant and systemic
therapies have been sought. Among patients
who have undergone an intralesional procedure
with cryosurgery, the local recurrence rates are
less than 8%,3 because the freeze–thaw cycle kills
cells farther from the burred surface, extending
the depth of the effective curettage. However,
pathologic fracture and vascular injury have
been associated with this form of adjuvant
therapy.4 Other adjuvant therapies, such as ther-
apy with phenol, hydrogen peroxide, or an argon
laser, have been used with varying degrees of
 Case Records of the Massachuset ts Gener al Hospital

A B C

D E F

Figure 1. Imaging Studies Obtained on Admission.

Anteroposterior and lateral radiographs of the lumbar spine (Panels A and B, respectively) show a destructive lesion of
the L5 body (Panel A, arrow) and left pedicle (Panel B, arrow). Axial and reformatted sagittal CT scans (Panels C and D,
respectively) show a large destructive mass extending from the body of L5 into the retroperitoneum (Panel C, arrow),
invading and displacing the psoas and iliacus muscle. The great vessels are displaced anteriorly. An axial, gadolinium-
enhanced, T1-weighted MRI image with fat suppression (Panel E) and a coronal T1-weighted MRI image (Panel F) show
the hypervascular mass extending into the spinal canal (Panel E, arrow) and the surrounding soft tissues.

success, but phenol and an argon laser are not
used routinely when the tumor is close to nerves,
as it was in this case. En bloc wide resection is
a treatment option for an aggressive or recurrent
giant-cell tumor of bone. When extensive bone
destruction is present, as it was in this case,
bulk structural allografts, endoprosthetic im-
plants, or a combination of the two can be used
for reconstruction. Reconstruction with a bulk
structural allograft can be used in either the
spine or the limbs. Endoprosthesis is used for
structural defects in the limbs (e.g., for a distal
femoral resection), whereas different types of
anterior spinal cages that are made of various
metals are used for anterior structural defects
(e.g., for vertebral-body replacement); vascular-
ized grafts, such as a fibular graft, can also be
used for anterior structural defects, in conjunc-
tion with the hardware.
For giant-cell tumor of the spine, nonoperative
or minimally invasive treatments may be consid-
ered if the patient is asymptomatic and there are
no structural problems with the spinal column.
For a symptomatic patient, we can consider en
bloc excision or embolization alone or in combi-
nation with intralesional surgical procedures.
Radiotherapy alone would not decompress neural
elements in a timely fashion in most neoplasms,
except in lymphoma and Ewing’s sarcoma.
For this patient, we recommend en bloc exci-
sion with a planned intralesional surgical mar-
gin, rather than a piecemeal intralesional excision.
Even with embolization of most of the tumor
vasculature, intralesional procedures are not in-
frequently associated with clinically significant
bleeding, which is more difficult to control in the
axial region than in the limbs. We performed a
two-stage operative procedure to remove the L5
giant-cell tumor. During the first stage, posterior
spinal-canal decompression and spinal stabiliza-

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tion from L3 to the pelvis were performed with
the use of standard techniques. After the spinal
decompression, a partial diskectomy was per-
formed at the L4–L5 and L5–S1 levels. Decorti-
cation of posterior elements was performed, and
processed corticocancellous allograft bone chips
were placed to achieve bone fusion at a later time.
Radiologic Management
Dr. Rosenthal: Six days after the first stage of the
operation, tumor embolization was performed by
our interventional radiologists. The right com-
mon femoral artery was accessed, and a midseg-
ment of the median sacral artery, a medially di-
rected branch off the right L4 segmental artery,
a right iliolumbar artery, and a left L4 segmental
artery were all injected, through a microcatheter,
with a contrast slurry of polyvinyl alcohol in the
form of irregular 250-to-355-μm particles.
Embolization is used in the treatment of giant-
cell tumor to decrease vascularity in preparation
for resection. These tumors are usually highly
vascular; in some instances it is possible to actu-
ally feel the tumor pulsate with each heartbeat.
Embolization within 24 hours before operation
can occlude large-vessel flow and reduce the risk
of hemorrhage at the time of surgery. This is
particularly important for axial and deeply situ-
ated tumors (such as those of the sacrum), in
which hemostasis may be difficult or an intra­
lesional resection may be required.5
Serial embolization (performed every 6 weeks
until no neovascularity is present) without resec-
tion can also be used to provide long-term tumor
control for tumors that are associated with un-
acceptable operative risks, but we believe it should
be regarded as a secondary choice.6 It is unclear
whether the inclusion of chemotherapeutic
agents, as compared with the use of thrombotic
agents alone, improves results.
Further Surgical Management
Dr. Hornicek: During the second stage of surgery,
performed 6 days after the first stage, anterior
exposure of the lumbosacral spine was obtained.
En bloc excision of the tumor with ligation of
the left common iliac vein was performed, fol-
lowed by anterior stabilization of the spinal
column. The nerve roots exiting the lumbar
spine were spared during the excision; we ac-
cepted the presence of remaining microscopic
disease on the nerve roots because this is con-
sidered to be a benign tumor. Reconstruction of
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of m e dic i n e
the vertebral body was performed with the use
of an expandable spinal-segment cage (Fig. 2).
Pathol o gic a l Discussion
Dr. Kerr: The resected specimen showed bone in-
volved by a giant cell–rich tumor (Fig. 3), charac-
terized by a monotonous proliferation of oval-to-
polyhedral mononuclear cells and osteoclast-type
giant cells. The mononuclear cells had uniform,
ovoid nuclei, vesicular chromatin, and small,
prominent nucleoli. The nuclei of these cells were
morphologically very similar to those of the
osteoclast-type giant cells. Giant cells were evenly
distributed throughout the lesion and often con-
tained more than 50 nuclei per cell, substantial­
ly more than are usually seen in osteoclasts.
Mitotic activity was present, without atypical
mitotic figures. Although giant cells may be
seen in association with any tumor involving
bone, certain primary bone tumors are charac-
terized by a giant cell–rich pattern and would
enter into the differential diagnosis in this case.
Brown tumor is one such tumor, although
this patient does not have a history of hyper-
parathyroidism. Both brown tumor and giant-
cell reparative granuloma, another tumor in
the differential diagnosis, are characterized by
osteoclast-type giant cells that cluster around
areas of hemorrhage and are unevenly distributed
within the lesion. The proliferating cells are
spindle-shaped and their nuclei do not resemble
those of the giant cells. Chondroblastoma is also
characterized by a giant cell–rich pattern, but it
is seen in persons who have skeletal immaturity
and is centered on the epiphysis. Again, the nuclei
of the mononuclear cells do not resemble those
of the osteoclast-type giant cells. Osteosarcoma
is the most important entity to rule out in the
differential diagnosis. The diagnosis of osteo-
sarcoma requires the presence of malignant cells
producing osteoid or bone, a feature that was
absent in the specimens from this patient.7,8
Given this differential diagnosis and the mor-
phologic features present in this case, the diag-
nosis of giant-cell tumor of bone was rendered.
Giant-cell tumor of bone is a benign but local­
ly aggressive neoplasm of mesenchymal mono-
nuclear cells that are thought to have an osteo-
blast-like phenotype. It was previously thought
that the giant cells were composed of collections
of mononuclear cells and that both components
were neoplastic, but numerous lines of evidence
 Case Records of the Massachuset ts Gener al Hospital

A B

Figure 2. Radiographs Obtained after Tumor Resection and Reconstruction.

Anteroposterior and lateral radiographs of the lumbar spine (Panels A and B, respectively) show removal of the L5
vertebral body, reconstruction with the use of a cage, and stabilization with pedicle screws secured to posterior rods.

now show that the mononuclear cells are the
neoplastic cells and that they recruit large osteo-
clast-type giant cells that are reactive in nature.9,10
Nonetheless, the morphologic similarity between
the nuclei of the mononuclear cells and those of
the giant cells remains an important histologic
clue to the diagnosis of giant-cell tumor of bone.
The mononuclear mesenchymal cells have muta-
tions in the histone H3 family protein (H3F3A)
and express high levels of RANKL (receptor
activator of nuclear factor-κβ ligand), whereas
the osteoclast-type giant cells express receptor
RANK.9 This patient had the typical epidemio-
logic features of a patient with giant-cell tumor
of bone, including skeletal maturity, an age be-
tween 20 and 45 years, and female sex. Giant-
cell tumor of bone accounts for 5% of primary
bone tumors. Local recurrence is seen in ap-
proximately 25% of cases, whereas metastasis
occurs in only 1 to 2% of cases and transforma-
tion to a high-grade sarcoma in less than 1% of
cases.7,8
The rare but well-documented phenomenon of
pulmonary metastasis from a giant-cell tumor
of bone that appeared to be histologically be-
nign has been associated with younger age, more
radiographically aggressive disease (according to
the radiographic staging system of Enneking
et al., in which bone tumors are classified as
latent, active, or aggressive), local recurrence, and
an axial location.12 In contrast to frankly malig-
nant tumors, pulmonary metastases often have
an indolent behavior, and thus giant-cell tumor
of bone has been considered to be among the
rare benign metastasizing tumors. Although
metastases usually involve the lung, they may in
rare cases involve other distant sites.13 Malignant
transformation in giant-cell tumor of bone is
classified as either primary (a sarcoma with
overt histologically malignant features arising in

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 The n e w e ng l a n d j o u r na l of m e dic i n e

A B

C D

Figure 3. Lumbosacral Resection Specimen (Hematoxylin and Eosin).

At low magnification (Panel A), there is an admixture of cellular tumor fragments (blue) and closely associated por-
tions of cortical and cancellous bone (pink) with attached articular cartilage. The tumor erodes into bone (Panel B)
and is composed of a diffuse proliferation of ovoid mononuclear cells, osteoclast-type giant cells, and scattered
foam cells. At higher magnification (Panel C), the giant cells appear to be relatively evenly distributed throughout
the lesion, and many are composed of a large number of nuclei. The mononuclear cells (Panel D) have eosinophilic
cytoplasm that appears to be syncytial in nature. The nuclei of the mononuclear cells and the giant cells are nearly
identical, with nuclear contours that are ovoid to slightly irregular, vesicular chromatin, and prominent nuclei. Mitotic
activity is noted, but no atypical mitotic figures are seen (Panel D).

association with histologically benign giant-cell
tumor of bone) or secondary (a sarcoma arising
at the site of a previously treated giant-cell tumor
of bone). These high-grade sarcomas may be as-
sociated with suppression of p53 activity and mu-
tation of HRAS10,13 and with a poor prognosis.14
Discussion of M a nagemen t
Medical Oncologic Management
Dr. Edwin Choy: After the tumor was resected,
adjuvant systemic therapy was considered. Evi-
dence for the inclusion of chemotherapy in the
treatment of giant-cell tumor of bone is scant
and limited to anecdotes, case reports, and case
series. Cisplatin, doxorubicin, ifosfamide, and
cyclophosphamide have typically been used.
However, the benefits of these agents have been
clinically marginal at best.15 Given the typically
benign behavior of giant-cell tumor of bone, we
did not think that chemotherapy should be used,
since the biopsy did not show that the tumor
had a component that had dedifferentiated into
a high-grade sarcoma.
This patient received adjuvant therapy with
zoledronic acid at a dose of three times monthly,
starting 1 month after the second stage of sur-
gery had been completed. Bisphosphonates are
often used to treat benign bone tumors (e.g.,
fibrous dysplasia) that are not amenable to sur-
gical resection. However, as with chemotherapy,
evidence for the use of bisphosphonate therapy
is also limited to case reports and small, retro-
spective studies.16-19 When the patient had suffi-
ciently recovered, approximately 3 months after
the second stage of surgery had been completed,

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 Case Records of the Massachuset ts Gener al Hospital

A B C

D E F

Figure 4. Follow-up CT Scans.

Five months after tumor resection was completed (Panel A), a local recurrence occurred at the tumor bed (arrow).
Five months after radiotherapy was completed (Panel B), the mass had decreased in size and the margins had be-
come partly ossified. Four years after radiotherapy was completed (Panel C), the margins of the lesion had become
progressively more ossified and the tumor had decreased slightly in size. Three months after the initial diagnosis was
made (Panel D), a small nodule appeared at the right lung base; it enlarged over the following 6 months (Panel E).
Six years after denosumab therapy was begun (Panel F), the nodule has remained stable.

she began to take self-administered interferon
alfa-2b at a dose of 3 million units per day.
The use of interferon as antiangiogenic ther-
apy for giant-cell tumor of bone was largely pio-
neered by Kaban and Folkman. They found effi-
cacy of interferon as both primary therapy20 and
adjuvant therapy.21,22 However, interferon often
results in depression, influenza-like symptoms,
and elevation of liver enzyme levels. Although
interferon therapy was associated with an accept-
able side-effect profile in this patient, her tumor
progressed after only 5 months of interferon
therapy.
Dr. Rosenthal: Repeat CT scans showed disease
progression. A paraspinous soft-tissue mass had
increased to 8.1 cm by 7.8 cm (Fig. 4A), a perito-
neal soft-tissue mass along the anterior surface
of the descending colon had increased to 5.0 cm
by 4.0 cm (not shown), and lung nodules had
developed or grown (Fig. 4D).
Dr. Choy: The peritoneal mass was associated
with clinically significant gastrointestinal bleed-
ing. Therefore, urgent surgery with a subtotal
colectomy, partial gastrectomy, and partial re-
section of the jejunum was performed.
Dr. Kerr: Examination of the resection speci-
men of the left colonic mass revealed a hemor-
rhagic tumor centered in the bowel wall. Histo-
logic examination revealed mononuclear cells,
osteoclast-type giant cells, and bland spindle
cells. These findings were similar to those pres-
ent in the patient’s primary tumor and were diag-
nostic of giant-cell tumor of bone involving the
colonic wall (Fig. 5).
Radiation Oncologic Management
Dr. Yen-Lin Chen: Giant-cell tumors have tradition-
ally been considered radioresistant, because there
is usually a lack of obvious response after radio-
therapy. However, it is more difficult to achieve
local control in the axial skeleton than in the
limbs after surgical treatment, and therefore an
adequate dose of radiotherapy is an appropriate
option for salvage therapy. Radiotherapy is associ-
ated with high rates of local control in patients
who cannot undergo surgical treatment or who
have recurrent disease.23,24
One concern about radiotherapy is malignant
transformation of a benign tumor. However,
most reports of malignant transformation are
based on data that were obtained before the
use of megavoltage radiotherapy. In a series of
21 patients with giant-cell tumors of the sacrum
who received orthovoltage radiotherapy, transfor-

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 The n e w e ng l a n d j o u r na l of m e dic i n e

A B C

C D

Figure 5. Left-Colon Resection Specimen.

The segment of left colon was distorted by a 6.5-cm tannish-red hemorrhagic mass that occupied and expanded the
muscular wall of the colon and indented the overlying tan, glistening mucosa (Panel A). At low magnification, the
histologic section showed intact colonic mucosa with an underlying dense, expansile tumor proliferation (Panel B,
hematoxylin and eosin). Some regions of the tumor showed spindle-shaped cells with storiform growth and hemo-
siderin deposition, features reminiscent of nonossifying fibroma or benign fibrous histiocytoma, a frequent focal
finding in giant-cell tumors of bone (Panel C, hematoxylin and eosin). However, most areas of the tumor had the
same mononuclear and giant-cell proliferation that was characteristic of the patient’s primary tumor (Panel D, hema-
toxylin and eosin), without areas of high-grade atypia or abnormal mitoses that would characterize an overtly malig-
nant process.

mation into a high-grade sarcoma occurred in
3 patients.25 Megavoltage radiotherapy for giant-
cell tumor of bone does not appear to be associ-
ated with a high rate of transformation to a
frankly malignant tumor. Rates of local control
range from 60 to 90% after the administration
of radiation doses ranging from 35 Gy in 15 frac-
tions to 60 Gy in 30 fractions. A dose higher
than 40 Gy appears to be important for local
control.23,24,26,27
After recovering from abdominal surgery, the
patient underwent radiotherapy for a recurrent
L5–S1 giant-cell tumor. The recurrent tumor of
the lumbar spine was treated with a cumulative
dose of 58 Gy at 2 Gy per fraction. The duodenal
metastasis was treated with a cumulative dose of
56 Gy at 2 Gy per fraction, while exposure to the
uninvolved intestine was kept to a dose of 45 Gy
or lower. The bleeding slowly resolved after a
week of radiotherapy and did not recur after the
therapy was complete. The urgent use of the radia-
tion shrank the rapidly recurring L5–S1 tumor
and controlled the bleeding from the duodenal
metastasis and thus sufficiently stabilized the
patient’s clinical status to allow her to receive
systemic treatment.
Further Medical Oncologic Management
Dr. Choy: One month after the completion of ra-
diotherapy, the patient was found to have a left
ureteral obstruction, which required placement
of a ureteral stent.
Dr. Rosenthal: Follow-up CT performed 5 months
after the completion of radiotherapy revealed a

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 Case Records of the Massachuset ts Gener al Hospital
decrease in the size of the L5–S1 mass of more
than 50% (Fig. 4B) and a reduction in the size of
the duodenal metastasis of more than 80% (not
shown). However, chest CT revealed enlarging
lung metastases (Fig. 4E).
Dr. Choy: Five months after completion of ra-
diotherapy, the patient was enrolled in a phase 2
trial of denosumab for patients with giant-cell
tumor of bone. Denosumab is a fully human
monoclonal antibody targeting RANKL. It was
initially developed for the treatment of post-
menopausal osteoporosis. RANKL is highly ex-
pressed on stromal cells in the tumor that, in
turn, release cytokines that support osteoclasts,
regulate osteoclastogenesis, and promote pro-
gression of giant-cell tumors of bone. A small
pilot study involving 37 patients28 and a phase 2
study involving 282 patients29 showed that, in
patients with either recurrent or unresectable
giant-cell tumor of bone, denosumab elicited a
tumor response (defined as a partial or complete
response according to the RECIST [Response
Evaluation Criteria in Solid Tumors] or EORTC
[European Organisation for Research and Treat-
ment of Cancer] criteria or the criteria of Choi
et al.) in 136 of the 190 patients who could be
radiographically evaluated and showed no dis-
ease progression in 179 of the 190 patients. On
June 13, 2013, denosumab was approved by the
Food and Drug Administration to treat giant-cell
tumor of bone.
An important but unanswered question for
patients receiving denosumab therapy is when
to discontinue treatment. In patients receiving
monthly injections of denosumab at a dose of
120 mg, the risk of the development of osteo-
necrosis of the jaw is approximately 1% per
year.30,31 The consequences of this can be severe
and require surgical management. Some of this
risk can be ameliorated by good dental hygiene
(daily tooth brushing and flossing, dental exami-
nations and cleaning twice a year, and avoidance
of invasive oral procedures). Patients receiving
denosumab are also at risk for spontaneous frac-
tures.32 Because denosumab is a potent inhibitor
of osteoclasts, the skeleton is unable to remodel
during the entire time the patient is exposed to
denosumab treatment. Although bone density
may increase, certain areas of the skeleton may
paradoxically become predisposed to spontaneous
fractures after several years of denosumab ther-
apy. For this patient, whose disease was very
aggressive and life-threatening, we opted to con-
n engl j med 375;8 nejm.org  August 25, 2016
The New England Journal of Medicine
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tinue the treatment indefinitely. Almost immedi-
ately after starting denosumab therapy, the pa-
tient’s requirement for narcotics for pain control
decreased, and no new lesions subsequently de-
veloped. The lung nodule has remained stable in
size (Fig. 4F), and she remains well while receiv-
ing denosumab therapy.
The patient had multiple urinary tract infec-
tions that required frequent replacement of her
ureteral stents (10 stents over a period of 3 years)
until she opted to have an elective nephrectomy.
She underwent the procedure without complica-
tions. At the time of this conference, approxi-
mately 6 years after the patient was enrolled in
the denosumab study, she remains in the study,
continues to receive denosumab every 4 weeks,
and is doing well, with no new evidence of pro-
gression or relapse of giant-cell tumor of bone.
Dr. Nancy L. Harris (Pathology): Are there any
questions or comments?
A Physician: What do the specimens of giant-
cell tumor of bone look like after treatment with
denosumab?
Dr. Kerr: The spectrum of morphologic changes
in giant-cell tumor of bone that occur after treat-
ment with this agent is currently an area of on-
going study. From the published reports of such
cases, post-treatment tumors appear to have a
marked decrease in osteoclast-type giant cells;
the giant cells tend to be smaller than those
seen in the pretreatment biopsy specimens and
to cluster at the periphery of the tumor.9 Treated
tumors show sclerotic bone deposition that in-
creases with the duration of treatment, as well
as a variable decrease in mononuclear cells.9,11,33
In some cases, the histologic pattern of bone
deposition may mimic that of primary osteosar-
coma or malignant transformation within giant-
cell tumor of bone, and thus knowledge of the
history of denosumab treatment and the associ-
ated spectrum of induced morphologic changes
is important.9
A nat omic a l Di agnosis
Giant-cell tumor of bone.
This case was discussed at Cancer Center Grand Rounds.
Dr. Choy reports receiving fees for serving on advisory boards
from Bayer, Amgen, and EMD Serono, consulting fees from
Pfizer and NPS Pharmaceuticals, and grant support from Am-
gen; and Dr. Hornicek, receiving fees for educational courses
from Stryker. No other potential conflict of interest relevant to
this article was reported.
Disclosure forms provided by the authors are available with
the full text of this article at NEJM.org.
787
 Case Records of the Massachuset ts Gener al Hospital

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