Can p63 serve as a biomarker for diagnosing giant cell tumor of bone? A systematic review and meta-analysis

ABSTRACT BACKGROUND: Tumor protein p63 (p63) has been reported to be highly expressed in giant cell tumor of bone (GCTB). Whether p63 can be treated as a diagnostic marker for GCTB remains unclear. OBJECTIVE: We conducted a meta-analysis to evaluate the applicability of p63 in diagnosing GCTB. DESIGN AND SETTING: Systematic review and meta-analysis carried out in a public hospital, Hong Kong, China. METHODS: We searched PubMed, EMBASE and the Cochrane Library from inception to April 30, 2019. Literature in English or Chinese about the differential diagnosis of GCTB using p63 were included. ­Animal experiments, reviews, correspondence, case reports, expert opinions and editorials were excluded. Studies were also excluded if they did not provide sufficient information to construct a 2 × 2 contingency table. We calculated individual and pooled sensitivities and specificities. We used I² as an indicator of heterogeneity. RESULTS: Out of 88 records identified, 8 articles on 788 GCTB patients fulfilled the inclusion criteria and were included in the present analysis. Bivariate analyses yielded a pooled mean sensitivity of 0.87 (95% confidence interval, CI, 0.72-0.95) and specificity of 0.71 (95% CI, 0.56-0.82) for using p63 as a biomarker in diagnosing GCTB. The area under the receiver operating characteristic curve was 0.86 (95% CI, 0.82-0.88). CONCLUSION: p63 is a helpful indicator in diagnosing GCTB due to its high sensitivity and specificity. ­Nonetheless, the results need to be carefully interpreted based on other diagnostic methods such as imaging. SYSTEMATIC REVIEW REGISTRATION: 164115 (PROSPERO registration number)

Modern Interpretation of Giant Cell Tumor of Bone: Predominantly Osteoclastogenic Stromal Tumor

Owing to striking features of numerous multinucleated cells and bone destruction, giant cell tumor (GCT) of bone, often called as osteoclastoma, has drawn major attractions from orthopaedic surgeons, pathologists, and radiologists. The name GCT or osteoclastoma gives a false impression of a tumor comprising of proliferating osteoclasts or osteoclast precursors. The underlying mechanisms for excessive osteoclastogenesis are intriguing and GCT has served as an exciting disease model representing a paradigm of osteoclastogenesis for bone biologists. The modern interpretation of GCT is predominantly osteoclastogenic stromal cell tumors of mesenchymal origin. A diverse array of inflammatory cytokines and chemokines disrupts osteoblastic differentiation and promotes the formation of excessive multi-nucleated osteoclastic cells. Pro-osteoclastogenic cytokines such as receptor activator of nuclear factor kappa-B ligand (RANKL), interleukin (IL)-6, and tumor necrosis factor (TNF) as well as monocyte-recruiting chemokines such as stromal cell-derived factor-1 (SDF-1) and monocyte chemoattractant protein (MCP)-1 participate in unfavorable osteoclastogenesis and bone destruction. This model represents a self-sufficient osteoclastogenic paracrine loop in a localized area. Consistent with this paradigm, a recombinant RANK-Fc protein and bisphosphonates are currently being tried for GCT treatment in addition to surgical excision and conventional topical adjuvant therapies.

Expressão imuno-histoquímica dos fatores de reabsorção óssea em lesões centrais e periféricas de células gigantes / Immunohistochemical expression of bone resorption factors in central and peripheral lesions of giant cells

As Lesões de Células Gigantes, tanto as Lesões Centrais (LCCG) quanto as Periféricas (LPCG), correspondem a um grupo de lesões orais que apresentam-se histologicamente semelhantes, porém demonstram um comportamento clínico variável. O propósito deste estudo foi comparar a expressão imuno-histoquímica dos fatores de reabsorção óssea RANK (Receptor Ativador do Fator Nuclear kappa B), RANKL (Ligante do Receptor Ativador do Fator Nuclear kappa B) e OPG (Osteoprotegerina) entre LCCG e LPCG. Adicionalmente, esses fatores foram analisados nas LCCG quanto à agressividade destas. A amostra consistiu de 61 casos, sendo 30 casos de LPCG e 31 de LCCG (16 não-agressivos e 15 agressivos). A análise foi realizada por meio da quantificação das células mononucleadas (MO) e células gigantes multinucleadas (CG) imunopositivas aos anticorpos anti-RANK, anti-RANKL e anti-OPG, em 10 campos. Além disso, de acordo com a proporção entre quantidade total de células positivas para RANKL e para OPG, os casos foram categorizados em: RANKL>OPG, OPG>RANKL e RANKL=OPG. As LCCG apresentaram maior quantidade de MO (p=0,002) e células totais (p=0,003) positivas para RANKL, em comparação com as LPCG. As LCCG ainda revelaram uma associação significativa com a proporção de RANKL>OPG (p=0,001). A análise dos fatores de reabsorção óssea não revelou diferenças significativas entre LCCG agressivas e não-agressivas (p>0,05). Foi constatada correlação positiva dos marcadores entre si, bem como uma correlação negativa entre o tamanho das lesões e a quantidade de MO (p=0,004) e células totais (p=0,009) positivas para OPG. Diante desses resultados, concluise que o maior potencial reabsortivo das LCCG frente às LPCG pode ser decorrente da elevada expressão de RANKL. Além disso, as diferenças nos comportamentos biológicos de LCCG agressivas e não-agressivas parecem não estar relacionadas com a expressão desses fatores de reabsorção óssea.

The Giant Cell Lesions, both the Central Giant Cells Lesions (CGCL) as the Peripheral Giant Cells Lesions (PGCL), correspond to a group of oral lesions that are histologically similar entities; however they show a variable clinical behaviour. The purpose of this study was to compare the immunohistochemical expression of bone resorption factors RANK (Receptor Activator of Nuclear Factor kappa B), RANKL (Receptor Activator of Nuclear Factor kappa B Ligand) and OPG (Osteoprotegerin) between CGCL and PGCL. Additionally, these bone resorption factors were examined in terms of aggressiveness of these lesions. The sample consisted of 61 cases, 30 cases of PGCL and 31 CGCL (16 non-aggressive and 15 aggressive). The analysis was performed by quantification of mononuclear cells (MO) and giant multinucleated cells (CG) immunopositive to anti-RANK, anti-RANKL and anti-OPG antibodies in 10 fields. Moreover, according to the proportion between the amount of cells positive for RANKL and OPG, the cases were categorized into: RANKL>OPG, OPG>RANKL e RANKL=OPG. CGCL showed a higher amount of MO (p=0.002) and total cells (p=0.003) both positives to RANKL compared with the PGCL. Additionally, the CGCL revealed a significant association with the ratio of RANKL>OPG (p=0.001). Analysis of the bone resorption factors revealed no significant differences between aggressive and non-aggressive CGCL (p>0.05). It was observed a positive correlation between the markers themselves, and a negative correlation between lesion size and quantity of OPG positive MO cells (p=0,004) and total cells (p=0,009). Through these results, we suggest that the greatest CGCL resorptive potential compared to the PGCL, may have occurred to the high expression of RANKL. Furthermore differences in the biological behavior of aggressive and non-aggressive CGCL appear to be related to the expression of these bone resorption factors.

Fungating primary locally malignant giant cell tumor of ulna: a case report.

A giant cell tumor with local aggressiveness and penetration of cartilage is quite rare. We present a case of fungating giant-cell tumor of lower end of the ulna with wrist involvement including penetration of cartilage and diaphysis. Involvement with all these characteristics, according to the literature reviewed, is the first case of its type. We are of the opinion that the fungation may be due to incision and drainage and delayed presentation at tertiary care centre.

Tumor de células gigantes costal ocupando todo o hemitórax / Giant cell tumor of the rib occupying the entire hemithorax

Os autores relatam o caso de uma paciente de 28 anos de idade portadora de tumor de células gigantes originário da costela. O tumor de grandes dimensões (25 × 17 cm) ocupava todo o hemitórax e causava atelectasia do pulmão esquerdo. Tratava-se de uma neoplasia mesenquimal benigna, a qual raramente acomete as costelas. Foi realizada toracotomia com ressecção em bloco da parede torácica e do tumor. O objetivo deste artigo é enfatizar que, apesar da grande dimensão do tumor, ele pôde ser completamente ressecado, e o pulmão foi reabilitado.

The authors report the case of a 28-year-old female patient with a giant cell tumor originating from the rib. The tumor, measuring 25 × 17 cm, occupied the entire hemithorax and caused atelectasis of the left lung. This tumor was a benign mesenchymal neoplasm, which rarely affects the ribs. A thoracotomy involving en bloc resection of the chest wall and tumor was performed. Despite the large dimensions of the tumor, complete resection was possible, and lung function was restored.

[Osteomalacia and giant cell tumor: a rare case]

Oncogenic octeomalacia is an unusual and rare clinicopathologic syndrome characterized by mesenchymal tumors that apparently produce osteomalacia and biochemical abnormalities consisting of hypophosphatemia and normocalcemia. We have investigated the mechanism by which a giant cell tumor of bone caused biopsy-proved osteomalacia in a 50-year-old woman. A 50-year-old woman presented with generalized bone and pelvicrural pain, associated with fatiguability and muscle weakness. The diagnosis of osteomalacia was retained, associated with a giant cell tumor. The coexistence of giant cell tumor of bone and osteomalacia suggested the diagnosis of oncogenic osteomalacia. Resolution of the biochemical abnormalities of the syndrome after tumor resection, established this diagnosis. oncogenic osteomalacia can be a form of vitamin-D-refractory osteomalacia due to altered vitamin D3 metabolism

Tumor de células gigantes do metatarso: relato de caso e revisão da literatura / Giant cell tumor of the metatarsal bone: case report and review of the literature

O tumor de células gigantes é uma neoplasia rara e representa 5% dos tumores ósseos primários. Acomete com maior freqüência joelho e punho, sendo raro em pequenos ossos do pé. Os autores apresentam um paciente do sexo masculino, 32 anos de idade, há quatro meses com dor no pé direito. A radiografia simples demonstrou lesão osteolítica e insuflante acometendo o primeiro metatarso do pé direito. A tomografia computadorizada revelou lesão radiolucente com bordas bem definidas. Foi realizada biópsia da lesão, cujo estudo histológico definiu o diagnóstico de tumor de células gigantes. Os autores enfatizam a correlação entre os achados de imagem e a histologia.

Giant cell tumor of bone is a rare neoplasm and account for 5% of all primary bone tumors. It is common in the knee and wrist, but rare in the small bones of the foot. The authors report a 32-yearold male patient presented with a four-month history of right foot pain. Plain radiographs showed an expansive lytic lesion involving the first right metatarsal bone. Computed tomography scan demonstrated a radiolucent lesion with well-defined borders. Biopsy was performed and the histological diagnostic was giant cell tumor. The authors emphasize the correlation between the imaging and histological findings.

Giant cell tumour of talus--a case report.

Giant cell tumour of the talus bone is rare and is usually seen in skeletally mature adults. Here a case of giant cell tumour of the talus in a skeletally immature boy of 15 years is reported. The patient presented with swelling and tenderness of the left ankle with an osteolytic lesion seen in the talus on x-ray. A trephine biopsy followed by left talar excision was done. Following the biopsy report the patient underwent arthotomy and joint clearance. There was no recurrence noted at six months follow-up.

A correlação entre exames de imagem, características anatomopatológicas e imunoistoquímicas num caso de tumor de céculas gigantes e agressivo do osso, com localização em coluna / Correlation between imaging tests and anatomicopathological and immunohistochemical characteristics in a case of severe giant cell tumor of bone located at spine

O Tumor de Células Gigantes (TGC), é um tumor benigno, com ocorrência de recidiva em cerca de 20-34 por cento dos casos. A localização habitual é na epífise dos ossos longos. O objetivo deste trabalho é relatar um caso de TGC em vértebra, com diagnóstico inicial de Cisto Osseo Aneurismático (COA), e discutir os diagnósticos diferenciais possíveis, correlacionando-os com as características dos exames de imagens. Paciente com 37 anos, do sexo feminino, com quadro clínico de dor na coluna e paraparesia há 2 meses. O diagnóstico inicial foi de COA. Na radiografia a lesão era lítica, com, erosão e destruição da cortical..A tomografia e ressonância evidenciavam lesão cística e hemorrágica, com extensão para partes moles. A revisão das lâminas e análise do espécime cirúrgico ressecado, submetido à coloração HE e imunoistoquímica com marcador para p53, permitiram o diagnóstico de TGC. Muitas lesões, benignas apresentam células gigantes multinucleadas. Os exames de imagem nem sempre permitem um diagnóstico conclusivo. O diagnóstico definitivo de TGC depende do exame anatomopatológico, com avaliação cuidadosa do componente estromal e a imunoexpressão positiva para a proteína p53. O tratamento é a ressecção cirúrgica, com margens amplas seguida por instrumentação nos casos de tumor localizados na coluna vertebral.

Giant Cell Tumor (GCT) is a benign tumor, with a recurrence rate of about 20 percent - 34 percent of the cases. It is usually located at long bone epiphysis. The objective of this study is to report a GCT case in a vertebra, which was early diagnosed as Aneurysmal Bone Cyst (ABC), and to discuss potential differential diagnosis, correlating them to patterns shown on imaging tests. This patient is a 37 year-old female, with clinical picture of pain in spine and paraparesis that started two months earlier. An early diagnosis of ACB was delivered. At X-ray, the injury was lithic, with erosion and cortical destruction. Tomography and resonance showed a cystic and hemorrhagic injury, extending to soft parts. Slides review and the analysis of dried surgical matter submitted to HE and immunohistochemical staining with p53 marker allowed for GCT diagnosis. Many benign lesions present with multi-nucleated giant cells. Imaging tests not always enable a conclusive diagnosis. A definite GCT diagnosis depends on anatomicopathological test, with careful evaluation of the stromal component and positive immunoexpression for p53 protein. Treatment is delivered as surgical resection, with wide margins, followed by instrumentation in cases of tumors located at spine.

Giant cell tumor of the frontal bone and the frontal sinus

We describe a 7-year-old girl with Giant Cell Tumor involving the frontal bone and the frontal sinus. She presented with headache and a large swelling at the forehead. On skull x-ray a large nonspecific lytic lesion was seen. Total resection of the tumor and cranioplasty of the skull defect was performed and there was no relapse after 4 - year follow-up

Fibroma condromixoide de hueso pisiforme de carpo: reporte de un caso clínico / Chondromyxoid fibroma of bone pisiforme carpus: clinical report of a case

El fibroma condromixoide es un tumor de origen cartilaginoso benigno que contiene matriz mixoide y condroide, se diagnostica más frecuente en la metáfisis de los huesos largos de adultos jóvenes o adolescentes. El presente caso se refiere a un paciente masculino de 14 años de edad, estudiane, quien inició su enfermedad hace dos meses, posterior a traumatismo directo en borde cubital de mano izquierda, presentando aumento de volumen que progresó rápidamente con signos inflamatorios, siendo tratado en otro centro asistencial como absceso en mano izquierda, realizándosele cultivo con resultado negativo. El examen radiológico evidencia lesión redondeada en contacto con hueso pisiforme. La biopsia de la lesión arroja como resultado fibroma condromixoide. Tres meses después de la resección tumoral no se evidencian ni signos clínicos ni radiológicos de recidiva.

Tumor de células gigantes / Giant cell tumor

The authors report and discuss the history, clinical behavior, pathological aspects, and new concepts about imaging diagnosis and surgical treatment of giant cell tumor. When the diagnosis is obtained at an early stage, the tumor can be easily and safely treated by less complex surgical techniques

Allograft replacement in limb salvage surgery for bone tumors.

A retrospective study of a series of eleven patients with active, aggressive benign and malignant bone tumors who were treated by radical resection and massive match-sized allograft replacement was reviewed. There were seven giant cell tumors and four osteosarcoma cases involving mainly either the lower end of the femur or upper end of the tibia. The age of the patients ranged from 11 to 50 years. As the follow-up period was rather short, ranging from 9 to 60 months, the patients are all still alive. Complications included two infections, one local recurrence, and two with resorption of the articular surface of the osteoarticular graft. Though psychosocial benefit was gained in patients with this limb salvage procedure, functional evaluation did not yield a satisfactory result.

Giant cell tumour of talar body.

Giant cell tumour (osteoclastoma) of talar bone is a rare entity and is seen more commonly in the third decade of life. We report this disease entity in a 17-years-old girl. The patient presented with painful swelling of the left ankle with an osteolytic lesion in the talus on conventional radiographs. Intralesional curettage and autologous bone grafting was performed following which patient's pain and swelling disappeared. Complete range of movement at the ankle joint was regained with minimal restriction at the subtalar joint. There is no evidence of relapse at six months follow up.

Osteoclastoma like giant cell tumour of the thyroid--a variant of undifferentiated carcinoma--a case report.

A case of osteoclastoma like giant cell tumour of thyroid is reported in a patient who presented with dysphagia and swelling in the neck. The light microscopy showed numerous osteoclast-like giant cells embedded in mononuclear stromal cells, the overall appearance resembling that of giant cell tumour of bone.

Subcutaneous and osteolytic rhinosporidiosis.

A young man presented with multiple Subcutaneous nodules over scalp, hand, feet and osteolytic lesions of small bones of hand. Clinically and radiologically he was diagnosed as a case of Giant Cell Tumour. Aspiration cytology and biopsy proved it to be rhinosporidiosis. Epidemiological study revealed that he perhaps contracted this infection as an occupational hazard. This is the third reported case of osteolytic lesions due to rhinosporidiosis. Diagnostic dilemmas of subcutaneous and osteolytic rhinosporidiosis are discussed.

Tumor de células gigantes do sacro: relato de caso / Giant-cell tumor of the sacrum: case report

Os autores relatam caso de tumor giganto-celular (TGC) do sacro em uma paciente de oito anos e três meses de idade. O TGC é entidade raramente vista em pacientes esqueleticamente imaturos, como também em localizaçao sacral. Existem poucos casos descritos na literatura. Em nosso serviço tratamos de sete pacientes até o momento. Este chama a atençao por ser o paciente mais jovem até agora descrito. Os estudos publicados mencionam comprometimento neurológico freqüente, embora este aspecto nao tenha estado presente neste caso.