Giant cell tumors of long bonesBy

Ahmad M. Shahin, M.D.Prof. and head of orthopedic department Chief of bone oncology and reconstruction unit

Elmenofia university

EGYPT

Giant cell tumor (GCT)

Is a benign neoplastic lesion locally osteolytic without matrix calcification

Arise in the metaepiphyseal region of long bonesHistologically it is consisted of three cell types; mononuclear histiocytic cells ,multinucleated giant cells that resemble osteoclast and neoplastic stromal cells

•

The high incidence of local recurrence(0 % to 65% )and the tendency

to give metastasis in rare cases raised the question of the nature of these tumors

A aggressive Benign? Or Locally malignant?

The pathogenesis and etiology of giant cell tumor of bone

•In the primary culture characteristic multinucleated giant cells and mononuclear cells were coexisted

•The values of interleukin 1 and prostaglandin E2 in the obtained from the primary culture were high.

•In subcultures, multinucleated giant cells were not persisted and only stromal cells were visible and the values of IL-1 and PGE2 were much lower

•the exposure of the passaged stromal cells to the medium containing IL-1 stimulated the stromal cells to produce PGE2 and proteolytic enzymes

•These findings demonstrated that coexistence of multinucleated giant cells with mononuclear cells should be needed for the tumor

•Komiya S et.al from Japan

The nature of giant cell tumor of bone

•Cell culture experiments with GCT cells revealed that stromal cell to be the proliferating component of the GCT

•The monocyte and the multinucleated giant cell, were lost

after a few cell culture passages •stromal cells secrete a variety of cytokines and

differentiation factors, including MCP1, ODF, and M-CSF

•Wülling M, Engels C, Jesse N, Werner M, Delling G, Kaiser E. Hamburg, Germany

•These molecules are monocyte chemoattractants and are essential for osteoclast differentiation, suggesting that the stromal cell stimulates blood monocyte immigration into tumor tissue and enhances their fusion into multinucleated

giant cells .The multinucleated giant cell is able to resorb bone leading to extended osteolysis

This new model of GCT genesis supports the hypothesis that the stromal cell is the neoplastic componentwhilst the monocytes and the multinucleated giant cells are just

reactive components of this tumor

The histopathological parameters

•The mitotic count•The presence or absence of nuclear atypia

•The degree of cellularitypresent Conventional mitotic figures are

restricted to mononuclear cells .

If atypical forms or strong nuclear atypia is noted, a secondary sarcomatous malignancy is almost always

Jaffe and Lichtenstein

•Grade 1 –•No appreciable a typism of the stormily cells ,mitoses are few ,

• •Grade 2-

•Stromal cells may be slightly or strikingly atypical but not sufficiently to diagnose frank malignancy

•abnormal mitotic figures may be found•

•Grade 3-•Frankly and obviously malignant with capacity to metastasize

Netherlands Committee on Bone Tumours .

• According to the latter grading system, • Grade 1 and 2 are considered as being , • Grade 3 as borderline malignant,• Grade 4 as malignant tumours.• Grade 4 tumours show histological overlap

with malignant fibrous hystiocytoma of bone. In this grading system mitoses, pleiomorphism of the spindled mononuclear cells, giant cells and the individual size of the giant cells will be taken into account

In this grading systemMitoses, pleiomorphismof the spindled mononuclear cells, giant cells and the individual size of the giant cells will be

taken into account.

Most important is the mitotic activity. When mitoses are occasional observed the risk of developing recurrences and pulmonal

metastases is neglectable .If more than 1 mitosis is present per 1 high power field, patients are significantly at risk for developing recurrence and (pulmonal metastases (23%

Grading of giant cell tumours according to the Netherlands Committee on Bone Tumors.

grade 1: 4%,grade 2: 88% grade 3: 5%grade 4: 3%

.

EnnekingEnneking

•Stage 1-one with a surrounding rim of reactive bone without deformation or expansion

•Stage 2-the margin is irregular and the overlying cortex expanded or deformed.

•Stage 3-is one with no clear defined margin , cortical destruction and soft tissue extension.

Campanacci et.al

1-well circumscribed with minimal cortical thinning

2-moderately expansible with moderate to severe thinning of adjacent cortex

3-no longer contained by a reactive rim of bone

HIGH RISK GCT

•Recurrent GCT•GCT in the pelvis, sacrum, spine•GCT extend to joint or soft tissue

•GCT with pathological fracture

Treatment•Radical amputation in 1800's

•Curettage and bone graft 1912 [Bloodgood] •Intralesional curettage preserves the bone anatomy

•The main problem with intralesional curettage was the high incidence of local recurrence rate that varied from 25% to 50%

•Wide resection was advised to have a better local control however this procedure was associated with impaired the limb function as it scarifies a significant segment of bone

•Recently Enhancement of intralesional procedures with liquid nitrogen, acrylic cement, phenol, hydrogen peroxide had been advocated with encouraging results

Intralesional curettage

•For all grade 1 or 2 lesions that had no intra-articular extension

•High speed burr•Pulsatile lavage

•hydrogen peroxide•Phenol Cauterization 80%

•Reconstruction with bone graft /composite bone graft bone cement/ bone cement

Wide resection

•Wide resection was advised in grade 3 lesions, tumors with extensive bone destruction, impossible joint salvage, or in expandable bones

•Reconstruction options include ostearticular allograft, resection arthrodesis, arthroplasty

GCT is an osteolytic mass in the epiphysis leading to

cortex thinning and expansion

A B

C

C

Malignant giant cell tumor

Is defined as a sarcoma arising in association with a well documented giant cell tumor, either synchronously or at the site of a previously documented giant cell tumor

Difficulty in separating benign from malignant has lead to such unfortunate terms as borderline malignant and tumors of uncertain malignant

Potential

Local Recurrence

•Location•Nature

•Presence of fracture•Local therapy•Tumor grade

Location

•Goldenberg et. Al 1970,

•Harness and Mankin 2004,

O,Donnell et.al 1994•Reported high incidence of local recurrence

with distal radius lesions treated with curettage

•They recommended more aggressive treatment for Grade 3 lesions at distal radius

Kremen et.al.2012

Reported no difference in the incidence of local recurrence among distal radius GCT compared to GCT recurrence in other regions of the body

AuthorPrimary Recurrent

O Donnell25%-

Malawer2.6%38%

Turcotte12%35%

Kremen11%22%

McDonald34%-

Our series23.5%42.8%

Prosser et. al 2005, Turcotte et. al.2002•Reported increased risk of local recurrence

among patients with recurrent GCT of bone•In this series there was increased risk in

patients with recurrent GCT cmopared to primary tumors.

•However there was no difference between recurrent and re-recurrent lesions.

•The pathology of recurrent tumors was identical to that of the initial lesions and does not represent biologically more aggressive lesions

Phenol as an adjuvant

•Phenol induces tumor necrosis with few

adverse effectsSome authors reported little effect of phenol on recurrenceHowever others did report decreased local recurrence rate with its use

In this study we did find decreased rate of local recurrence with phenol cauterization

•Bisphosphonates reduce local recurrence in extremity giant cell tumor of bone:

• A case–control study•a Department of Orthopaedics and

Traumatology, Prince of Wales Hospital, Shatin, Hong Kong

• .The use of bisphosphonates as an anti-osteoclastic agent in the management of osteolytic bone metastases is well accepted. Furthermore in vitro studies have shown that bisphosphonates also induce apoptosis in GCT stromal cells

Adjuvant zoledronic acid in ‘high risk’ Giant Cell Tumour of bone (GCT)

- A randomized phase II study

•Study title•Adjuvant zoledronic acid in ‘high risk’ Giant Cell Tumour of bone (GCT)

• -A randomised phase II study– •Principal Investigator

•J.R. Kroep•Number of centres

•3•Proposed countries

•Netherlands: Dutch Orthopaedic Oncology Group / Giant cell tumour group of EuroBoNet