Giant cell tumor of bone express p63.

p63 contributes to skeletal development and tumor formation; however, little is known regarding its activity in the context of bone and soft tissue neoplasms. The purpose of this study was to investigate p63 expression in giant cell tumor of bone and to determine whether it can be used to discriminate between other giant cell-rich tumors. Seventeen cases of giant cell tumor of bone were examined to determine the cell type expressing p63 and identify the isoforms present. Total RNA or cell protein was extracted from mononuclear- or giant cell-enriched fractions or intact giant cell tumor of bone and examined by RT-PCR or western blot, respectively. Immunohistochemistry was used to evaluate p63 expression in paraffin embedded sections of giant cell tumor of bone and in tumors containing multinucleated giant cells, including: giant cell tumor of tendon sheath, pigmented villonodular synovitis, aneurysmal bone cyst, chondroblastoma, and central giant cell granuloma. The mononuclear cell component in all cases of giant cell tumor of bone was found to express all forms of TAp63 (alpha, beta, and gamma), whereas only low levels of the TAp63 alpha and beta isoforms were detected in multinucleated cells; DeltaNp63 was not detected in these tumors. Western blot analysis identified p63 protein as being predominately localized to mononuclear cells compared to giant cells. This was confirmed by immunohistochemical staining of paraffin-embedded tumor sections, with expression identified in all cases of giant cell tumor of bone. Only a proportion of cases of aneurysmal bone cyst and chondroblastoma showed p63 immunoreactivity whereas it was not detected in central giant cell granuloma, giant cell tumor of tendon sheath, or pigmented villonodular synovitis. The differential expression of p63 in giant cell tumor of bone and central giant cell granuloma suggest that these two tumors may have a different pathogenesis. Moreover, p63 may be a useful biomarker to differentiate giant cell tumor of bone from central giant cell granuloma and other giant cell-rich tumors, such as giant cell tumor of tendon sheath and pigmented villonodular synovitis.     

H3.3 G34W突变抗体在骨巨细胞瘤中的表达及诊断价值

目的探讨H3.3 G34W突变抗体在骨巨细胞瘤(GCTB)中的表达情况及其对GCTB诊断的作用。方法收集解放军东部战区总医院病理科2001年6月至2019年4月诊断的83例GCTB、18例动脉瘤样骨囊肿、23例软骨母细胞瘤和28例骨肉瘤病历资料,采用免疫组织化学EnVision法检测H3.3 G34W突变抗体和p63的表达情况。结果83例GCTB中,69例(69/83)显示H3.3 G34W阳性,阳性率为83.1%,H3.3 G34W染色仅见于单核肿瘤细胞的细胞核,呈弥漫强阳性表达。H3.3 G34W在57例发生于长骨的GCTB中表达的阳性率为96.5%(55/57),而在26例发生于非长骨的GCTB中阳性率仅为53.8%(14/26)。所有复发(9/9)或转移性GCTB(2/2)、denosumab治疗后GCTB(3/3)、原发性恶性GCTB(3/3)和继发性恶性GCTB(5/5)均为H3.3 G34W阳性。所有动脉瘤样骨囊肿和软骨母细胞瘤均为H3.3 G34W免疫组织化学染色阴性。28例骨肉瘤中,H3.3 G34W的阳性率为10.7%(3/28)。富于巨细胞的骨肉瘤(GCRO)是骨肉瘤中唯一表达H3.3 G34W的组织学亚型。p63在71.1%(59/83)的GCTB中表达,而在动脉瘤样骨囊肿、软骨母细胞瘤和骨肉瘤中的阳性比例分别为3/18、43.5%(10/23)和21.4%(6/28)。H3.3 G34W突变抗体在GCTB诊断中的灵敏度和特异度分别为83.1%和95.7%。结论H3.3 G34W突变抗体是诊断GCTB高度灵敏和特异的标志物,有助于与具有相似形态学的骨肿瘤的鉴别。该抗体的局限性是少数存在G34突变但不是G34W突变的GCTB不能被检测出。骨肉瘤中H3.3 G34W突变蛋白的偶然表达可能是一个潜在的诊断难题,该免疫组织化学结果需谨慎解释。     

Cytogenetic-morphologic correlations in aneurysmal bone cyst, giant cell tumor of bone and combined lesions. A report from the CHAMP study group.

Aneurysmal bone cyst and giant cell tumor of bone are relatively rare bone tumors that sometimes coexist. We examined the karyotypes of 3 aneurysmal bone cysts, 12 giant cell tumors, and 3 combined lesions. All aneurysmal bone cysts showed involvement of chromosome segments 17p11-13 and/or 16q22. In addition, in 1 of the 3 giant cell tumors with secondary aneurysmal bone cyst, both chromosome bands were rearranged as well, albeit not in a balanced translocation. Seven out of 12 giant cell tumors were characterized by telomeric associations. One giant cell tumor showed a dup(16)(q13q22), suggesting the presence of a (minor) secondary aneurysmal bone cyst component, despite the absence of histological proof. Our results, combined with literature data further substantiate that segments 16q22 and 17p11-13 are nonrandomly involved in at least some aneurysmal bone cysts, irrespective of subtype (primary, secondary, intra/extraosseous, solid or classic). These findings strongly suggest that some aneurysmal bone cysts are true neoplasms. In addition, telomeric associations are the most frequent chromosomal aberrations in giant cell tumor of bone, the significance of which remains elusive. In combined giant cell tumor/aneurysmal bone cyst each component seems to retain its own karyotypic abnormality.     

S-100 protein immunostaining in the differential diagnosis of chondroblastoma

In an effort to investigate the utility of immunostaining for S-100 protein in the differential diagnosis of chondroblastoma, the expression of S-100 protein in nine chondroblastomas was compared with that in six giant cell tumors, six aneurysmal bone cysts, four giant cell reparative granulomas, six cases of fibrous dysplasia, two cases of osteitis fibrosa cystica, two nonossifying fibromas, and one clear cell chondrosarcoma. Five enchondromas, three typical chondrosarcomas, and one mesenchymal chondrosarcoma were also included as control tumors. The proliferating stromal cells in seven of the nine chondroblastomas stained for S-100 protein, as did the lacunar chondrocytes in all of the enchondromas and chondrosarcomas and rare stromal cells in the clear cell chondrosarcoma. In contrast, none of the other tumefactive bone lesions included in this study demonstrated S-100 protein immunoreactivity. These results suggest that immunohistochemical assessment of S-100 protein may be a method for diagnostically separating chondroblastoma from pathologic entities that could be histologically confused with it in the presence of limited biopsy material. However, clear cell chondrosarcoma would appear to represent an exception to this general statement.     

Telomerase activity in benign bone tumors and tumor-like lesions

To assess the role and status of telomerase activity in benign bone tumors and tumor-like lesions, we performed telomerase assays in four giant cell tumors of bone, four fibrous dysplasias, three osteochondromas, three aneurysmal bone cysts, two osteoblastomas, one juvenile bone cyst and one myositis ossificans. A very sensitive non-radioactive TRAP assay was applied. Low level activity was detected in 7 of 18 tumor samples (38.9%), and high level activity was not detected in any of the cases. Telomerase activity was observed in all patients with osteochondromas, in two of the three aneurysmal bone cysts, in one of the four giant cell tumors of bone and in one of the four fibrous dysplasias, but not in osteoblastomas, juvenile bone cyst and myositis ossificans. Although the origin of this enzyme is still unclear, it might play a role in precancerous immortalization of benign bone tumors. Other possible reasons explaining the occurrence of telomerase activity, such as migrating lymphocytes or contamination of immortalized non-tumor cells, should not be ruled out. Telomerase activity, however, does exist in those samples having no malignant phenotype, for which reason telomerase assays are not always useful for the clinical and diagnostic approach in benign bone tumors. Determination of the telomerase status in benign lesions may contribute to a better understanding of the regulation mechanism of telomerase activity during progression of bone tumors.     

Immunohistochemical analysis of 36 cases of chondroblastomas: A single institutional experience

Chondroblastoma is a relatively uncommon, primary benign bone tumor, frequently identified in young individuals. Despite its classical radiologic and histopathological features, at times, it is fraught with a diagnostic challenge, especially differentiating it from a giant cell tumor of bone (GCTB); an osteosarcoma and a chondrosarcoma. Lately, few studies have shown the diagnostic utility of immunohistochemical (IHC) expression DOG1 antibody in chondroblastomas. The present study was undertaken to evaluate IHC expression of S100 protein, DOG1 and p63 in 36 chondroblastomas.From January 2013 to July 2019 (6-year duration), 106 chondroblastomas were diagnosed, with IHC staining performed in 36 cases. Conventional Hematoxylin and Eosin stained microsections and IHC stained sections were reviewed in 36 cases. IHC staining of p63 (intranuclear), S100 protein (nuclear and cytoplasmic) and DOG1 (cytoplasmic membranous) was recorded in various cases.Seventy-four tumors occurred in males and 32 in females, within age-range of 7–55 years (average = 18.6), frequently in tibia (33/106; 31.1%), followed by femur (26, 24.5%) humerus (22, 20.7%), calcaneum (5) and scapula (4). IHC staining for S100P was positive in 33/36cases (91.7%); DOG1 in 16/19 (84.2%) cases and p63 in 10/15cases (66.6%). DOG1 immunostaining was negative in 25 various other tumors. Sensitivity and specificity for S100P, DOG1and p63 in chondroblastomas was (91.6%, 59.3%); (84.2%, 100%) and (66.6%, 46.6%), respectively. P63 was positively expressed in 15/27 (55.5%) GCTBs.S100 protein and DOG1 can be utilized for a confirmatory diagnosis of a chondroblastoma, especially for differentiating it from its other differentials, such as GCTB, in view of certain associated therapeutic implications. P63 is not useful in that scenario.     

Expression of Ia and monocyte-macrophage lineage antigens in giant cell tumor of bone and related lesions

An immunohistochemical study of six giant cell tumors of bone and eight related lesions (aneurysmal bone cyst, fibrous histiocytoma, and giant cell tumor of tendon sheath) was performed using a panel of monoclonal antibodies directed to the Ia and monocyte-macrophage lineage antigens. In all types of lesion, osteoclastlike multinucleate giant cells were negative for both types of antigen, but a proportion of mononuclear cells gave positive reactions. While the possibility that these cells are reactive cannot be excluded, in giant cell tumor and malignant fibrous histiocytoma, their frequency and their morphologic similarity to the rest of the tissue suggest that they may be an intrinsic part of the neoplasm. This finding is consistent with the presumed fibrohistiocytic nature of these tumors.     

Chondroblastoma: varied histologic appearance,potential diagnostic pitfalls,and clinicopathologic features associated with local recurrence

Chondroblastoma is a rare, benign bone tumor. Although it has distinctive clinicopathologic features, its wide morphologic spectrum may pose diagnostic problems. We present the clinicopathologic features of 42 patients (28 males, 14 females; age range, 8 to 66 years), with emphasis on unusual histologic features, potential diagnostic pitfalls, and factors associated with recurrence. Thirty-four tumors were in long bones, with the most common site being the proximal femur. Unusual histologic features included the presence of atypical, epithelioid, spindle, and foamy cells and necrosis and a diffuse basophilic myxoid matrix. Tumors with focal osteoclast-like giant cell rich areas (n = 11), prominent cystic change (n = 8) and extensive fibromyxoid areas (n = 3) resembled giant cell tumors, aneurysmal bone cysts, and chondromyxoid fibromas, respectively. The diagnosis of referring pathologists was inaccurate in 34% of cases. Six patients (14%) had local recurrence. The only clinical feature significantly associated with increased risk of local recurrence was duration of symptoms for less than 6 months (log rank P =.003). None of the histologic features was significantly associated with recurrence. These included worrisome features such as cellular atypia, necrosis, and mitoses. None of the patients had metastases. An increased awareness of the morphologic spectrum of chondroblastomas will enable pathologists to avoid diagnostic pitfalls. We emphasize the need for a combined clinical, radiologic and histologic approach to the diagnosis of chondroblastomas.     

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.     

A diagnosis of giant cell-rich tumour of bone is supported by p63 immunohistochemistry,when more than 50 % of cells is stained

Some primary malignant or benign tumours of bone contain numerous multinucleated cells. These “giant cell-rich tumours of bone” have overlapping features and clinical and radiological data are needed to reach an accurate pathological diagnosis. We studied the potential contribution of p63 immunohistochemistry to the reliability of the histological diagnosis. We performed a multicentric retrospective study of 291 giant cell-rich tumours of bone which included 119 giant cell tumours of bone (GCTB), 76 aneurysmal bone cysts (ABC), 49 chondroblastomas (CB), 15 nonossifying fibromas (NOF), 10 giant cell reparative granulomas (RG) of jaws, 1 giant cell lesion of small bones, 2 hyperparathyroidism-related brown tumours (BT), 17 bone sarcomas with numerous osteoclasts and 2 malignant giant cell tumours of bone. p63 is expressed in ABC, CB, NOF, RG, BT and GCTB, but its expression in more than 50 % of mononuclear cells is strongly suggestive of a diagnosis of GCTB. In contrast, malignant GCTB were mostly negative. Our results show that p63 is expressed in a broad range of benign giant cell-rich tumours of bone, consistent with data in the recent literature, while infrequent in malignant tumours. With a cut-off 50 %, the presence of p63 positive cells is useful in supporting a diagnosis of giant cell-rich tumour of bone. However, a final diagnosis cannot be made without due consideration of all clinical/radiological and pathological data.     

骨肿瘤MDM2和p53基因的改变

目的从基因水平研究ＭＤＭ２和ｐ５３基因在骨肿瘤中的表达，探讨其在骨肿瘤发生发展中的作用。方法用地高辛标记原位杂交技术研究了３８例骨肿瘤（骨肉瘤１２例，软骨肉瘤１０例，骨巨细胞瘤１４例，软骨母细胞瘤２例）ＭＤＭ２和ｐ５３的表达情况，并分析两种基因表达之间的相互关系。结果ＭＤＭ２在骨肉瘤、软骨肉瘤和骨巨细胞瘤中的阳性率分别为４１．７％、５０．０％和３５．７％。ｐ５３的阳性率分别为５８．３％、４０．０％和２１．４％。２例软骨母细胞瘤ＭＤＭ２和ｐ５３均为阳性。ＭＤＭ２与ｐ５３基因表达呈显著正相关（Ｐ＜０．００５）。结论ＭＤＭ２和ｐ５３基因改变是骨肿瘤的一种常见现象，可能参与骨肿瘤的发生与发展。     

L‐type amino acid transporter‐1 and CD98 expression in bone and soft tissue tumors

L‐type amino acid transporter‐1 (LAT1) is expressed in many cancers. We examined LAT1 and CD98 expression immunohistochemically in surgically resected specimens of various bone and soft tissue tumors. Out of 226 cases, 79 (35%) were LAT1⁺ and 95 (42%) were CD98⁺. In bone tumors, LAT1 was highly expressed in osteoblastoma (89%), chondrosarcoma (50%), and osteosarcoma (60%); in soft tissue tumors, LAT1 was highly expressed in rhabdomyosarcoma (80%), synovial sarcoma (63%), Ewing's sarcoma (60%), epithelioid sarcoma (100%) and angiosarcoma (100%). In malignant soft tissue tumors, LAT1 expression was associated with higher histological grade. High CD98 expression was seen in many bone tumors of intermediate and high malignancy. Among soft tissue tumors, CD98 was expressed in tendon sheath giant cell tumor and malignant peripheral nerve sheath tumor (57%), Ewing's sarcoma (50%) and undifferentiated sarcoma (64%). Some of the malignant soft tissue tumors expressed both LAT1 and CD98. This study showed that LAT1 and CD98 was expressed in many malignant and intermediate bone tumors, and some malignant soft tissue tumors.     

Tenosynovialer Riesenzelltumor

Morphological, ultrastructural, and immunohistochemical findings of 12 diffuse type-tenosynovial giant cell tumors/pigmented villonodular synovitis are presented compared to 30 localized tenosynovial giant cell tumors (giant cell tumor of tendon sheath). Diffuse-type-tenosynovial giant cell tumor is characterized by a striking vascularisation pattern composed of densely arranged thin-walled, partly slit-like and partly hyalinized small blood vessels within the papillary synovial fronds. These vessels may show abnormal structures with incompletely arranged endothelial cells/pericytes. The fibrohistiocytic tumor cells probably cause considerable compression/distortion or destruction of the small vessels which might be responsible for an increased blood deposition and massive hemosiderosis. Accompanying multinucleated osteoclast-like giant cells seemingly are recruited from circulating blood monocytes. Microhemorrhagic foci with multinucleated giant cells could be detected in 83% of diffuse-type and 67% of localized-type tumors. Apart from the described vessels, typical morphological findings in diffuse-type tenosynovial giant cell tumors included "giant" hemosiderotic granules, (at least 2-3 times the diameter of an erythrocyte) "giant" siderophages, pseudoalveolar clefts and irregularly anastomosing synovial fronds. Neither mitotic rate nor the amount of giant cells/amount of nuclei of giant cells revealed statistically significant differences between localized-type and diffuse-type of tenosynovial giant cell tumor. Immunohistochemically, the diffuse-type exhibited focal expression of CD31 (in 75% of tumors) and calretinin (in 63%) besides CD68-staining.     

Frequency and diagnostic value of the virus-like filamentous intranuclear inclusions in giant cell tumor of bone,not associated with Paget's disease

Summary This paper deals with the paramyxovirus-like intranuclear inclusions observed in giant cells tumours of bone (GCTB). Twenty-one (49%) of 43 cases of GCTB (1977–1985), either fresh and/ or cultured, show these ultrastructural inclusions.Fifty samples of various bone lesions in which giant cell lesions occurred, including aneurysmal cysts, hyperparathyroidism, osteoblastoma, human and rat osteopetrosis, GCT of tendon sheaths, and non skeletal granuloma were used as controls. These, together with 20 samples of normal bone (osteoclasts) did not contain intranuclear or intracytoplasmic viral inclusions.     

Giant cell tumor of the scapula associated with secondary aneurysmal bone cyst

Giant cell tumors are distinctive neoplasms characterized by a profusion of multinucleate giant cells scattered throughout a stroma of mononuclear cells. Most giant cell tumors are found at the epiphyses of long bones, especially around the knee joint. Flat bone involvement is rare. However, a case of giant cell tumor with secondary aneurysmal bone cyst was encountered at the scapula of a 25-year-old man. Since the occurrence of a giant cell tumor with secondary aneurysmal bone cyst on flat bones (i.e., the scapula) is extremely rare, the above-mentioned case is worthy of reporting.     

Expression of podoplanin in human bone and bone tumors: New marker of osteogenic and chondrogenic bone tumors

Podoplanin is known as a lymphatic marker because its expression is detected in lymphatic but not vascular endothelium. Podoplanin is also expressed in several normal tissues including osteocytes or osteoblasts. A systematic examination of the podoplanin expression was conducted in normal skeletal tissues and some bone tumor cell lines, and the diagnostic value determined in primary bone tumors. Podoplanin mRNA was expressed at a high level in bone marrow tissue and cartilage, and was upregulated with differentiation to osteoblasts in bone marrow cells. Strong podoplanin expression was seen in osteocytes, chondrocytes, and osteoblasts on immunohistochemistry. Podoplanin mRNA was expressed at a high level in several osteosarcoma and chondrosarcoma cell lines, whereas podoplanin was expressed at a low level in a Ewing's/primitive neuroectodermal tumor cell line. In the clinical samples, osteosarcomas (22/26) expressed podoplanin at various levels. In small cell osteosarcomas (2/2), podoplanin was expressed strongly, although the tissue samples included few diagnostic osteoids. Chondrosarcomas (10/10) expressed podoplanin strongly, and chondroblastomas (5/5) expressed podoplanin moderately, while podoplanin was absent or expressed at low levels in Ewing's sarcomas (0/5), chordomas (0/6) and giant cell tumors of bone (1/7). Therefore, podoplanin may be a sensitive immunohistochemical marker of osteogenic and chondrogenic bone tumors.     

Chondroblastoma and its differential diagnosis

Chondroblastoma is one of the most well defined cartilaginous tumors of bone on imaging and pathological findings. However in practice, the pathologist is faced with diagnostic difficulties. The most recent features of the tumor are developed in the review: clinical findings, skeletal distribution, and above all, the results of the imaging study which has to be strictly correlated with histology for the diagnosis as well as for the differential diagnosis, location, osteolysis, matrix production, periosteal reactions, MRI studies. Histopathology of chondroblastoma is described: cellular component, architecture, and secondary changes. Usefulness of cytopathology is also stressed on smears or tumor imprints. Main findings of recent and various immunohistochemical stains are described and discussed as well. Ultrastructural and cytogenetic studies are summarized. Treatment, natural history, and prognosis of the tumor are developed. The three most important differential diagnoses are giant cell tumors, clear cell chondrosarcomas, and aneurysmal bone cysts.     

Comparative DNA cytometric investigations on aneurysmal bone cysts and giant cell tumors

Giant cell-rich bone lesions consist of tumor-like lesions and true neoplastic giant cell tumors. In this study it was investigated whether DNA cytometry may contribute to the differential diagnosis between aneurysmal bone cysts and giant cell tumors. Statistically significant differences in the frequency of tetraploid stemlines were detected. Nevertheless, the knowledge of age, localization and radiological signs in addition to morphological findings are essential to distinguish between these lesions.     

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.