Histopathology of giant cell tumors of the bone: With special emphasis on fibrohistiocytic and aneurysmal bone cyst like components

Abstract

Objective: The aim of this study was to define histopathological features of giant cell tumor of bone, especially accompanying fibrohistiocytic or aneurysmal bone cyst like components, in the light of our institutions experience. Methods: A total of 120 cases (64 females and 56 males; mean age: 36.2 (12–80)) with ‘GCT’ diagnosed between the years 1996–2016 were included in this retrospective analysis. Cases were evaluated according to clinical features such as age, gender, localization, recurrence, metastasis and histopathological features. Results: Tumors were localized most frequently at proximal tibia and distal femur, respectively. In 11 cases areas rich in fibrohistiocytic component and in 20 cases aneurysmal bone cyst like component were observed. In 2 cases both components were present. Twenty three cases recurred. In 1 case which was primarily located at calcaneus, tumor metastasized to lung 4 years later during follow-up. Conclusion: GCT can be confused with other tumor or tumor-like lesions involving giant cells. Secondary changes such as fibrohistiocytic or aneurysmal bone cyst-like components and coagulation necrosis were frequently seen in conventional giant cell tumor of bone. For tumors having prominent fibrohistiocytic and/or aneurysmal bone cyst-like components, in order to detect characteristic areas representing GCT, additional sampling is essential. Although secondary histopathological changes do not appear to affect clinical outcome, these features are important in differential diagnosis. Approximately one fifth of GCT cases show recurrence and sacrum and foot bones were the most frequent sites for recurrence. Level of evidence: Level IV, diagnostic study.

Full text

Histopathology of giant cell tumors of the bone: With special
emphasis on fibrohistiocytic and aneurysmal bone cyst like
components
Nil Çomuno
glu
a
,
*
, Nuray Kepil
a
, Sergülen Dervis¸o

glu
b
a
Istanbul University, Cerrahpasa Medical Faculty, Department of Pathology, Istanbul, Turkey
b
Medipol University, Department of Pathology, Istanbul, Turkey
article info
Article history:
Received 5 May 2017
Received in revised form
13 July 2018
Accepted 8 October 2018
Available online xxx
Keywords:
Giant cell tumor of bone
Osteoclastoma
Bone tumors
Pathology
Bone
abstract
Objective: The aim of this study was to define histopathological features of giant cell tumor of bone,
especially accompanying fibrohistiocytic or aneurysmal bone cyst like components, in the light of our
institutions experience.
Methods: A total of 120 cases (64 females and 56 males; mean age: 36.2 (12e80)) with ‘GCT’diagnosed
between the years 1996e2016 were included in this retrospective analysis. Cases were evaluated according
to clinical features such as age, gender, localization, recurrence, metastasis and histopathological features.
Results: Tumors were localized most frequently at proximal tibia and distal femur, respectively. In 11
cases areas rich in fibrohistiocytic component and in 20 cases aneurysmal bone cyst like component
were observed. In 2 cases both components were present. Twenty three cases recurred. In 1 case which
was primarily located at calcaneus, tumor metastasized to lung 4 years later during follow-up.
Conclusion: GCT can be confused with other tumor or tumor-like lesions involving giant cells. Sec-
ondary changes such as fibrohistiocytic or aneurysmal bone cyst-like components and coagulation
necrosis were frequently seen in conventional giant cell tumor of bone. For tumors having prominent
fibrohistiocytic and/or aneurysmal bone cyst-like components, in order to detect characteristic areas
representing GCT, additional sampling is essential. Although secondary histopathological changes do
not appear to affect clinical outcome, these features are important in differential diagnosis. Approxi-
mately one fifth of GCT cases show recurrence and sacrum and foot bones were the most frequent sites
for recurrence.
Level of evidence: Level IV, diagnostic study.
©2018 Turkish Association of Orthopaedics and Traumatology. Publishing services by Elsevier B.V. This is
an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/
4.0/).
Introduction
Giant cell tumor of bone (GCT) is a rare neoplasm. The entity was
first described by Jaffe in 1940.
1
The peak incidence is in the third and
the fourth decades of life.
2e4
Clinically it is usually seen as a lytic lesion
of the epiphyseal region of bone. It most often occurs in the distal
femur and proximal tibia. Radiologically usually a well-circumscribed
lytic lesion over the epiphyseal region is found. Histopathologically,
these tumors are comprised of mononuclear cells, macrophages and
uniformly distributed multinuclear giant cells.
3,5,6
GCTisregardedasa
predominantly osteoclastogenic stromal tumor. It has been shown
that the giant cells in GCT were reactive osteoclasts.
7e9
The mono-
nuclear stromal cells were claimed to be the neoplastic and prolifer-
ative component of GCT's and it has been reported that these
neoplastic stromal cells had been capable of inducing osteoclast-like
differentiation.
6,10,11
Mononuclear monocytes were thought to be
the osteoclast precursor cells.
12,13
Mononuclear stromal cells may
show rare mitotic figures, however atypical mitosis is absent.
9
Mitotic
figures are not seen in the multinucleated giant cells.
3,6
Marked
cytologic atypia is not present in mononuclear stromal cells.
3,9
They frequently display secondary changes complicating char-
acteristic histopathological appearance. We evaluated our GCT
*Corresponding author. General Asım Gündüz Str., 69/2, Kadikoy, Istanbul,
34000, Turkey. Tel.: þ90 212 4143000 22138.
E-mail addresses: nilustundag@yahoo.com (N. Çomuno
glu), nuraykepil@yahoo.
com (N. Kepil), sergulen.dervisoglu@gmail.com (S. Dervis¸o

glu).
Peer review under responsibility of Turkish Association of Orthopaedics and
Traumatology.
Contents lists available at ScienceDirect
Acta Orthopaedica et Traumatologica Turcica
journal homepage: https://www.elsevier.com/locate/aott
https://doi.org/10.1016/j.aott.2018.10.0 07
1017-995X/©2018 Turkish Association of Orthopaedics and Traumatology. Publishing services by Elsevier B.V. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/).
Acta Orthopaedica et Traumatologica Turcica xxx (2018) 1e5
Please cite this article in press as: Çomuno
glu N, et al., Histopathology of giant cell tumors of the bone: With special emphasis on fibrohistiocytic
and aneurysmal bone cyst like components, Acta Orthop Traumatol Turc (2018), https://doi.org/10.1016/j.aott.2018.10.007

cases diagnosed within 20 years period in a single institute retro-
spectively and discussed the histopathological findings.
Materials and methods
Archival material of the cases diagnosed as "Giant cell tumor of
bone"between the years 1996e2016 were retrieved and included
in this retrospective analysis. Cases were evaluated according to
radiological features, clinical features such as age, gender, locali-
zation, recurrence, metastasis and histopathological features
including accompanying fibrohistiocytic or aneurysmal bone cyst
like components.
Results
The case series included 120 patients, 64 female (53,3%) and 56
male (46,7%). Age range was between 12 and 80 (Table 1) with a
mean age of 36.2 years. Tumors were localized most frequently at
tibia (all 28 cases at the proximal part) and femur (21 of 25 cases at
the distal part). In Table 2, localizations of the tumors are shown.
Radiological findings of 62 patients were available. Radiological
consultation was done for these cases. A characteristic plain
roentgenogram of GCT located at proximal metaphysis of tibia was
shown in Fig. 1.
In 11 cases, areas rich in fibrohistiocytic component were
detected (9,2% of the cases) (Figs. 2 and 3). In six of these tumors,
this component was essentially fibroxanthomatous (Fig. 4). In 20
cases secondary aneurysmal bone cyst like component were
observed (16,7% of the cases) (Fig. 5). In 2 cases both components
were present. In all these cases, with additional sampling (2 sam-
ples for every 1 cm of the maximum diameter of the tumor, instead
of 1 sample per 1 cm), characteristic areas consisting of mono-
nuclear stromal cells and a second population of mononuclear
monocytes and multinucleated giant cells, representing GCT were
detected
2
(Figs. 6 and 7).
Coagulation necrosis were observed in 6 of the 23 recurrent
cases (26%) and 10 of the remaining 97 cases (10,3%). One of these
cases, displaying extensive necrosis, had been diagnosed as giant
cell rich osteosarcoma in another pathology institute. Tumor had
brisk mitotic activity and slight cytologic atypia adjacent to necrotic
areas (Fig. 8), however atypical mitosis and malignant osteoid for-
mation could not be detected.
Twenty three cases recurred (19,2% of the cases). Recurrence in-
terval for 17 cases was known. Fourteen of these 17 cases showed
recurrence within 3 years and2 cases after 4 years.In one of our cases,
Table 1
Age distribution according to gender.
Table 2
Localization.
Fig. 1. Plain roentgenogram of a well defined lucent lesion of proximal tibia.
N. Çomuno
glu et al. / Acta Orthopaedica et Traumatologica Turcica xxx (2018) 1e52
Please cite this article in press as: Çomuno 
glu N, et al., Histopathology of giant cell tumors of the bone: With special emphasis on fibrohistiocytic
and aneurysmal bone cyst like components, Acta Orthop Traumatol Turc (2018), https://doi.org/10.1016/j.aott.2018.10.007

Fig. 2. Areas rich in fibrohistiocytic component (H-E, x100).
Fig. 3. Areas rich in fibrohistiocytic component (H-E, x100).
Fig. 4. Fibroxanthomatous areas (H-E, x100).
Fig. 5. Secondary aneurysmal bone cyst like areas (H-E, x40).
Fig. 6. Mononuclear cells and multinucleated giant cells (H-E, x100).
Fig. 7. Mononuclear cells and multinucleated giant cells (H-E, x200).
N. Çomuno
glu et al. / Acta Orthopaedica et Traumatologica Turcica xxx (2018) 1e53
Please cite this article in press as: Çomuno
glu N, et al., Histopathology of giant cell tumors of the bone: With special emphasis on fibrohistiocytic
and aneurysmal bone cyst like components, Acta Orthop Traumatol Turc (2018), https://doi.org/10.1016/j.aott.2018.10.007

the tumor, which was located at proximal tibia,showed recurrence 16
years later. Six cases showed multiple recurrences (2 or 3 occurrence).
Sacrum was the most frequentsite showing recurrence. Five of the 23
recurrent cases were located at sacrum (21,7%).
Metastasis to lung, 4 years after the primary diagnosis was
detected in one case. Tumor was primarily located at calcaneus.
During follow-up, tumor showed recurrence 3 times in 8 year-
period following metastasis. Three months later following exci-
sion of the multiple metastases, new pulmonary metastatic nod-
ules were detected and they were excised also.
The treatment modalities of 20 of 23 recurrent cases and of 48 of
the nonrecurrent 97 cases were known. In recurrent cases, curet-
tage and cementing for 14 patients, resection for 4 patients, firstly
curettage and then resection in recurrence for 2 patients were
performed. For 1 patient radiotherapy, for 4 patients RANKL in-
hibitor (Denosumab) and for 1 patient chemotherapy were used. In
1 patient endoprosthetic replacement were used for her recurrent
tumor and since this replacement tumor did not recur. Twenty
eight cases of nonrecurrent 48 cases were treated by curettage and
cementing, 18 cases by resection, 2 cases by firstly curettage and
then resection in recurrence. For 1 patient radiotherapy and for 2
patients RANKL inhibitor (Denosumab) were used.
Discussion
GCT is a locally aggressive neoplasm with an unpredictable
course. Although it has been reported that the occurrence of GCT in
patients younger than 20 years and older than 55 years was un-
usual,
3
in our case series 8 patients were younger than 20 (6,7% of
the cases) and 13 patients were older than 55 (10,8% of the cases)
(These incidences are consistent with the literature).
14,15
Nonepiphyseal GCT has been reported to be extremely rare.
3
In
our series we have observed 1 case at metaphysis.
The most common involved site was reported to be the distal
end of the femur and the second was the proximal end of the
tibia.
2e5
In our case series, proximal tibia was the most frequent site
for the tumor and the second most common site was distal femur.
It has been claimed that approximately 3e4% of GCT cases had
been localized at small bones of hands and feet. In our series in 3
patients tumor was located at feet bones and 2 cases in hand (Total
5/120; 4,2%). GCT of small bones may be confused with giant cell
reparative granuloma. Histopathologically, in giant cell reparative
granuloma, mononuclear stromal cells are absent. It has been
suggested that GCT of these bones had shown higher recurrence
rate than the one in the long tubular bones.
2
In 3 of our cases
located at foot bones showed recurrence supporting this observa-
tion. A tumor of calcaneus bone, in addition to recurrences, dis-
played pulmonary metastases also.
The well defined histopathologic pattern of GCT is frequently lost
by secondary reactive changes such as fibrohistiocytic proliferation,
hemorrhage, necrosis and aneurysmal bone cyst formation. Fibro-
histiocytic reaction sometimes become prominent and therefore in
such cases differential diagnosis between nonossifying fibroma
(NOF) and benign fibrous histiocytoma should be made. NOF occurs
in metaphysis. Stroma is more fibroblastic in NOF than that of GCT,
sometimes forming storiform pattern, and giant cells are more
irregularly scattered in NOF. It has been observed that at the end
stage of reparative processes following hemorrhage and necrosis;
lipoidization, scarring and fibrohistiocytic proliferation had been
formed.
1,16
Benign fibrous histiocytomas do not contain broad sheets
of mononuclear cells.
17
In our case series we observed areas rich in
fibrohistiocytic component in 11 cases. In six of these tumors,
fibroxanthomatous pattern was dominant. In all cases characteristic
areas representing GCT were found. We could not detect any adverse
effect of these histopathological features on clinical outcome.
Aneurysmal bone cyst-like areas are frequently detected in GCT.
Especially solid areas in aneurismal bone cyst may be misdiagnosed
as GCT. In ABC, giant cells are smaller and giant cells are unevenly
distributed. In solid type of ABC, stroma is more fibrotic than that of
GCT.
17
With additional sampling in all cases, areas showing typical
GCT were detected except for 1 case. In this case, tumor presented
with typical solid type ABC areas and the definitive diagnosis could
not be made, GCT could not be excluded. Five months later tumor
recurred and this time it displayed typical GCT areas with sec-
ondary ABC-like areas.
Necrosis with or without hemorrhage can be observed occa-
sionally in conventional GCT. Adjacent to the necrotic areas,
mononuclear stromal cells may show cytologic atypia focally,
mimicking malignancy.
2
However no atypical mitosis is present,
supporting the benign nature of these changes. In our case series,
although 16 cases showed necrosis, in no case marked cytologic
atypia or atypical mitosis were present. Giant-cell rich osteosar-
coma is a tumor that should be differentiated from GCT. In giant-
cell rich osteosarcoma, nuclear pleomorphism, abnormal mitotic
figures and malignant osteoid formation is characteristic. For only
one case e28 year-old male patient ewhich was located at met-
aphysis of fibula, evaluated in our institute within this 20 year-
period, showing these histopathological findings, a diagnosis of
‘osteosarcoma rich in giant cells’was given. This tumor showed soft
tissue invasion also. A case which had been sent to our institute for
consultation with a diagnosis of giant cell rich osteosarcoma, was
revised and the diagnosis was changed as GCT, because no atypical
mitosis or malignant osteoid formation had been detected.
Malignant GCT is a rarely observed entity. Related with differ-
ential diagnosis, it was reported that in primary malignant GCT, the
tumor gradually progressed into the sarcomatous area.
18
Although
Bertoni et al had reported that in secondary malignant GCT, no
residual conventional GCT had been found, Gong et al had observed
in 4 of their 11 cases.
18,19
We have not detected malignant trans-
formation in any of our GCT cases.
Up to 50% of GCTs shows recurrence after curettage within 3
years.
1,3,20
Rarely recurrence may occur after more than 3 years. In
our series, one tumor showed recurrence 16 years later. Six cases
showed multiple recurrences. Interestingly, sacrum was the site
displaying recurrence most frequently (5 of the 23 recurrent cases
e21,7%). Wide surgical excision was reported to reduce recurrence
rate.
1
In our case series recurrence was seen in 19,2% of patients.
Pulmonary metastases are reported to occur in approximately
1e2% of GCT patients.
3
These nodules are amenable to surgical
Fig. 8. Slight cytologic atypia adjacent to necrotic areas (arrows) (H-E, x200).
N. Çomuno
glu et al. / Acta Orthopaedica et Traumatologica Turcica xxx (2018) 1e54
Please cite this article in press as: Çomuno 
glu N, et al., Histopathology of giant cell tumors of the bone: With special emphasis on fibrohistiocytic
and aneurysmal bone cyst like components, Acta Orthop Traumatol Turc (2018), https://doi.org/10.1016/j.aott.2018.10.007

excision and they have a relatively good prognosis, however some-
times pulmonary spread can lead to death of the patient.
2
In our
series we have observed only 1 patient with pulmonary metastases.
Multifocal GCT is reported to occur very rarely without preex-
isting Paget's disease.
3
In our series we have seen this situation in
one case. Primary tumor was located at distal femur. It showed
recurrence at the same localization and 4 months later second
recurrence was presented at distal tibia. Interestingly, at the same
time with the second recurrence, a fibrohistiocytic focus was
detected at talus bone. Hyperparathyroidism was not detected,
therefore this fibrohistiocytic focus was thought to represent a
burned out GCT.
Main treatment option in GCT is surgery (usually curettage and
cementing) and complementary radiotherapy. RANKL inhibitors
(denosumab) and biphosphonates are new agents generally used
for unresectable or metastatic disease. In our series RANKL in-
hibitors (denosumab) was only used in 6 patients and 2 of these
patients showed recurrence in spite of therapy.
Conclusions
- Proximal tibia was the most frequent site for GCT.
- Secondary changes such as fibrohistiocytic or aneurysmal bone
cyst-like components and coagulation necrosis were frequently
seen in conventional GCT.
- For tumors having prominent fibrohistiocytic and aneurysmal
bone cyst-like components, in order to detect characteristic
areas representing GCT, additional sampling is essential.
- Secondary histopathological changes do not appear to affect
clinical outcome, however recognizing these patterns is
important in differential diagnosis and correct diagnosis of GCT.
- Sacrum and foot bones were the most frequent sites for
recurrence.
- Approximately one fifth of GCT cases show recurrence.
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Please cite this article in press as: Çomuno
glu N, et al., Histopathology of giant cell tumors of the bone: With special emphasis on fibrohistiocytic
and aneurysmal bone cyst like components, Acta Orthop Traumatol Turc (2018), https://doi.org/10.1016/j.aott.2018.10.007