PRIMARY MALIGNANT GIANT CELL TUMOR : A CHALLENGING

DIAGNOSTIC OF RARE CASE

Authors : Adi.Wasis.Prakosa1, Paulus Rahardjo2, Rosy Setiawati2, Mohammad

Hardian.Basuki3, Sjahjenny Mustokoweni4
Affiliation :
Radiology Resident, Faculty of Medicine Universitas Airlangga, Dr. Soetomo General
Academic Hospital, Surabaya, Indonesia1
Radiology Department Consultant, Faculty of Medicine Universitas Airlangga, Dr. Soetomo
General Academic Hospital, Surabaya, Indonesia2
Orthopedics & Traumatology Department Consultant, Faculty of Medicine, Universitas
Airlangga, Dr. Soetomo General Academic Hospital, Surabaya, Indonesia3
Anatomical Pathology Department Consultant, Faculty of Medicine, Universitas Airlangga,
Dr. Soetomo General Academic Hospital, Surabaya, Indonesia4

Keywords : Tumor of Bone, Giant Cell Tumor, malignant transformation, PMGCT

BACKGROUND
Giant Cell Tumor of Bone (GCTB) is a well-known locally destructive benign entity
that occurs predominantly in young adults' meta-epiphyseal long bones. Occasionally, GCTB
can undergo sarcomatous malignant transformation, becoming a malignant giant cell tumor of
bone (MGCT). This transformation can be either primary (PMGCT) considered to be very
rare, or secondary (SMGCT)

CASE REPORT
A 23-year-old female patient was referred with a painful, progressing lump located on
her left knee for 5 months. The lump was getting bigger and the pain became worse. Physical
examination showed a fixed and solid consistency mass at the left knee. Extremity radiograph
revealed an eccentric lytic lesion on epi-metaphysis one-third distal of the left femur with
borderline geographic IC and permeative type bone destruction, wide transitional zone, and
soft tissue bulging
Extremity MRI presented a sharp margin and regular edge mass with surrounding
bone marrow edema. On the other hand, core biopsy examination exhibited no clear signs of
malignancy. Because of the discrepancy results, a multidisciplinary scientific discussion was
carried out. The patient had decided to undergo double set-up surgery with Intra Operative
Consultation (IOC) for an open biopsy. The IOC result stated that the lesion tended to
malignancy and wide resection with femur reconstruction was done. PMGCT with
accompanying osteosarcoma became the patient's final diagnosis.

DISCUSSION
Clinical and radiological evaluation of benign and malignant GCTs may not
differentially diagnose one form from the other. The presence of a high-grade sarcomatous
component is an essential finding for the diagnosis of PMGCT. Failure to comprehensively
tumor samples may lead to misdiagnosing of PMGCT.
CONCLUSION
PMGCT is a very rare case and the diagnostic is challenging. Clinical presentation
and radiological evaluation are not enough to distinguish PMGCT from the other diagnosis
and histological examination take a crucial role to get a clear final diagnosis

BACKGROUND

Giant Cell Tumor of Bone (GCTB) is a well-known locally destructive benign entity

that occurs predominantly in meta-epiphyseal long bones, axial skeleton, or hand and feet

small bones of young adults. It represents 5% to 6% of all bone neoplasms. It shows female

predominance and is common in patients aged 20 – 40(1). Radiographically, GCTB exhibits

an eccentric lytic lesion with non-sclerotic and sharply defined margins. Mostly it has

aggressive features such as a wide transitional zone, cortical thinning, and sometimes,

cortical bone destruction, generating particular problems around joints, compromising joint

function and mobility(2). Moreover, in two to three percent of cases, GCTB can indicate lung

metastases. Occasionally, GCTB can undergo sarcomatous malignant transformation,

becoming a malignant giant-cell tumor of bone (MGCT), which may be osteosarcoma,

fibrosarcoma and undifferentiated pleomorphic sarcoma. This transformation can be either

primary or secondary MGCT, was first described nearly 85 years ago by Stewart and the

difference between primary and secondary was established by early investigators such as

Hutter and Dahlin . In primary malignancy of giant cell tumor (PMGCT), synchronous
(3)

high-grade sarcomatous growth that contains an area of highly pleomorphic mononuclear

cells is seen along with conventional GCTB when it was first diagnosed. On the other hand, a

secondary malignant giant cell tumor (SMGCT) is metechronous sarcomatous growth,

occurring at the site of GCTB previously happened and treated by radiotherapy or surgery,

with or without adjuvant radiotherapy (3). Epidemiologically, the incidence of MGCT is

less than 0,5% of the total group of malignancy and 5,8% of all GCT. Most of them arise

secondarily after treatment and PMGCT is considered to be very rare. Likewise, the literature
and source of MGCT is very limited and the inadequate data makes understanding the

biological behavior and radiological feature of this disease challenging . Only a few case
(4)

reports in Indonesia. We present a case of atypical PMGCT of the distal left femur that

referred to our hospital (4)

CASE REPORT

A 23 years old female patient was referred to our hospital with pain, progressing lump

located on her left knee for 5 months. One year and two months before, the patient

experienced a motorcycle traffic accident and her leg was struck down by the vehicle. After

the incident, she still could stand up and only suffered bruises on her left knee. He went to a

traditional bone setter twice and had traditional massage therapy. Nine months after that, she

complained of a lump size of a fist accompanied by pain in her left knee. She described the

pain as sharp, intense, and mechanically related. The lump was getting bigger and the pain

became worsen, so her family decided to bring her to the regional hospital in her hometown.

In that hospital, she underwent Left Knee Magnetic Resonance Imaging (MRI) examination

and histological examination. The orthopedic had decided to refer the patient to Dr. Soetomo

General Hospital due to high suspicion of a primary bone tumor.

Physical examination of the left knee showed no deformities and no length

discrepancy. The patient presented with a fixed and solid-consistency mass approximately

4x5 cm in size with edema surrounding the mass. Tenderness was exhibited on one-third

distal of the left femur but no vascular or neurological abnormalities were apparent (Figure

1). The patient underwent a left femur and knee radiograph examination, and the result

showed an eccentric lytic lesion on epi-metaphysis one-third distal of the left femur. The

lesion also revealed geographic IC-type bone destruction with a wide transitional zone and
soft tissue bulging around it. No calcification matrix and no periosteal reaction were observed

from radiography (Figure 2).

Figure 1. A mass at the left knee, anteroposterior (A), medial (B) and lateral (C) view. Fixed
and solid consistency mass approximately 4x5 cm in size with edema surrounding the mass

Figure 2. Plain radiograph (A) anteroposterior and (B) lateral view revealing an eccentric
lytic lesion on epi-metaphysis one-third distal of the left femur with geographic IC type bone
destruction, wide transitional zone and soft tissue bulging

A left Knee MRI from a prior hospital presented a mass with a sharp margin and

regular edge, about 4,4 x 3,2 x 6, 0 cm in size, located in the distal epi-metaphysis medial site

of the left femur and accompanied by surrounding bone marrow edema. There was no mass

infiltration to ligaments, muscles and neurovascular near the lesion. Based on the radiograph
and MRI examination above, the radiological finding lead to the primary aggressive bone

tumor, most likely a differential diagnosis of GCT or non-classical osteosarcoma (Figure 3)

Figure 3. A) Extremity MRI axial, (B) sagittal and (C) coronal view showing a mass with
sharp margin and regular edge located in distal epi-metaphysis medial site of the left femur
and accompanied by surrounding bone marrow edema

A histological examination of the core biopsy from a prior hospital showed there were

no clear signs of malignancy, with proliferating mononuclear cells, including multinucleated

giant cells that contain more than 20 nuclei. The nuclei in multinucleated giant cells were

similar to the nuclei in the stroma (Figure 4)..

Figure 4. Histopathological examination of distal femur lesion from core biopsy at the prior
hospital revealed no clear signs of malignancy, with proliferating mononuclear cells,
including multinucleated giant cells that contain more than 20 nuclei.

Due to the discrepancy between the radiological picture and the result of the

histological examination, a multidisciplinary scientific discussion was carried out between all

the disciplines involved. From the discussion, it was decided that the patient would undergo

surgery with a double setup and planned Intra Operative Consultation (IOC) for open biopsy
to ensure enough sample to allow a proper histological diagnosis before it was determined

whether the patient would undergo curettage or resection.

On the next day, when the patient underwent surgery, the result of the IOC exhibited

that the lesion tended to be a malignancy, so it was decided to do wide resection and femur

reconstruction (Figure 5).

Figure 5. (A) and (B) Intraoperative image showing the tumor extent. (C) and (D) Distal left
femur tissue post-wide resection

Cryosurgery was done to make a further diagnosis, with the result of open biopsy

after wide resection showing the proliferation of multinucleated giant cells, round oval nuclei,

fascicular, between the stroma which consisted of the oval to spindle nucleated cell,

hyperchromatic, which were embedded in the malignant osteoid matrix forming a lace-like

pattern (Figure 6). This finding above allowed the final diagnosis of PMGCT with an
accompanying osteosarcoma component. Adjuvant chemotherapy was planned for the patient

according to the existing protocol.

Figure 6. (A-B) Histopathological examination from wide resection tissue showed the
proliferation of multinucleated giant cells, round oval nuclei, fascicular, between the stroma
which consisted of oval to spindle nucleated cells, hyperchromatic which were embedded in
the malignant osteoid matrix, forming a lace-like pattern

DISCUSSIONS

MGCTB is also called differentiated GCTB. Many kinds of literature discussing this

topic are often confusing because of the lack of clear definitions. As said above, malignancy

in giant cell tumor of bone was first described by Stewart in 1938. Over time, “Malignant

giant cell tumor” terminology has been used as a non-specific term to explain giant cell tumor

with various degrees of anaplasia, malignant fibrous with multinucleated cells and locally

aggressive giant cell tumor. Focusing on the pathophysiology of the lesion, Jaffe was the first

to identify a unique morphology in which stromal mononucleated cells showed noticeable

atypia (5). Then Dahlin et al stated another concept of MGCT that there should be histological

evidence of giant cell tumor along with the malignant sarcomatous stromal component.

Naschimento later put forward that for the definitive diagnosis of MGCT, there should be

significant areas of high-grade non-osteogenic sarcoma within the stromal component of the

lesion. Furthermore, the appearance of metastasis at the finding of GCT itself should not be

held as a hallmark for malignization of the tumor, but instead as an unusual feature for a

borderline benign tumor (6).

 It is important to underline the separation between primary and secondary GCTB.

Unni et al presented PMGCT as a sarcoma de novo juxtaposed on a giant cell tumor, whereas

SMGCT is a sarcoma at the site of previously treated (surgery or radiotherapy) histologically

proven GCT . PMGCTs are extremely rare, characterized by a spontaneous malignant

(7)

transformation of benign conventional GCT to lesions with sarcomatous features after the

initial diagnosis. The clear pathophysiologic mechanism of this transformation remains

unknown. Long term prognosis for this malignant transformation seems to be poor. Anract et

al reported a poor prognosis for MGCTB with a five years survival rate of only 50% despite

surgery and chemotherapy combination. Domovitov et al also found a 16% mortality rate for

MGCTB patients. Furthermore, many studies have shown that the PMGCT tends to be lesser

aggressive than the SMGCT. PMGCT has a better outcome rather than SMGCT as pointed

out by Nascimento et al. In the other study, Gong et al also found a better prognosis for

PMGCT when compared with SMGCT (2).

The diagnosis of malignant giant cell tumor of bone is challenging. Clinical and

radiological evaluation of benign and malignant GCTs may not differentially diagnose one

form from the other. Most often, the clinical presentation of PMGCT is not specific with

lump, pain and swelling as common symptoms in many cases including our case. Like

benign-classic GCTB, the malignant version preferentially invades the ends of long bones

such as proximal tibia, distal tibia, distal tibia and distal femur. In addition, radiographically,

PMGCT show very similar features to the benign one. Both of them exhibit eccentric lesions

with non-sclerotic and sharply define margins. They can also show aggressive features as

well as a wide zone of transition, cortical thinning, remodeling and cortical bone destruction.

It is still extremely difficult to distinguish PMGCT from the benign type, even if the former

has metastasis or soft tissue invasion because the typical GCT can encourage aggressive bone
destruction, benign metastasis (pulmonary metastasis is the most common) and local invasion
(4)

Histological examination take a crucial role in PMGCT diagnosis. Histologically,

GCTB comprises neoplastic cells such as osteoclast precursor and spindle shape stromal cells

and reactive cells including large, multinucleated, osteoclast-like giant cells. The histological

analysis becomes complicated because the high-grade sarcoma of PMGCT often exists next

to histologically benign GCTB. The presence of this high-grade sarcomatous component is an

essential finding for the diagnosis of PMGCT. The presence of benign GCTB features within

the tumor can misguide the diagnosis if the malignant finding is missed on the biopsy.

Moreover, failure to comprehensively tumor samples may lead to misdiagnosing of benign

GCTB. This happened in our case, from the first biopsy taken by core biopsy procedure, there

was no high-grade sarcomatous finding that we found. At the second biopsy, taken by open

biopsy during wide resection surgery, the malignant features were founded clearly with more

biopsy area involved. Special attention should also be taken to patients who have more than

one biopsy specimen. All multiple biopsy specimens must be re-evaluated carefully before

excluding PMGCT to avoid misdiagnosis of SMGC (5).

Another important differential diagnosis of MGCTB that can be difficult to

distinguish is “Giant cell rich” or “Osteoclast rich” osteosarcoma . Both of them are
(8)

associated with osteoclast-like giant multinucleated cells and have similar pathophysiological

characteristics. Some information including tumor location (diaphyseal or meta-diaphyseal),

presence of direct osteoid formation by malignant giant cells and absence of typical findings

of benign GCT are important to distinguish each other. It is necessary especially for

clinicians to differentiate Giant-cell rich or osteoclast-rich osteosarcoma from PMGCT due to

different neoadjuvant chemotherapy requirements between the two, which the neoadjuvant
 chemotherapy is recommended for giant-cell-rich osteosarcoma whereas PMGCT is treated

by surgical resection without adding of neoadjuvant chemotherapy (9).

CONCLUSION

The management of patient with GCT should not only stop at physical and

radiological examinations but must be complemented by histological examination. In

addition, PMGCT is a very rare case and the diagnosis is challenging. Clinical presentation

and radiological evaluation are not enough to distinguish PMGCT from the other differential

diagnosis such as giant cell-rich osteosarcoma or benign GCT itself due to nonspecific and

similar findings among them. Histological examination takes a crucial role in PMGCT

diagnosis. Comprehensive histologic sampling is essential to ensure accurate diagnosis of

PMGCT. A clear final diagnosis is very important for the clinician to give prompt treatment

to the patient.

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