Radiological and histopathological appearance of giant cell

tumour of bone before and after the different therapeutic

strategies.

Poster No.: C-1165

Congress: ECR 2015
Type: Educational Exhibit
Authors: P. Garcia Barquin, M. Millor Muruzbal, J. D. Aquerreta, M. San
Julian, J. L. Solorzano, J. M. Bondia, M. A. idoate; Pamplona/ES
Keywords: Pathology, Neoplasia, Diagnostic procedure, MR, CT,
Conventional radiography, Musculoskeletal bone
DOI: 10.1594/ecr2015/C-1165

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Learning objectives

1. Learning objectives

The aim of this exhibit is

- To focus on the radiological and histopathological appearance of giant cell tumour of

bone (GCTB).

- To review the different therapeutic strategies and the recurrences.

Background

2. Background

Giant cell tumor of bone (GCTB) is a rare benign primary bone tumor, that commonly
occurs in young adults. It accounts for 5% of all primary bone tumors and 20% of the
benign skeletal tumors. Some studies show an increased prevalence among females (1).

Although it is categorized as benign, GCTB is also know for its locally agressive behavior,
high recurrence rates and the metastasic potential with predilection to the lungs.

They tipically affect the epiphyseal or metaphyseal region of the long bones (2).

Radiological appearance

On conventional radiographs, GCTB appears as lytic lesion, with a well defined non
esclerotic margin and with tipically an eccentric location. The lesion normally involves the
epiphysis and the adjacent metaphysis and there is frequent extension to the subchondral
plate, sometimes with joint involvement. Fig. 2 on page 3 .GCT occurs in patients
with closed physes.

On CT they are agressive lesions with thinning and destruction of the cortex. CT scans
give a more accurate assessment of cortical thinning and penetration, and the presence
or absence of bone mineralization. Fig. 3 on page 4

The MR imaging findings are usually nonsepecific. On T1 weigthed imaging they appear
as intermediate or low signal homogeneous lesions. On T2 weigthed imaging they are

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very variable. They can be hyperintense but they may also show low signal intensity due
to the presence of hemosiderin, high collagen content and high cellularity. This sign is
very characteristic of this tumor.

After gadolinium administration they present diffuse enhacement (3,4).

MRI is particularly useful for assessing the integrity of the surrounding soft tissue,
including neurovascular structures, and the extent of subchondral extension into adjacent
joints (4). Fig. 4 on page 5 , Fig. 5 on page 6 , Fig. 6 on page 7 .

Positron emission tomography with 2-deoxy-2-[fluorine-18]fluoro- D-glucose integrated

with computed tomography (18F-FDG PET/CT) showed an increased standardized
uptake value (SUV) on the tumor.

Histological appearance

Histologically it is characterized by multinucleated giant cells with a background of

mononuclear stromal cells (4, 5). Fig. 7 on page 8

Images for this section:

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Fig. 2: Normal GCT appearance. A 70 years old female with pain in right wrist since
two years ago. (A and B). Anteroposterior and lateral conventional radiographs show
a meta-epiphyseal expansile lytic lesion in the right distal radius with extension to the
subchondral bone and with a narrow zone of transition and internal septa. The pathologic
analysis demonstrated a giant cell tumor of bone. Patient of 22 years old who presents
with pain in left knee. (C and D). Anteroposterior and lateral radiographs demonstrate the
presence of a lytic lesion in the left tibia that is eccentric in location and extends to the
subchondral bone and corresponds to a pathologically proved GCT.

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Fig. 3: GCT CT appearance. 21 year old woman with severe pain in right buttock radiating
from both lower extremities. (A and B). Axial CT scans images show a lytic lesion with
soft tissue component in the sacrum with destruction of the cortex that corresponds to a
pathologically proved GCT of the sacrum.

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Fig. 4: MRI appearance of GCT. A 70 years old female with pain in right wrist since
two years ago. (A). Coronal T1 image shows a GCT of the distal radius presenting
as a hypointense lesion in the distal radius. (B). On coronal STIR sequence GCT
shows increased signal intensity. (C) .On T1 weigthed after intravenous gadolinium
administration , the tumour present diffuse homogeneous enhancement.

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Fig. 5: MRI appearance of GCT. 21 year old woman with severe pain in right buttock
radiating from both lower extremities. A. Sagittal T1 weigthed sequence shows a
mass in the sacrum with low signal intensity. B and C. On Sagittal T2 weigthed and
STIR sequences, the tumour is predominantly hypointense due to the presence of
hemosiderin or high collagen content, this sign is very characteristic of this tumor. MRI is
particularly useful for assessing the integrity of the surrounding soft tissue, including the
neurovascular structures, and the extent of subchondral extension into adjacent joints.

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Fig. 6: MRI appearance of GCT. 27 year old woman refers hypoesthesia saddle with
constipation. A. 18F-FDG PET/CT revealed a destructive tumor of the sacrum with
increased uptake. B. Sagittal T2-weighted sequence demosntrates a locally aggressive
sacral lesion extending from S2 to S4, breathing and destroying the anterior and posterior
cortex. The lesion associates a soft tissue component that extends into the sacral canal.
The mass is slightly hyperintense and homogeneous on T2-weighted sequence. C and
D. Sagittal and axial T1-weighted images after administration of paramagnetic contrast,
the tumour presents a marked homogeneous enhancement.

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Fig. 7: Histopathological appearance of GCT. The histological section of the biopsy
demonstrates a mesenchymal benign tumor cell thick . The tumor is basically composed
of a double cell component consisting on mononuclear stromal cells , rounded or
spindle, interspersed with frequent multinuclear giant cells , osteoclast-like appearance.
(heamtoxylin-eosin stain. (A) x10, (B) x20.)

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Findings and procedure details

3. Therapeutic strategies

A. Surgery

Surgery is the treatment of choice for a resectable giant cell tumor of bone (GCTB).

The goal of surgery is to locally control the tumor and achieve the best functional outcome.

Options for surgical treatment include intralesional curettage, marginal excision, a wide
local excision, or en bloc resection.

The type of surgery chosen depends on the site and size of the tumor in relation to
surrounding structures and tumor extent, and whether or not a pathologic fracture has
occurred which may compromise reconstructive options. Normally the surgical curettage
should be considered as the first

approach for treatment of high grade GCT in weightbearing areas, especially in young
patients, with wide excisions only used as a fallback procedure should curettage fail. (6,
7).

En bloc resection is performed when there is a major bone and joint destruction, to
aggressive recurrences, or expendable bony areas such as the head of the fibula. En
bloc resection is always followed by a reconstructive surgery, which can be accomplished
by an autograft (as a vascular graft fibula), an allograft, a prosthesis or an arthrodesis.
(6, 7). Fig. 8 on page 12 , Fig. 9 on page 13, Fig. 10 on page 14 and Fig.
11 on page 15 .

In an attempt to decrease local recurrence rates after intralesional curettage, various

surgical adjuvant therapies have been tried. Examples include the use of bone cement
(polymethylmethacrylate), aqueous zinc chloride, phenol and cryotherapy with or without
cement or bone graft. (8,9).

Bone cement has emerged as the preferred adjuvant agent. Furthermore, the radiologic
features of a cement-filled cavity are ideal to permit early identification of local
recurrences (10).

B. Radiotherapy

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GCTB is a radiosensitive tumor, and radiotherapy is highly effective, resulting in long-
term local control rates (11).

Some studies have reported that when complete surgical resection is not possible,
adjuvant radiotherapy may minimize the risk of local recurrence. So it must be considered
as an adjuvant treatment to surgery.

Special locations

Large midline GCTB of the sacrum are difficult to treat. Surgery carries a high risk
of morbidity and disability, and radiation carries at least the potential risk of long-term
malignant transformation(12).

C. Trans-arterial embolization

There are several studies leading to significant reduction in the size of the GCT
after trans-arterial embolization. However the endovascular option is still been as a
preoperative neo-adjuvant therapy to the surgical resection to reduce the intraoperative
bleeding rates (13,14). Fig. 12 on page 16 and Fig. 13 on page 17 .

D. Systemic therapy

RANKL inhibitors: Denosumab

Denosumab is a new human monoclonal antibody against the RANK-ligang. It has been
demonstrated to have a significant impact in the natural history of GCT, because its anti-
osteoclastic activity (15).

On June 2013 Denosumab was approved by FDA for the treatment of unresectable GCT
of bone. Benefit in patients with GCTB was shown in a phase II study in which 37 patients
with recurrent or unresectable GCTB were treated with denosumab (15,16).

Histologically, denosumab significantly reduced or eliminated giant cells, and also

reduced the relative content of presumably neoplastic stromal cells, while promoting the
formation of new bone (17).

Many studies have demonstrated the benefit of denosumab in patients with GCTB.
But there are few reports of the radiological changes of GCT after denosumab, limited
to case reports and few examples.Denosumab has shown good results consisting on
the development of a peripheral sclerotic rim and reconstitution of cortical bone on
conventional radiographs and CT On MRI, size reduction, lower signal intensity on T2-
weigthed images and less enhancement after contrast admistration can be observed

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(18,19,20). Fig. 14 on page 18 , Fig. 15 on page 19 , Fig. 16 on page 20 ,
Fig. 17 on page 21 , Fig. 18 on page 22 and Fig. 19 on page 23 .

The long-term effects of denosumab in the GCTB population are not known, a fact which
should be taken into account in therapeutic decision making (21).

4. Complications

Recurrences

The recurrence rates after surgery with curettage and placement of cement have been
relatively high (15-25%).

It is necessary to monitor continuously patients with TCG and conduct a detailed

comparative study with previous studies images to differentiate the postoperative
changes of tumor recurrence and other complications.

Follow-up radiograhps should be analyzed for any lucency at the cement bone interfaces
or expansin of cortical bone.

CT or MRI allows a good identification of the osteolysis and the presence of a soft tissue
mass (22). The recurrences tipically appear in the periphery of the cavity at the interface
with the healthy tissue. They are characterized by an aggressive bone destruction and
osteolysis rapidly progressive filling material.

On MRI the recurrences have an expansive nodular appearance and intense intravenous
contrast enhancement of the tumor.

Fig. 18 on page 22 , Fig. 19 on page 23 and Fig. 20 on page 24 .

Other complications that can occur after surgery are the collapse of the articular surface,
the leakage of the filler material, the presence of pathological fractures or postoperative
infections.

Images for this section:

Page 12 of 28
Fig. 8: Example of intralesional curettage and bone cement. Anteroposterior and lateral
radiographs of the distal radius showing a GCT before (A and B) and after the surgical
treatment with intralesional curettage and bone cement placement (C and D).

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Fig. 9: Example of intralesional curettage and bone graft. Anteroposterior and lateral
radiographs in this other patient with a GCT of the tibia reveals the radiographs before (A
and B) and after the surgical treatment with curettage, cryosurgery and filled with allograft
cancellous bone (C and D).

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Fig. 10: Example of en bloc resection. Lateral radiographs in this other patient with a GCT
of the first methacarpal before (A) and after the surgical treatment with en bloc resection
and reconstruction with bone graft stabilized by osteosynthesis plate and screws (B).

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Fig. 11: Example of en bloc resection. A. Coronal CT of a lytic lesion of the proximal
phalanx of the third finger that corresponds to a GCT of bone. It was treated with resection
of the proximal phalanx and replaced with a silicone prosthesis (B).

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Fig. 12: Example of trans-arterial embolization. Note in this patient a hyperpervascular
lesion which depends on several small pedicles of the radial artery (A). The lesion was
embolized using 100 micro particles. The angiographic results were satisfactory (B).

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Fig. 13: Example of trans-arterial embolization of GCT. Hypervascular mass located in
the sacrum and dependent on various branches of both internal iliac arteries. Also distal
branches of the median sacral artery are involved (A). Embolization using 100-300 micro
particles was performed .The angiographic results were satisfactory (B). (C,D,E and F)
(Hematoxylin-eosin stain; C X10; DX4;EX4; FX10). The histological section shows a bone
tissue that is occupied by a homogeneous atypical mesenchymal cell proliferation thick,
consisting of a double cell population. On the one hand a component of mononuclear
cells abundant basophilic cytoplasm core rounded with slight strengthening of the
nuclear membrane and presence central nucleolus is observed . The second population
consisted of multinucleated giant cells , osteoclast appearance, showing cores similar to
those characteristics of the mononuclear cells . Frequently basophilic microspheres for
embolization was observed (yellow arrows). In addition corresponding to cortical showing
no significant microscopic alterations bone tissue is appreciated.

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Fig. 14: Denosumab is a fully human monoclonal antibody against RANKLigand.

Page 19 of 28
Fig. 15: Response to Denosumab in combination with other treatments. This woman
presents a lytic lesion of the sacrum in the lateral radiograph (A).The pathologic analysis
demonstrated a giant cell tumor of bone. The tumour was treated with embolization
(december 2011), curettage (december 2011) and radiotherapy (february 2012). The
lateral radiographs after the different therapeutic strategies on February and June are
shown (B and C). Then she began the treatment with Denosumab. After two years with
Denosumab we can observed an important radiological response with peripheral sclerotic
rim accurately demonstrated on conventional radiograph (D).

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Fig. 16: Response to Denosumab in combination with other treatments. Same patient
of the previous figure. Axial CT scans performed on January after de embolization
and the surgery with curettage.(A and B). After treatment with Denosumab, the patient
developed an important peripheral sclerotic rim accurately demonstrated on axial CT with
an important disappearance of the soft tissue component (C and D).

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Fig. 17: Response to Denosumab. This woman with a destructive lesion of the first
metacarpal with small bone partitions inside and severe bone insufflation.(A) The lesion
corresponds to a GCT of bone. It was treated with embolization, Denosumab and PTH.
After 3 months we can observed a dramatic response with an important sclerosis and
marked ossification of the tumour, allowing the surgery.(B). (C and D). Post treatment
histological section of the surgical specimen. Severely disturbed of the bone tissue due
to the presence of marked reaction mature with fibrous aspect in relation to received
treatment. No tumor giant cells are observed . Instead, a cellular fibrous lesion mature-
looking , with a very unique aspect, is recognized. It seems to be secondary to previous
treatment received (Denosumab).

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Fig. 18: Response to Denosumab in a recurrence. 22 years old patient with pain in left
knee. The lateral conventional radiograph demonstrates a lytic lesion in the tibia that
corresponds to a GCT (A). It was treated with curettage and bone cement placement
(B). The radiograph of control one year later reveals an increased area of lucency very
suggestive of a recurrence of GCT (yellow arrow) (C). After starting treatment with
Denosumab on April 2014, a slow and gradual increase in density with increasing internal
trabeculae and better edge definition is identified (yellow arrow) (D).

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Fig. 19: MRI imaging findings in a response to Denosumab in a recurrence. Same patient
of the previous figure. Sagittal T2 - weigthed (A), STIR coronal (B) and axial T1 - weigthed
(C) images demonstrated a lesion treated with cement in the tibia with a solid component
on the posterior edge of the tumour cavity, very suggestive of a recurrence of a GCT
(yellow arrows) . After treatment with Denosumab, ten months later (October 2014), we
can observed lower signal intensity on T2- weigthed and STIR coronal images (D and
E) probably due to the presence of more fibrosis. Note also the thickening and better
definition of the cortical on the T1-weigthed image (F).

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Fig. 20: Recurrence of GCT. Patient 27 years old with pain on the inside of the left knee.
(A) Axial CT scan demonstrates a lytic lesion in the tibia. MRI images show a tibial tumor
displaying hypointense on coronal T1-weigthed (B) and hyperintense on coronal proton
density fat -supression imaging (C). The lesion corresponds to a pathologically proved
GCT. The patient was operated in November 2012 by curettage and filled with bone
cement placement. 10 months later an MRI of control was performed. In relation to the
posterior edge of the cement cavity there was a small nodular lesion of 6mm, which was
demonstrated on the axial T1- weigthed image after contrast administration (D), coronal
STIR (E) and coronal T1 weigthed image after contrast (F) with marked enhancement.
These imaging findings were very suggestive of a tumor recurrence.

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Conclusion

Conclusions

- It is important to recognize the different radiological and histopathological features of

GCT before and after the different therapeutic strategies.

- On CR, GCTB appears as lytic lesion, with a well defined non esclerotic margin and
with tipically an eccentric location.

- CT and/or MR are required for make an accurate tumor assessment but the histological
confirmation is always mandatory.

- Typical MR features of GCT include hypointensity on T2- weigthed images and avid
enhancement after intravenous gadolinium administration.

- GCT treatment remains mostly surgical; nonetheless Denosumab hasshown good

results consisting on the development of a peripheral sclerotic rim on conventional
radiographs and CT, lower signal intensity on T2- weigthed images and less
enhancement after gadolinium administration.

- Denosumab may be an option for recurrent and surgically unsalvageable GCT.

Personal information

References

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