Case 2 -

Benign Metastasising Giant Cell Tumour of Bone Vaiyapuri P. Sumathi The Royal Orthopaedic Hospital NHS Trust University of Birmingham Birmingham, UK

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Clinical History: The patient is a 40 year old man who was referred to the Royal Orthopaedic Hospital for evaluation of left knee pain. The pain was present for six months but had become worse at the time of presentation. Imaging studies revealed a pathological fracture through a large lytic lesion in the distal femur. Following a biopsy the distal femur was resected. He was under close observation and 10 months following surgery he complained of left knee pain.Subsequently, 14 months following surgery he complained of chest pain and investigations revealed multiple nodules in both lung fields. One of the nodules was biopsied. Case 2 - Slide 1 Click to view with ImageScope Click to view with a Web-Based Viewer Case 2 - Figure 1 Coronal STIR image demonstrates an expansile lesion in the subarticular location of the distal femur. It shows some internal cystic change with a multi-locular appearance and cortical thinning. Case 2 - Figure 2 Macroscopic appearance of the bisected specimen of the left distal femur shows a fairly well circumscribed large haemorrhagic tumour involving the epi-metaphysis. The lesion contains several blood filled cystic spaces. Tan coloured solid areas are noted towards the edge of the tumour. The tumour has breached the cortex laterally with soft tissue extension. Case 2 - Figure 3 Lower power view of the lesion shows a narrow rim of reactive new bone formation at the edge of the lesion. Cystic spaces resembling aneurysmal bone cyst are prominent. Case 2 - Figure 4 High power view which shows a mixture of cytologically bland mononuclear cells which have indistinct cell borders. There is very little intercellular matrix. The multinucleated giant cells have numerous nuclei and resemble the nuclei of the stromal cells. Case 2 - Figure 5 Section shows vascular invasion. The tumour emboli consist of mononuclear cells and osteoclast type giant cells. Case 2 - Figure 6 Low power view of the resected lung nodule showed a striking resemblance to the primary tumour and consists of haemorrhagic cystic and solid areas. Case 2 - Figure 7 High power view of the lung nodule composed of mononuclear stromal cells and multinucleated osteoclast - like giant cells. Pathological/Microscopic Findings and any Immunohistochemical or Other Studies: The distal femur resection specimen revealed an eccentric, subarticular large haemorrhagic lesion involving the lateral distal femur. The lateral cortex was indistinct with an incomplete thin shell of bone. The tumour had solid and cystic areas. The articular surface was uninvolved. Microscopically the lesion consisted of a mixture of mononuclear stromal cells and multinucleated giant cells. The mononuclear cells have indistinct cell borders, round to ovoid nuclei and scant cytoplasm. There was no intercellular matrix. Mitotic activity was low in the count of less than one per ten high power fields. There was no evidence of cytological atypia. Reactive new bone formation was prominent at the periphery of the lesion. Focally there was evidence of vascular invasion with the tumour emboli consisting of mononuclear stromal cells and osteoclast type giant cells. Areas of secondary cystic degeneration reminiscent of aneurysmal bone cyst were noted. Histological examination of the resected lung nodule showed striking resemblance to the primary tumour with solid and cystic areas. Similar to the primary tumour that was resected from the distal femur, the lung lesion consisted of mononuclear stromal cells and osteoclast type giant cells. There were no features to suggest malignancy. Differential Diagnoses: Giant cell rich lesions represent a group of morphological and biologically diverse tumours of the skeleton, the common factor being non neoplastic osteoclast like giant cells. Multinucleated osteoclast- like giant cell is not pathognomic of Giant Cell Tumour (GCT) of bone and can be found in wide variety of normal, reactive, benign and malignant neoplastic conditions. The key to distinguishing these lesions is their distinctive clinical and radiological characteristics. Purely on morphological basis giant cell tumour of bone is indistinguishable from brown tumour of hyperparathyroidism and giant cell reparative granuloma. Other differential diagnoses that need to be considered are benign fibrous histiocytoma, solid variant of aneurysmal bone cyst, non ossifying fibroma, chondroblastoma and giant cell rich osteosarcoma. Brown tumours develop as a complication of hyperparathyroidism and may be solitary or multiple. The jaw is the preferred location but can involve any bone. Radiographically other characteristics of hyperparathyroidism are apparent including generalized osteoporosis and sub-periosteal bone resorption of the phalanges. As hyperparathyroidism is characterised by hypercalcemia, hypophosphatemia and elevated parathormone levels, these biochemical parameters serves as useful adjunct in distinguishing from other giant cell rich bone lesions particularly central reparative granuloma which also occurs in the jaw. Histologically these lesions consist of lobules separated by fibrous septae which may contain reactive woven bone. The lobules comprises of plump fibroblasts, with a distinct spindled morphology, haemosiderophages and osteoclast type giant cells which appears to be concentrated around areas of haemorrhage and lack the even distribution seen in GCT. In the diagnostic fields of GCT the mononuclear cells lack the spindled morphology and the nuclei of the mononuclear cells are identical to the nuclei of the osteoclast-like giant cells which is not a finding in brown tumour. When secondary changes within GCT, such as a prominent spindled mononuclear cells with foam cells predominates, it can be mistaken for benign fibrous histiocytoma. Occasionally aneurysmal bone cyst (ABC) features may predominate obscuring the underlying pathology. In cases which show ABC features in an epiphyseal location, thorough sampling and identification of typical giant cell areas is necessary. Solid variant of ABC has some histological resemblance to GCT but these tumours occur at a younger age i.e. skeletally immature and in metaphyseal location. Primary ABC manifests USP6 fusion genes which may be useful in distinguishing GCT with prominent secondary ABC changes. Rarely nonossifying fibroma may be mistaken for GCT. The features that help in distinguishing from GCT include its occurrence in skeletally immature individuals and in metaphyseal location. Histologically it is characterised by irregular distribution of compressed and attenuated multinucleated giant cells in a fibroblastic background. Less frequently, GCT can be confused with chondroblastoma, which is an uncommon cartilage tumour that occurs in the epiphysis of long tubular bone. Histologically the tumour produces matrix in form of poorly formed hyaline cartilage and the cellular component consists of chondroblasts, which have crenated nuclear outline and longitudinal grooves. Also present are variable numbers of osteoclast like giant cells, which are randomly distributed. Their nuclei are oval and vesicular and do not resemble those of the chondroblasts. Giant cell rich osteosarcoma, a variant of conventional high-grade intramedullary osteosarcoma arises in metaphyseal region of long bone in adolescent. These tumours exhibit significant cytological atypia and high mitotic activity including abnormal forms. Very rarely the malignant cells are deceptively bland and mimic GCT. In such cases of giant cell rich lesion occurring in the metaphysis of an adolescent, thorough sampling in search of neoplastic osteoid production and careful radiological correlation is recommended to arrive at a correct diagnosis. Final Diagnosis: BENIGN METASTASISING GIANT CELL TUMOUR OF BONE Case Discussion: This case presents a wide range of differential diagnostic consideration, which includes reactive, benign and malignant conditions and appropriate diagnosis has treatment and prognostic relevance. Giant cell tumour of bone (GCT) is a relatively rare benign bone tumour [1] and accounts for 4 -5% of all primary bone tumours and 20% of all benign primary bone tumours. Typically occurs in skeletally mature patients aged 20 – 40 years and less frequently occurs in children (5 – 7%). Multicentric GCT also occurs in younger group of 10- 20 years and are found in <1% of patients. There is a slight female preponderance. GCT usually occurs de novo but can occur as a rare complication of Paget’s disease. GCT is characterised by numerous osteoclast type giant cells and neoplastic mononuclear stromal cells and macrophages. Although named as GCT, the neoplastic cells are the background mononuclear stromal cells. These cells have round to ovoid nucleus and scant cytoplasm. Osteoclast giant cells have identical nuclear morphology presumably formed by the fusion of mononuclear stromal cells. Neoplastic cells do not produce intercellular matrix. Mitotic count is variable and has no pragmatic significance. The cytological atypia particularly prominent around areas of haemorrhage can be variable. GCT of bone has a variable and unpredictable clinical course. Up to 50% of tumours may recur locally and 2-3% metastasise to the lungs [2]. Metastasis usually occurs on an average of 3-4 years of primary diagnosis but may be present at the time of diagnosis. GCT can undergo malignant transformation in 1-3% of cases spontaneously or can occur at the site of previously documented GCT following radiotherapy. Metastatic lung nodule in GCT recapitulates morphologic features of the primary tumour and do not show any features of malignancy. Lung nodules were common in patients with aggressive primary tumour and an association with repeated surgery has been suggested. It is still uncertain whether they represent tumour implants rather than neoplastic secondaries [3]. Vascular invasion is present in 30% of GCT and it is believed that some of the emboli might get lodged in the lung parenchyma and become viable. The presence of vascular invasion in GCT does not predict the development of lung metastases. The behaviour of the lung nodules is unpredictable. Some may grow slowly, regress spontaneously or progress to cause death. Review of the Literature/Treatment Options : The understanding of the biological development of GCT is still relatively incomplete. Studies have indicated that GCT is a neoplastic variation of the normal osteoblast- osteoclast relationship. The mononuclear stromal cells, the proliferative neoplastic component, exhibits an osteoblast phenotype, expressing alkaline phosphatase and the receptor activator for nuclear factor kappa B ligand (RANKL), a factor that is essential for osteoclast formation. These cells also express osteoprotegerin (OPG), an inhibitor of osteoclastogenesis, and TRAIL, a receptor that binds OPG [4]. A variety of cytokines IL-1,-6,-11,-17 and differentiating factors such as monocyte chemoattractant protein-1(MCP1) & M-CSF which act as monocyte chemo-attractant are also secreted. These factors initiate osteoclastogenesis that results in bone resorption leading to extensive osteolysis [5, 6]. The osteoclast like giant cells express proteases particularly cathepsin K [7]. Studies have also shown that stromal cells also contribute to osteolysis by the production of matrix metalloproteinases (MMPs) MMP-1, MMP- 8 and MMP-13 [8]. Gene expression profiling analysis have shown that p63 is highly expressed in majority of GCT of bone and this serves as useful immunohistochemical marker in the histological diagnosis of GCT of bone but its mechanism and its contribution to pathogenesis is unclear [9, 10]. The underlying genetic basis for expression of RANKL by the stromal cells has not been identified. Cytogenetics studies have shown that the most common chromosomal aberration of giant cell tumours is telomeric association [11]. Surgery is the treatment of choice. Radiotherapy is often used for patients with incomplete excision or where surgical intervention would induce fuctional deficits. Chemotherapy, interferon a and bisphosphonates have been used in unresectable GCT. Recent discoveries in understanding the biology of GCT has led to several targeted therapy. Agents that target RANKL, denosumab a fully human monoclonal antibody to RANKL, have been studied and have demonstrated 86% response rate [12]. Other agents such as imatinib mesylate which blocks CSF1 signalling pathway, critical for monocyte differentiation, and agents that block VEGF signalling essential for osteoclast formation may be of potential use in the treatment of GCT. Conclusion(s): Lung metastases of conventional benign GCT of bone are rare and are commonly seen in aggressive tumour with soft tissue extension. These tumours need to be distinguished from lung secondaries of GCT of bone which has undergone sarcomatous transformation. Unless symptomatic or show tumour progression surgery for pulmonary metastases is not required as some may regress spontaneously. The understanding of the pathogenesis of GCT of bone has led to the development of novel targeted therapeutic agents. References: WHO. Pathology and genetics of tumours of soft tissue and bone. Lyon:IARC Press;2002. MG Rock, DJ Pritchard and KK Unni Metastases from histologically benign giant-cell tumour of bone J Bone Joint Surg Am. 1984;66: 269-274 M Alberghini, K Kliskey, T Krenacs, P Picci, L Kindblom, R Forsyth, N A Athanasou ; Morphological and immunophenotypic features of primary and metastatic giant cell tumour of bone. Virchows Archiv (15 December 2009) Lau YS, Sabokbar A, Gibbons CL, Giele H, Athanasou N. Phenotypic and molecular studies of giant-cell tumors of bone and soft tissue. Hum Pathol. 2005 Sep; 36(9):945-54. Wuelling M, Engels C, Jesse N, Werner M, Kaiser E, Delling G; Pathogenesis of Giant Cell tumour; J Cancer Research Clin Oncol 2001 Aug; 127(8): 467-74. Werner M, Giant cell tumour of bone: Morphological, biological and histogenetical aspects; Int Orthopaedics 2006 Dec; 30 (6): 484-9. Lindeman J H, Hanemaaijer R, Mulder A, Dijkstra PD, Szuhai K, Bromme D, Verheijen JH, Hogendoorn PC; Cathepsin K is the principal proteose in giant cell tumour of bone. AMJ Pathology 2004 Aug; 165(2): 593-600. Cowan RW, Mak IW, Colterjohn N, Singh G, Ghert M. Collagenase expression and activity in the stromal cells from giant cell tumour of bone. 2009 May; 44 (5):865-71. Cheng-Han Lee, Inigo Espinosa, Kristin C Jensen, Subbaya Subramanian, Shirley X Zhu, Sushama Varma, Kelli D Montgomery, Torsten O Nielsen, Matt van de Rijn and Robert B West. Gene expression profiling identifies p63 as a diagnostic marker for giant cell tumor of the bone Modern Pathology (2008) 21, 531-539 B Dickson, Shu-Qui Li, J S Wunder, P C Ferguson, B Eslami, J A Werier, R Turcotte, R Kandel. Giant cell tumour of bone express p63, Modern Pathology (2008)21,369- 375. Sciot R, Dorfman H, Brys petal Cytogenetic morphologic correlation in aneurysmal bone cyst, giant cell tumour of bone and continual lesions. Mod Pathol 2001 13; 1206-1210. Thomas DM, Skubitz KM Giant cell tumour of bone Curr Opin Oncol Jul;21:338-344