Histological and clinical characteristics of malignant giant cell tumor of bone

Malignant giant cell tumors of bone (MGCTB) are rare, and the diagnosis can be difficult due to the occurrence of a variety of malignant tumors containing giant cells. To better understand its clinicopathological features, we have reviewed our experience with 17 cases of MGCTB. Five cases were primary malignant giant cell tumor of bone (PMGCTB), and 12 cases were giant cell tumors of bone initially diagnosed as benign but malignant in a recurrent lesion (secondary MGCTB, SMGCTB). The patients included six women and 11 men (age ranged from 17 to 52 years; mean, 30.5 years). The tumor arose in the femur (six cases), the tibia (seven cases), the humerus (three cases), and the fibula (one case). Microscopically, PMGCTB showed both conventional giant cell tumor and malignant sarcoma features. SMGCTB were initially diagnosed as conventional giant cell tumor of bone, the recurrent lesion showing malignant features. Histologically, the malignant components included osteosarcoma (11 cases), undifferentiated high-grade pleomorphic sarcoma (two cases), and fibrosarcoma (four cases). SMGCTB cases showed strong expression of p53. Follow-up information revealed that four patients died of lung metastasis, two patients are alive with lung metastases, and 11 patients are alive without tumor. MGCTB should be considered as a high-grade sarcoma. It must be distinguished from GCTB and other malignant tumors containing giant cells. p53 might play a role in the malignant transformation of GCTB.     

Carcinosarcomatous malignancy, osteosarcoma and squamous cell carcinoma, in giant cell tumor of the right distal femur

We report a new type of secondary malignant giant cell tumor of bone, the malignancy of which was assigned to a carcinosarcoma, i.e., osteosarcoma and squamous cell carcinoma. It occurred 25 years after curettage and bone graft surgery under the diagnosis of giant cell tumor of the right distal femur. Although secondary malignant giant cell tumor is known as a sarcoma arising at the site of a previously diagnosed giant cell tumor, this case should be regarded as a new type of secondary malignant giant cell tumor of bone.     

Tumor progression in a giant cell type malignant fibrous histiocytoma of bone: Clinical,radiologic, histologic,and cytogenetic evidence

A malignant fibrous histiocytoma (MFH) of bone arising in the fibula of a 21-year-old woman is described. Clinical, radiologic, and histologic findings demonstrated rapid tumor progression. Chromosomal analysis of the biopsy specimen showed great karyotypic heterogeneity, whereas the resection specimen four weeks later displayed a rather homogeneous karyotype. Both revealed a clonal t(14;22)(q11;p12). Several other clonal and non-clonal chromosomal aberrations were observed. Some of these were previously described in giant cell tumor of bone (GCTB) and may correlate with aggressive behavior, e.g., aberrations involving 8p 11, 19q 13, and 20q 13. The change from karyotypic heterogeneity to relative homogeneity may be related to tumor progression. The chromosomal findings further suggest that the giant cell type of MFH of bone may be related to malignant GCTB. Genes Chrom Cancer 10:66–70 (1994). © 1994 Wiley-Liss, Inc.     

Malignant giant cell tumor of tendon sheath

Summary A benign, but aggressive, giant cell tumor of tendon sheath developed over a period of 20 years into a metastasizing, histologically malignant giant cell tumor. Ultrastructure of the malignant tumor showed the same five cell types as described in giant cell tumors of tendon sheath. Even the same crystals were identified in the osteoblast-like and osteoclast-like cells.It therefore appears reasonable to assume that giant cell tumors of tendon sheath indeed are neoplasms with a malignant potential and not an inflammatory reaction of synovial cells as previously suggested.Both the benign and malignant tumors seem to be of mesenchymal derivation with partial osseous differentiation. No ultrastructural similarities with fibrous histiocytoma were apparent.     

Tenosynovial giant cell tumor: case report and review

Tenosynovial giant cell tumors are a group of generally benign intra-articular and soft tissue tumors with common histologic features. They can be roughly divided into localized and diffuse types. Localized types include giant cell tumors of tendon sheath and localized pigmented villonodular synovitis, whereas diffuse types encompass conventional pigmented villonodular synovitis and diffuse-type giant cell tumor. Localized tumors are generally indolent, whereas diffuse tumors are locally aggressive. Recent developments indicate that tenosynovial giant cell tumors are clonal neoplastic tumors driven by overexpression of CSF1. Herein, I report a case of intra-articular, localized tenosynovial giant cell tumor (or localized pigmented villonodular synovitis) and review the classification, histopathology, and recent developments regarding its pathogenesis.     

Gene expression profiling identifies p63 as a diagnostic marker for giant cell tumor of the bone.

Giant cell tumor of the bone (GCTOB) is a primary bone tumor that occurs mainly in young adults and is capable of locally aggressive growth. Its histologic appearance can resemble a number of benign and malignant tumors but no useful diagnostic marker is known currently. To identify diagnostic markers for this tumor, global gene expression profiling using cDNA microarray was performed on 6 fresh-frozen GCTOB, 3 aneurysmal bone cysts, 4 fibrous dysplasias and 12 giant cell tumors of tendon sheath/diffuse-type giant cell tumors. Unsupervised hierarchical clustering separated the tumors based on their histopathologic types, and significance analysis of microarray identified several genes including TP73L (encoding the p63 protein) that are significantly highly expressed in GCTOB relative to these other tumors. The diagnostic utility of p63 was subsequently confirmed using anti-p63 antibody on a series of 26 GCTOB, 25 aneurysmal bone cysts, 15 chondroblastomas, 13 giant cell reparative granulomas, 13 chondromyxoid fibromas, 4 brown tumors, 4 fibrous dysplasias, 53 giant cell tumors of tendon sheath/diffuse-type giant cell tumors and 385 additional mesenchymal tumors in tissue microarrays. Strong p63 nuclear staining was present in 18 of 26 (69%) GCTOB, 3 of 15 (20%) chondroblastomas and in 1 of 25 (4%) aneurysmal bone cysts while none of the other tumors commonly considered in the differential diagnosis of GCTOB showed any detectable p63 staining. Strong p63 staining is rare in bone and soft-tissue tumors in general. In contrast to the pattern of p63 staining, the majority of the chondroblastomas (70%) demonstrated S-100 immunoreactivity while only a minority of the GCTOB (8%) was immunoreactive for S-100. These findings altogether show that p63 can be used as a diagnostic marker to aid the clinical diagnosis of GCTOB.     

骨的恶性巨细胞瘤临床病理观察

目的 探讨骨的恶性巨细胞瘤临床病理学特征及其诊断和鉴别诊断.方法 对13例恶性巨细胞瘤的临床及病理学资料进行回顾性分析.结果 13例恶性巨细胞瘤中原发性恶性巨细胞瘤6例,发病年龄21-71岁,平均年龄39.5岁.复发后继发性恶性巨细胞瘤7例,发病年龄27-52岁,平均年龄36.7岁.6例原发性恶性巨细胞瘤除可见到骨巨细胞瘤区域外,还可见到高度恶性的梭形细胞肉瘤区域,7例继发性恶性巨细胞瘤其原发性肿瘤均为骨巨细胞瘤,而复发性肿瘤则呈恶性纤维组织细胞瘤/未分化肉瘤形态.结论 诊断恶性巨细胞瘤时需将临床、影像及病理结合,并除外其他肉瘤如富含巨细胞的骨肉瘤、富含巨细胞的恶性纤维组织细胞瘤等.     

Giant cell tumor of soft tissue arising in breast

Primary giant cell tumor of soft tissue (GCT-ST) arising in breast is exceedingly rare. We report a case of a 60-year-old woman with a primary breast giant cell tumor that appeared histologically identical to giant cell tumor of bone and had a clinically malignant course. The patient presented with a cystic mass of the breast, suspected on imaging to be an organizing hematoma, possibly related to previous injury. Histopathological evaluation revealed a neoplasm composed of mononuclear cells admixed with osteoclast-like giant cells resembling giant cell tumor of bone. Immunohistochemical staining was positive for CD68, smooth muscle actin, and vimentin, but was negative for a panel of epithelial and additional muscle markers. These features were most consistent with GCT-ST, an uncommon neoplasm of low malignant potential. Despite aggressive surgical treatment achieving clear surgical margins, the patient expired with pulmonary metastases within a year of her initial presentation. This case demonstrates the difficulty of predicting clinical behavior of GCT-ST of breast on the basis of histological features and depth of tumor alone. To our knowledge, this is the first case report of a GCT-ST arising in the breast associated with a fatal outcome. The distinction of this entity from other more common primary breast tumors with giant cell morphology is also emphasized.     

Primary giant cell tumor of soft tissues similar to bone giant cell tumor: A case report and literature review

In this report we describe a primary giant cell tumor (GCT) of soft tissues located in the left dorsal wrist of a 52-year-old man. Plain radiographs did not reveal any lesion in his carpal or hand bones. Although the tumor was clinically considered a ganglion initially, the microscopic features were identical to those found in classic GCT of bone. Light microscopy showed a lesion composed of a homogeneously mixed proliferation of spindle and polygonal mononucleated stromal cells and evenly distributed multinucleated, osteoclast-like giant cells. Whereas most bone tumors have an extraosseous counterpart, only 13 cases of GCT in soft tissues had been published until 1998. Moreover, 64 new cases have been reported in three series. Nevertheless, most major reviews and textbooks do not consider this tumor as a specific entity and regard it as a low grade variant of malignant GCT of soft tissue. We describe the clinical, histologic, and immunohistochemical features of this rare benign neoplasm emphasizing the differential diagnosis with its malignant soft tissue counterpart, an ominous tumor.     

Soft tissue giant cell tumor of low malignant potential: a proposal for the reclassification of malignant giant cell tumor of soft parts.

Although "giant cell tumor of soft parts" has traditionally been considered a single entity as reflected in the original term "malignant giant cell tumor of soft parts (MGCT)" and later by the term "malignant fibrous histiocytoma, giant cell type" the degree of atypia and mitotic activity varies in this group, suggesting biologic heterogeneity. The clinicopathologic features of 31 tumors meeting the traditional criteria of MGCT but having only mild to moderate nuclear atypia are presented. Patients with these tumors (19 females; 12 males) ranged in age from 14 to 84 years (mean, 40 years) and presented with masses of involving either superficial (n = 16) or deep (n = 13) soft tissue. Most occurred on the arm or hand (n = 16) and ranged in size from 0.7 to 6.5 cm (mean, 2.1 cm). The tumors consisted of sheets and nodules of rounded mononuclear cells that blended with spindled cells and benign osteoclastic giant cells. Pleomorphic giant cells were absent. Osteoid was noted in 10 cases, but features typically associated with tenosynovial giant cell tumors (such as dense stromal hyaline, siderophages, and xanthoma cells) were nearly always absent. Mitotic figures ranged from 1-10/10 HPF (mean, 2-3/10 high-powered field), and angiolymphatic invasion was present in 10 cases. Necrosis was absent, however. The mononuclear cells expressed CD68, tartrate-resistant acid phosphatase, and smooth muscle actin, but lacked CD45, S100 protein, desmin, and lysozyme, an immunophenotypic profile identical to that of giant cell tumor of bone. Follow-up information in 19 patients (mean, 3 yrs; median, 1-7 yrs) indicated recurrences in four patients, but none developed metastasis. This behavior contrasts significantly with the high-grade behavior traditionally associated with MGCT of soft parts. These giant cell tumors can be consistently recognized by the lack of cytologic atypia even in the face of mitotic activity and vascular invasion. Although their long term metastatic risk is not fully defined, we propose they be termed "giant cell tumors of low malignant potential" and regarded as the soft tissue analogue of giant cell tumor of bone. The term "malignant giant cell tumor of soft parts" or giant cell malignant fibrous histiocytoma should be restricted to histologically high-grade lesions.     

Malignant giant cell tumor of bone

Summary The fine structure of the different cell types constituting a primary malignant giant cell tumor of bone has been studied and the localization of acid phosphatase in relation to the subcellular organelles been demonstrated. Three distinct cell types with characteristic ultrastructural features were observed: giant cells, fibroblast-like cells, and cells with abundant lipid inclusions and mitochondria. Certain differences were noted between these three cell types and their counterparts in benign giant cell tumors of bone (described in a separate report). The enzyme histochemical and morphological data suggested that the giant cells in the malignant tumor might possess a more active and expansive lysosomal apparatus than corresponding cells in the benign variant.This investigation has been aided by a grant from the Swedish Cancer Society (grant 77:64, project No. 617-B77-06XA)     

Unusual aggressive course of a giant cell tumor of soft tissue during immunosuppressive therapy

Giant cell tumor of soft tissue with low malignant potential (GCT-ST) is a low-grade, primary soft tissue sarcoma with histological and clinical features similar to giant cell tumor of the bone. The main tumor localizations are the extremities, but it may also occur in the head and neck region. GCT-ST shows a recurrence rate of approximately 15%, but it very rarely metastasizes. The risk of cancer development, especially of the skin, is up to fivefold increased in immunosuppressed patients after organ transplantation. The association of sarcomas and immunosuppressive therapy is best known for Kaposi sarcomas, whereas other types of sarcomas are rarely found. We report of a GCT-ST of low malignant potential, which developed under long-term immunosuppression in a patient 12 years after heart transplantation. The tumor presented with an unusual aggressive course and metastatic site: the parotid gland. Therefore, we suggest that in patients with immunosuppression, even low malignant cancerous lesions should be carefully observed, as their local behavior may be aggressive with development of metastasis.     

The mechanism of metastasis in the so-called “benign giant cell tumor of bone”

A case of so-called “benign giant cell tumor of bone” with an incidental histologic finding of intratumor vascular invasion is reported. The mechanism and biology of metastasis are briefly discussed. For the purposes of this presentation, the mechanism of metastasis is divided into two types—active and passive. An active type of metastasis indicates malignancy, whereas a passive type denotes a benign process. The malignant features of the conventional or typical giant cell tumor of bone are demonstrated. It is proposed that this neoplasm be labeled malignant despite its seemingly benign histologic appearance. Relative to the degree of malignancy, a lesion of this nature may be classified as either a low or a high grade type of malignant giant cell tumor.     

Genetic profile of the giant cell glioblastoma

Giant cell glioblastoma is a rare glioblastoma variant characterized by the presence of large, bizarre, multinucleated giant cells. This glioblastoma subtype develops clinically de novo after a short clinical history and contains a high frequency of p53 mutations. In this study, we screened a series of 18 giant cell glioblastomas for additional genetic alterations. PCR-SSCP followed by DNA sequencing revealed PTEN mutations in 5 of 15 tumors (33%). Of these, two mutations were located in exon 5, two mutations in exon 6, and one mutation each in exons 1 and 9. Four mutations were point mutations and two mutations were deletions. One neoplasm contained two PTEN mutations (exons 5 and 6). None of the giant cell glioblastomas showed a homozygous deletion of PTEN orp16, or amplification of MDM2. Immunohistochemically, MDM2 overexpression was either not observed or detected in only a minor fraction of tumor cells. Differential PCR revealed EGFR amplification in only one of 17 tumors (6%). These results indicate that giant cell glioblastomas occupy a hybrid position, sharing with primary (de novo) glioblastomas a short clinical history, the absence of a less malignant precursor lesion and a 30% frequency of PTEN mutations. With secondary glioblastomas that develop through progression from low-grade astrocytomas, they have in common a younger patient age at manifestation and a high frequency (>70%) of p53 mutations.     

Detection of H3F3A p.G35W and p.G35R in giant cell tumor of bone by Allele Specific Locked Nucleic Acid quantitative PCR (ASLNAqPCR)

Giant Cell Tumor (GCT) represents about 20% of benign bone tumors, is locally aggressive although malignant transformation is extremely rare, <1% of cases but 2–3% give pulmonary metastasis. Age at onset is between 20 and 40 years with a slight predominance for the female gender.GCT is characterized by specific mutations in H3F3A gene encoding the protein histone 3.3. The study of these mutations is important for the differential diagnosis with giant cell rich sarcomas, chondroblastoma and aneurysmal bone cyst.To identify the most frequent H3F3A mutations we developed a novel allele specific Real Time Polymerase Chain Reaction method, based on Allele Specific Locked Nucleic Acid (ASLNAqPCR) that is here described. Molecular analyses were performed on 20 GCT and 2 osteosarcoma arising on a previous GCT. All cases were verified by Sanger sequencing. We demonstrated that ASLNAqPCR is a quick, sensitive and reliable method to identify mutations of the H3F3A gene, in giant cell tumor of bone, to support diagnosis in morphologically ambiguous cases.     

Expression of CD147, PCNA,VEGF, MMPs and their clinical significance in the giant cell tumor of bones

Background: Giant cell tumor of bone (GCT) is a potentially malignant tumor. CD147 is a multifunctional protein, which expresses itself in many tumors. In this study, we have investigated the correlation between CD147 and PCNA, VEGF, MMPs expression in giant cell tumor of bones. We have also explored the relationship between its clinical pathology and prognosis. Results: A significant difference of the expression level of CD147, MMPs was found in cases of GCT with Jaffe grading and prognosis (P<0.05). But, it was not in accordance with the patient’s age and sex. An expression of CD147 was positively correlated with MMP-9, VEGF, MVD, PCNA (r=0.271, P=0.025; r=0.411, P=0.000; r=0.872, P=0.000; r=0.394, P=0.001). Conclusion: The expression level of CD147 in giant cell tumors of bones is correlated with the development of cancers and relapse. There was a positive correlation between expressions of CD147 and MMP-9, VEGF, MVD, PCNA, and CD147. This is an important indicator in evaluating the malignant degree and prognosis of giant cell tumors of bone. It may be the new target for ensuring chemopreventive strategies.     

Biologic characterization of human bone tumors IX. Occurrence of macrophages

Fifty bone tumors were investigated using immunohistological methods for an assessment of the amount and nature of macrophage infiltration. Polyclonal antibodies against lysozyme, alpha 1-antichymotrypsin, and alpha 1-antitrypsin were used as markers, besides certain monoclonal antibodies against blood monocytes and mature tissue macrophages. Particularly high macrophage infiltration was found in malignant fibrous histiocytomas, giant cell-containing osteosarcomas, giant cell tumors of bone, and aneurysmal bone cysts. Moderate infiltrates were seen in some highly malignant osteosarcomas, in fibrosarcoma, and in chondroblastoma. A low macrophage content was observed in some osteosarcomas, in Ewing's sarcomas, chordomas, fibrous dysplasias, aggressive fibromatoses, and cartilage tumors. Osteoclast-like giant cells showed distinctly positive reactions with the monoclonal antibody against mature tissue macrophages. In fibrohistiocytic tumors (MFH, giant cell tumor, non-ossifying fibroma) only macrophages gave positive reactions with those antibodies, whereas the reaction of spindle-shaped tumor cells was always negative. These results strongly indicate that the macrophages found in bone tumors (including those of fibrohistiocytic type) result from reactive infiltration. The autochthonous tumor cells are most probably derived from local mesenchymal cells, and are thus cytogenetically unrelated to the infiltrating macrophages.     

Pulmonary metastasis of giant cell tumor of the bone diagnosed by fine-needle aspiration biopsy

Giant cell tumor is a benign but locally aggressive tumor that primarily affects the epiphyses of long bones of young adults. Pulmonary metastases in giant cell tumor are rare (about 1-9%). Here, we report a case of metastatic pulmonary giant cell tumor in a patient who had a previous history of giant cell tumor of the distal femur with multiple recurrences. The diagnosis of pulmonary metastasis was achieved by cytologic evaluation with concurrent immunohistochemical studies in material obtained by fine-needle aspiration biopsy. The aspirate smears contained clustered and dispersed mononuclear and osteoclast-like giant cells that had bland nuclei with inconspicuous nucleoli. All multinucleated cells showed immunoreactivity to KP-1 antibody, a histiocytic marker (not lineage specific) and only a subset of mononuclear cells (30%) stained with this marker. Twenty percent of the mononuclear cells also displayed increased Ki-67 and p53 protein expression. The pulmonary metastasis was similar morphologically and immunophenotypically to the recurrent giant cell tumor of the bone.     

Ovarian giant cell tumor with cystadenocarcinoma.

A 25-year-old woman had a malignant ovarian tumor with two distinct tumor patterns: pseudomucinous cystadenocarcinoma and malignant giant cell tumor of bone. One area of the tumor had a lining of tall columnar epithelium with abundant mucin production; however, another area of the same tumor had a number of large multinucleated giant cells that resembled osteoclasts, intermingled with mononuclear stromal cells. There was no blending of the two tumor patterns. Mitoses were frequent in both areas. A probable histogenesis of the tumor from a malignant teratoma is suggested.