GIANT CELL TUMOUR

PRESENTER:DR BASANTH REDDY

MODERATOR:DR ARUN HS
BONE TUM0RS
• The bone tumors represent specialized region of orthopedics that involves
meticulous evaluation, extensive treatment and comprehensive communication
with different specialties.

• Bone tumors are sarcomas that is an unfortunate occurrence in a patient, getting

rid from which requires immense patience and lots of hospital visits all associated
with the uncertainty of ever achieving cure.
 STAGING
• This is the first and most important step to learn as much about the pathology
clinically and its possible differential diagnosis before performing biopsy.

• This avoids wrong decisions that may be otherwise made and likely worsen the
eventual outcome of management.

• A comprehensive routine for staging needs skeletal survey, a total body scan (to
look for other bony lesions or metastasis), a high resolution computed tomography
(CT) scan of the chest and a magnetic resonance imaging (MRI) of the primary
lesion and most importantly thorough clinical examination.
• Staging systems recognize a neoplasia in terms of size, site, grade and metastasis.
The staging systems of the Musculoskeletal Tumor Society (also called the
Enneking system) and the American Joint Commission on Cancer (AJCC) are
quite popular.

• Both are useful for tumor evaluation planning strategies and predicting prognosis.
ENNEKING SYSTEM
• Bone acts as a compartment itself and any neoplasia inside the bone will be intracompartmental (T1);
with breach of periosteum, it becomes extracompartmental (T2)
The tumor growth at the distal metaphyseal region has breached the capsule and reactive zone at multiple places
resulting in development of “skip lesion” within the same compartment.
Also one can note a “satellite lesion” in the peripheral capsular and reactive zone of the primary tumor mass
separated by its own capsule
Nearby joint can still get involved by one of the following routes:

• Pericapsular spread and secondary capsule breach

• Fracture hematoma extending into joint
• Intra-articular structures like knee ligaments (cruciate)
• Skip metastasis (from direct seeding)
• Direct articular extension of tumor mass.
Tumor spread to joint. A tumor-like giant cell tumor can spread to joint
space through various routes—commonly the capsular attachments are
the sites for tumor spread
(1)Intra-articular ligaments are the other sites for metastasis
(2)if the strong subchondral bone is breached then intra-articular seeding
can produce skip metastasis
(3)while a fast growing malignant tumor
(4)can grow into the joint space itself.
Traumatic injury can fracture the weakened bone leading to intra-
articular hematoma formation and seeding of the joint with tumor cells
The giant cell tumor of distal femur breaches the subchondral bone barrier in the notch region (block arrow) to
spread into joint. It was not very well-appreciated on radiographs
CLINICAL EVALUATION
• Benign tumors in children are usually noticed incidentally by parents. Otherwise,
most patients with bone tumors present with musculoskeletal pain, which is variably
followed by or is associated with swelling.

• Patients often recall a history of trauma but that is possibly an incidental correlation
but the history is quite prompt in many and needs to be researched.

• Pain is typically deep-seated, dull, aching increasing in night and often resembles
toothache.

• Pain may initially be intermittent and related to activity that quickly progresses in
intensity and becomes constant.
• Initially the pain is quite responsive to nonsteroidal anti-inflammatory drugs
(NSAIDs) and mild narcotics but flare-up require strong analgesics.

• Sudden increase in pain may represent malignant transformation of benign tumors or

hemorrhage in an existing lesion or a pathological fracture.

• Sometimes, the malignant lesion compress nearby neurovascular bundle often

infiltrating and impinging the nerves that produce radicular symptoms.

• Typically, patients with high-grade sarcoma present with a 1–6 months history of
pain while with low-grade tumors, such as chondrosarcoma, the history of mild to
moderate pain is often prolonged for 6–24 months.
• Swelling is better examined than explained. Progression of swelling should be noted
and its relation to pain. Constant increase in size with increasing pain, sudden
increase in swelling, association with fungation indicate aggressive lesion.

• Pain usually precedes swelling by months, but pain appearing with swelling may
indicate pathological fracture in an often benign lesion with ensuing hematoma.

• Syndromic association of few typical tumors should be carefully evaluated based on

the associated features.
PHYSICAL EXAMINATION
• Examination is imperative to understand the site, size, extent or tumor and
possibly determining the benign and malignant process.

• Site is inspected for soft tissue masses, overlying skin changes, adenopathy and
general musculoskeletal condition.

• Skin should also be examined for lesions such as hyperpigmented patches of

fibrousdysplasia (FD) and fibromatosis.
• A shiny adherent skin that is tethered to the underlying mass (uncommon) with
dilated superficial veins indicates aggressive pathology.

• Features that indicate malignant pathology include a short clinical history, rapidly
progressive lesion, pain not reduced by analgesics, general debility, large size of
tumor, shiny skin with dilated veins or fungation and presence of pathological
fracture.
RADIOGRAPHIC EVALUATION
• Despite advances in techniques, radiographs are first investigation to be
performed and can reveal significant information.
• They are primarily used to detect and characterize bone pathology.
LESION LOCATION
 Giant Cell Tumor (Osteoclastoma)
• It is a locally aggressive benign neoplasm characterized by large numbers of
osteoclast-like giant cells, distributed uniformly in sheets of neoplastic ovoid
mononuclear cells (plump epithelioid or spindle cells).

• GCT has propensity to locally recur after treatment (currently 10–20%) but a low
metastatic potential. It occurs slightly more often in females than in males.

• Young adults are commonly affected and peak incidence is seen around 20–45 years
of age.

• Unlike chondroblastoma and ABC, it is rarely seen in skeletally immature patients

(<5% have open physis at diagnosis).
• The tumor is not uncommon representing around 4–5% of all primary bone
neoplasms, and more than 20% of benign primary bone tumors.

• The primary areas of involvement are ends of long bones commonly the distal
femoral condyles, proximal tibial plateau, proximal humerus, and styloid process
of distal radius.

• The tumor commonly originates from the epiphyseal scar near metaphyseo-
epiphyseal junction.
• Large tumors by their sheer size may grow into the metaphysis and rarely up to
even the diaphysis. Multifocal GCTs (synchronous or metachronous) are known to
occur (1–2% of all cases) and are more aggressive than conventional form.

• It should be differentiated from metastasizing GCT. In axial skeleton (vertebrae

and sacrum) anterior column is predominantly involved.

• The term “benign” represents initial differentiation of this tumor from other
aggressive lesions that required amputation for treatment.
• This should be dropped however as 3% of GCTs are either primarily malignant or
would undergo malignant transformation commonly seen after radiation therapy.
• Tumors that recur multiple times are also prone to malignant transformation.
Rarely, the GCT has also been found to metastasize (benign metastasizing tumor)
similar to “benign” chondroblastoma. Some authors consider it to be a low-grade
primary bone sarcoma.
• Few aggressive forms of GCT have been found to be associated with Paget’s
disease.
• Genotypically, the reduction in telomere length (500 base pairs) has been
demonstrated in GCT
GIANT CELL LESIONS
Several tumors have giant cells as a component and are called giant cell lesions.
They are not GCT per se:

• NOFs (nonossifying fibroma, metaphyseal fibrous defect)

• Chondroblastoma
• Chondromyxoid fibroma
• Unicameral and ABC
• Hyperparathyroidism
• Paget’s disease
• Reparative giant cell granulomas/solid ABC.
RADIOLOGICAL
• Radiologically, the characteristic appearance of GCTs is an eccentric geographical
lytic lesion without matrix formation typically involving epiphysis and extending
to metaphysis .
• The tumors show a well-defined sclerotic transition between the lesion and host
bone. Bone response to the pathology in the form of periosteal elevation or
reactive bone formation are rare unless a pathological fracture is present.
• The cortex is expanded and thinned with frequent breach and soft tissue extension.
Soft tissue extensions have thin “egg-shell” of bone remaining.
• Benign and less aggressive forms have multiple thin trabeculae running as septae
across the lytic lesion giving a “soapbubble” appearance.
CLASSIFICATION
Campanacci into three radiological subtypes

• Type 1 (quiescent lesions): Well-defined margin with surrounding sclerosis and

little, if any, cortex involvement.
• Type 2 (active tumors): Well-defined margins, but lack surrounding sclerosis. Thin
and expanded cortex but no breach
• Type 3 (Aggressive tumors): Ill-defined margins often with cortical breakthrough
and soft tissue extension
HISTOPATHOLOGY
• Grossly, the GCTs are tan or fleshy rarely crossing the articular cartilage. Joint
extension can occur through cruciates or laterally (pericapsular).

• Histologically, two basic cell types are observed in GCT.

• The diagnosis rests on stromal cells (neoplastic component) consisting of

polygonal to somewhat spindle cells containing central round nuclei. These
deemed neoplastic cells originate from mesenchymal stromal cells and express
RANKL simulating formation and maturation of osteoclasts.
• Mitotic figures (2– 20 per 10 HPF) are often noted but do not correlate with the
biological behavior. Dispersed ramblingly throughout the stroma are defining
benign multinucleated osteoclast-like giant cells containing 50–100 nuclei.

• Foci of osteoid matrix may be observed but a chondroid matrix is virtually never
seen (pathological fracture is the only exception where chondroid matrix may be
seen in the healing callus).

• 40% of GCT have areas of vascular invasion.

CONTINUED..
• A “malignant GCT” is a variegated term. It has been used to describe primary
bone sarcomas rich in giant cells (osteosarcoma). The term also describes “dediff
erentiated” GCT that is juxtaposed (Collision tumor) with high-grade sarcoma (fi
brosarcoma or osteosarcoma).

• This is better called malignant transformation of GCT. The transformation is

usually “secondary” (radiation, etc.), and in this case, the GCT component is
“eaten up” by the evolving malignancy.
 MANAGEMENT
Treatment of GCT is surgical removal using the following different modalities:

• Curettage and bone grafting (no adjuvants)

• Curettage and chemical cytotoxic agents such as phenol, zinc chloride, alcohol,
hydrogen peroxide, carbolic acid (5–80% concentration)
• Curettage and physical agents (polymethylmethacrylate and cryosurgery)
• Heat cauterization of the walls of the lesion (using electrocautery)
• Extended curettage with high-speed burr and adjuvants
• Primary resection for expendable bones
• Wide excision and reconstruction using grafts or custom prosthesis

• Distal radius GCTs can be variable managed with extended curettage and bone
grafting, excision and reconstruction by proximal fibula, excision and reconstruction
with wrist arthrodesis.

• Radiation therapy for incomplete resection at surgically difficult sites or primarily

(used in past) abandoned for development of sarcomatous transformation (5%)

• Embolization, for unresectable tumors (pelvic and sacral large tumors—usually

requires multiple sitting as vascularity gets restored eventually). This can also be
used prior to surgical excision of large tumors.
• Simple curettage, with or without bone grafting, has a significantly high rate of local
recurrence of up to 60%.

• These intralesional and marginal procedures without adjuvants are associated with
higher recurrences (the recurrence is actually “persistence” of original disease) due
to inability to completely remove the microscopic disease, and recurrence is not
correlated with grade or site of lesion.
• Modern treatment of GCT with extended curettage (making a wide window, using
head lamps or dental mirror, angled curettes and high-speed burrs and pulsatile
lavage) and cryosurgery (using liquid nitrogen) to the tumor cavity has achieved a
recurrence rate of less than 3%.

• Routine use of adjuvants is recommended. Cryotherapy with liquid nitrogen

popularized by Marcove has various side effects and has been effectively
abandoned due to frostbite of soft tissues and bone necrosis
BONE CEMENTING
• Bone cement has a tumor kill effect by exothermic reaction and possible chemical
reaction (solvent aerosol is cytotoxic) that produces necrosis of tissue for 1–2 mm
from contact area.

• Some people have used methotrexate and Adriamycin in the bone cement to
augment cytotoxic effect.

• Bone cement has the advantage of filling the defect and having tumoricidal effect.
Advantages of cementing:
• Cytotoxic (exothermic and monomer aerosol)
• Radiographic detection of recurrence is easier—as a clear lucent line around the
cement.
• Good structural support and early weight bearing.

Disadvantages of cementing:
• Nonbiological and does not get incorporated in body ever. Cement resists
compression but is weak against tensile and torsional forces. It will not provide bone
strength in areas such as neck of the femur may result in an increased chance of
fractures due to “absolute” deficiency of bone mass.
• Degeneration and crushing of articular cartilage in subchondral lesions—it is
recommended to leave 5 mm of subchondral bone, and possibly, using bone grafting
to increase bone thickness.
NEWER TREATMENTS
• Bisphosphonates especially the newer forms (zoledronic acid and palmidronate)
nave been proposed to reduce the osteopenia due to osteoclastic effect of giant
cells and can be used as adjuvants to extended curettage. Also they have been
shown to have in vitro tumoricidal action.

• With the recognition of osteoclast differentiation factor RANKL [receptor

activator of nuclear factor kappa B Ligand] on tumor cells, targeted therapy
against the receptor has been shown to be promising.

• Denosumab is the first agent licensed to be used for this purpose by FDA in 2013.
DENOSUMAB
• Denosumab (AMG 162) is a recombinant human immunoglobulin G2 (IgG2)
antibody functionally similar to OPG with affinity and specificity for RANKL.

• Denosumab inhibits the RANKL/RANK formation on the osteoblast, and hence

preventing the osteoblast osteoclast interaction decreasing bone resorption.

• The effect is an increase in bone mass and strength in both cortical and trabecular
bone primarily by antiresorptive action and minimal, if any anabolic effect (it is
hence not an anabolic agent).
• Suppression of bone resorption is seen within first 24 hours.

• The freedom trial, development of new morphometric vertebral fractures was

chosen as the primary end point where by Denosumab showed significant
reduction in the new vertebral fractures at 3 years

• There was an overall reduction in the fracture risk.

• The efficacy of denosumab to reduce fracture risk has been shown to be

consistent across patients with varying degrees and types of osteoporosis and
fracture risk
• The discovery of the crucial role of RANK/RANKL pathway in the pathogenesis
of GCTB has given rise to the development of denosumab, a fully human
monoclonal antibody against RANKL.
• As neoadjuvant therapy for advanced GCTB which is unresectable or where
surgical resection probably results in severe morbidity, denosumab is the only
medicine approved by US Food and Drug Administration (FDA) and the
European Medicines Agency .
• Numerous clinical trials have shown denosumab correlates with beneficial tumor
response.
• However, recent studies revealing a higher rate of recurrence and patients of
sarcomatous transformation of GCTB after denosumab therapy are reported
increasingly.
• Microscopically, GCTB are typically comprised of RANK-positive circular
mononuclear cells, “reactive” rich RANK-positive multinucleated giant cells,
“neoplastic” densely cellular spindled RANKL-positive stromal-like tumor cells,
areas of sparse osteoid matrix and woven bone.
• Overexpression of RANKL by stromal cells not only promotes recruiting
monocyte precursors but also assists to form multinucleated osteoclast-like giant
cells.
• Compared with RANK, denosumab has higher specificity and affinity to RANKL.
As a result, denosumab could interrupt the RANK-RANKL binding which is
necessary for osteoclast formation, leading to the elimination of osteoclast-like
giant cells.
Denosumab is generally well tolerated, but some notable adverse events are:
• Osteonecrosis of the jaw
• Risk of hypocalcemia
• Potentially increased risk of severe infections
• Atypical fractures and delayed fracture healing
• Pancreatitis
• Neoplasia of the breast, reproductive system and gastrointestinal system are seen
more frequently with de nosumab treatment although the causal relationship as not
been established.
 REFERRENCES

• Essential orthopaedics Manish kumar varsheney.

• Article-Denosumab in giant cell tumor of bone:current status and

pitfalls.
THANK YOU