Full Papper Case Report
Giant Cell Tumor With Reactive of EXT 1
dr Nyoman Gde Aditya Gitapradita B
dr Gede Eka Wiratnaya SpOT
Department Of Orthopaedic and Traumatology Udayana University/Sanglah Hospital
November 2014
GIANT CELL TUMOR WITH REACTIVE EXT 1
INTRODUCTION
Giant cell tumour is a benign, locally aggressive neoplasm which is composed of sheets of neoplastic ovoid mononuclear cells interspersed with uniformly distributed large, osteoclastlike giant cells.1 It constitutes about 4-5% of all bone tumors and about 18% of all benign bone tumors. It is slightly more common in females.2 Multicentric giant cell tumors are very rare and tend to involve the small bones of the distal extremities.1 The main clinical symptoms are non-specific, local swelling, warmth, and pain radiating independently of weight-bearing.3 The characteristic histopathological appearance is of round to oval polygonal or elongated mononuclear cells evenly mixed with numerous osteoclastlike giant cells which may be very large and contain 50 to 100 nuclei.1 Treatment options for GCT at this site include curettage with bone grafting or cementing, en bloc excision and reconstruction with non vascular or vascular fibular autograft, osteoarticular allograft, ulnar translocation, or endoprosthesis.5
Hereditary Multiple Exostoses (HME) is an autosomal dominant inherited genetic condition with abnormal growth of bone, mainly affecting the epiphyses of long bones. The incidence in the Western population is 1.5%.7 Exostoses are the result of dysplasia of the peripheral aspect of the growth plate and are the most common type of benign bone tumor.8 The characteristic lesion in multiple exostosis is not the diffuse cortical exostosis, club- shaped thickening of the metaphysis, irregular in outline, heaped and cleft by innumerable bony excrescences or sessile exostoses.9 The lesions are frequently found in the vertebral borders of the scapulae, ribs, and iliac crests.10 Indications for surgery are pain, cosmetic complaints, vascular and neurologic complications, clinically important malalignment and of course malignancy. The causative factor for many complaints is extrinsic compression by the exostosis of the soft tissue envelope, affecting tendons, vessels or nerves. Hence treatment is relatively easy and consists of removal of the exostosis.7
Both of GCT and HME can occur on multiple site. Multicentricity of GCT of bone is an extreme rarity accounting for less than 1% of these tumors. Most of these cases are metachronously multicentric. HME lesions are solitary, but multiple lesions develop in individuals who have a genetic predisposition.8 Case with two different type of bone tumours in one patient has not been reported before. We present a case of two different type of bone tumours (GCT and HME) in two different locations (distal radius and proximal fibula) within one patient.
CASE AND METHODS
Female patient was 31 yo, she was complained lump and pain on her left wrist since 4 months. Lump getting bigger since last 2 month and persistent pain. From physical examination we find lump on left wrist with with shine of skin, clear border and fixed on based without tenderness. The lump size its about 5x6 cm with AVN distal normal limit.
Limited for wrist extension and flexion. On the right and left knee we find multiple lump on proximal tibia n fibula, no tenderness, hard and fixed with clear margin. AVN distal with normal limit. Flexion and extension of the knee is normal limit. On plain xray of left wrist we find osteoblastic lesions with fuzzy borders, suggesting a rapid, and possibly a permeative with distruction of joint surface (Grade III). Planned for Frozen Section + Wide Excision + Non Vascularized Fibular Graft. The result of Frozen Section on durante Operation is equal to Giant Cell Tumor. We perform wide excision of the tumor include radiocarpal joint on distal and 3 cm upper the mass of the tumor. We substitute with fibular graft on left side. On proximal of fibular graft we find multiple mass that clinically equal of Multiple Osteochondroma (MHE). After that we perform histophatology of the mass tumor of the wrist and examination Imunohitochemitry BCL2 and EXT1. Histopathology consist of mononuclear cell and multinucleated giant cell large spread between stromal fibrous tissue this equal of morphology GCT. From immunochemistry of EXT1 we find positif reaction.
Picture 1. Clinical picture of left wrist
Picture 2. Clinical picture of right – left knee
Picture 4. Clinical intraoperation with tumor mass with size 12 cm (Giant Cell Tumor)
Picture 5. Clinical of non-vascularized fibular graft with tumor mass size 5 cm on proximal site (Osteochondroma)
Picture 6. Clinical post non vascularized fibular graft and put plate screw
Picture 7. Clinical donor site of non vascularised fibular graft
Picture 3. Plain X Ray of left wrist
Picture 8. X ray of left antebrachii and left wrist post operation free vascularised fibular graft
Picture 9. X ray of left cruris after resection of proximal fibula fo non vascularized fibular graft
Gambar 10. Sitoplasma eosinophilic, round ovale nucleus, vesicular cromatin with small nucleus prominent, slight mitosis but cant see mitosis atipik
Picture 11. Cell that give positif reaction of anti EXT 1 with imunohistochemistry method used B chomogen. A. Blue arrow due to positive reaction (brown-red). B. Red Arrow due to negative reaction (not brown-red)
Picture 12. Cell that give negative reaction of BCL 2 A. Positif control that had colouring on nucleus and sitoplasma, B. the reaction is negative because colouring negative on nucleus and sitoplasma
DISCUSSION
This case we find on x ray wrist was Grade III designated to the lesions with fuzzy borders, suggesting a rapid, and possibly a permeative, growth of the tumor.5 The aggressive grade-3 lesions break through the cortical bone and have a soft tissue component covered by a pseudocapsule and periosteum.3 Stage-3 GCTs, which have already destroyed the cortex tend to recur more often and when the defect is large and the joint surface destroyed, resection is indicated.4 From the histopathology that the characteristic histopathological appearance is of round to oval polygonal or elongated mononuclear cells evenly mixed with numerous osteoclastlike giant cells which may be very large and contain 50 to 100 nuclei.1 From this case we treatment with nonvascularised fibular autograft reconstruction arthroplasty of distal radius can be considered as a reasonable procedure after en bloc excision of Grade II/III GCT.5 This case we check Imunohistochemistry of BCL-2 to find the apoptosis of the cell tumor on GCT mass but the result is negative. Bcl-2 is an anti-apoptosis protein whose overexpression contributes to the uncontrollable proliferation of gliomas and other neoplasm’s. 6
Giant cell tumor of the bone is a benign, primary skeletal neoplasm with variable biologic aggressiveness that demonstrates telomeric associations of chromosomes 11, 16, 19, 20, and 21, reduction of telomere length, marker chromosomes, double minutes, chromosome fragments, ring chromosomes, and polyploidy. Overexpression of TGF-β, but not TGF-β, has been reported.11
GCT starting from the metaphysis has been described in skeletally immature patients at an open growth plate. The main clinical symptoms are non-specific, local swelling, warmth, and pain radiating independently of weight-bearing.3 The margins of the lesion vary;
this is the basis of a radiological grading/staging system. Type 1, ‘quiescent’, lesions have a well-defined margin with surrounding sclerosis and show little, if any, cortical involvement.
Type 2, ‘active’ tumours have well-defined margins, but lack sclerosis; the cortex is thinned and expanded. Type 3, ‘aggressive’ tumours have ill-defined margins often with cortical destruction and soft tissue extension. On occasion, a giant cell tumour has a trabeculated
‘soap-bubble’ appearance. In the tubular bones of the hands and feet, the x-ray appearances are similar to those seen in long bones.1
Treatment options for GCT at this site include curettage with bone grafting or cementing, en bloc excision and reconstruction with non vascular or vascular fibular autograft, osteoarticular allograft, ulnar translocation, or endoprosthesis. The recurrence rate for primary treatment of GCT is relatively higher for curettage or extended curettage as
compared to en bloc excision, making latter a more suitable and reliable option in cases showing aggressive lesions which so often is the case in distal radius. Grade I tumors had a well-defined border of a thin rim of mature bone and bony cortex was intact. Grade II lesions had relatively well-defined margins but there was no radio-opaque cortical rim. Grade III was designated to the lesions with fuzzy borders, suggesting a rapid, and possibly a permeative, growth of the tumor. grade I tumors are treated with extended curettage at our institute in a hope to avoid more radical surgery and this series includes only grade II and III treated with autograft reconstruction. Decision type of operative intervention (extended curettage vs resection/reconstruction) in grade II tumors was based on individual case with with one of the important consideration being the subcortical bone stock likely to be available after curettage.5
Ipsilateral fibular nonvascularised autograft reconstruction of the large defect created after resection of distal radius offers many advantages over other procedures. It has low donor site morbidity, if any, with predictable and satisfactory functional results and is relatively free of major complications although minor complications occur frequently.
Vascularised fibula has advantage of earlier union, several authors have reported similar union time for non vascularised fibular graft if rigid fixation and primary bone grafting is used. Non vascularised fibular autograft reconstruction of distal radius show substantial loss of function as compared to normal wrist, it still gives subjective results acceptable to most patients and comparable to all other available methods of such reconstruction.
Nonvascularised fibular autograft reconstruction arthroplasty of distal radius can be considered as a reasonable procedure after en bloc excision of Grade II/III GCT.5
From clinical picture of proximal cruris region both right and left, we find clinical picture of multiple exotosis. That prove it based on clinical picture when we used of left fibular bone as non vascularised fibular graft. Exostoses are the result of dysplasia of the peripheral aspect of the growth plate and are the most common type of benign bone tumor.
Almost all of the lesions are solitary. but multiplc lesions develop in individuals who have a genetic predisposition.8 From this case we suspected of two tumor in one patient. To confirm MHE on this patient we do imunohistochemistry EXT1 and the result is positive on en block GCT mass of left wirst. EXT is genetically heterogeneous with three loci on chromosomes 8q24.1, 11p13, and 19q. A first EXT1 locus on chromosome 8 (8q24.1) was discovered by Cook in 1993. Chromosome 8 was suspected as a potential locus for HME since it was already linked to the Langer-Giedion syndrome. On the distal end of 8q a locus responsible for the formation of exostoses in both genetic conditions was identified as the EXT1, or
exostosis gene 1. Later on a new gene on chromosome 11 (11p11-13) was identified as a locus for HME and named EXT2, exostosis gene 2. A third locus on chromosome 19p, suspected of causing HME was named EXT3, exostosis gene 3, but it is considered to be a minor contributor to the actual formation of exostoses7 Indications for surgery are pain, cosmetic complaints, vascular and neurologic complications, clinically important malalignment and of course malignancy. The causative factor for many complaints is extrinsic compression by the exostosis of the soft tissue envelope, affecting tendons, vessels or nerves. Hence treatment is relatively easy and consists of removal of the exostosis.7
From pathogenetic we can found similiarity between GCT and HME. GCT and HME demonstrates associations of chromosomes 11 with different pathological process.11 But it still need more investigation to confirm that there is relationship between these tumour or not.
The theory of one patient with two tumor just still hipothesis.
Picture 13. Diagram relations between GCT and MHE
CONCLUSION
This case prove that in one patient had two type of tumor, so need research in next time, is this tumor had correlation between GCT and MHE or both tumor not relationship and just different source.
Refferences
1. Fletcher et al. 2002. World Health Organization Classification of Tumours: Pathology and Genetics of Tumours of Soft Tissue and Bone. IARC Press : Lyon
2. Haque A and Ambreen M. 2007. Giant Cell Tumor of Bone: A Neoplasm or a Raeactive Condition. Int J Clin Exp Pathol vol 1, 489-501
3. Szendroi, M. 2004. Giant-Cell Tumour of Bone. British Editorial Society of Bone and Joint Surgery 2004;86-B:5-12
4. Bassiony A. 2009. Giant Cell Tumour of the Distal Radius: Wide Resection and Reconstruction by Non-vascularised Proximal Fibular Autograft. Ann Acad Med Singapore 2009;38:900-4
5. Saini. et all. 2011. En bloc excision and autogenous fibular reconstruction for aggressive giant cell tumor of distal radius: a report of 12 cases and review of literature. Journal of Orthopaedic Surgery and Research 2011. 6:14
6. Alireza K. et all.2010. Prediction of Clinical Course and Biologic Behavior of the Bone Giant
Cell Tumor Using Bax and bcl-2 Markers.Iran J Pathol (2010)5 (2), 53-59
7. Ryckx A, et al. 2013. Hereditary Multiple Exostoses. Acta Orthop. Belg., 2013, 79, 597- 607
8. Schmale GA, et al. 1994. The Natural History of Hereditary Multiple Exostoses. The Journal of Bone and Joint Surgery Vol 76A No.7 July 1994
9. Solomon L. 1963. Hereditary Multiple Exostoses. The Journal of Bone and Joint Surgery Vol 45B No 2 May 1963
10. Stieber GA, et al. 2001. Hereditary Multiple Exostoses: A Current Understanding of Clinical and Genetic Advances. The University of Pennsylvania Orthopaedic Journal 14: 39–
48, 2001
11. G Douglas L, Carlos A. Muro-Cacho. 2001. Genetic and Molecular Abnormalities in Tumors of the Bone and Soft Tissues. Tumors of the Bone and Soft Tissues. H. Lee Moffitt Cancer Center
& Research Institute at the University of South Florida, Tampa, Fla. May/June 2001, Vol. 8, No.3
