Immunohistochemical analysis of giant cell glioblastoma

Giant cell glioblastoma (GCG) is one of a group of rare tumors in which the cell population is abnormally large and includes multinucleated cells of gigantic sizes. Immunohistochemical studies were performed on four GCG cases and found that all giant cells and/or tumor cells were positive for glial fibrillary acidic protein (GFAP), S-100 protein, and vimentin, thus verifying the tumor's glial origin. The nuclei of multinucleated giant cells of three adult cases were frequently immunostained for proteins expressed during the cell cycle (proliferating cell nuclear antigen (PCNA) and Ki-67), thereby demonstrating the proliferative capacity of these cells. By contrast, those of a 12 year old girl expressed these cell cycle markers rather infrequently. Alpha I-anti-trypsin was detected with relatively high frequency in the giant cells, and its presence may explain their bizarre sizes and pericellular reticulin fiber formation. A literature review of 32 cases revealed that the GCG that occurs preferentially in young girls is a type of pleomorphic xanthoastrocytoma. By contrast, GCG in adult males has the same age incidence as ordinary glioblastomas and, as these, expresses high levels of cell cycle-related proteins. Thus, GCG, which is subclassified morphologically as ordinary glioblastoma, has distinct biological and clinical characteristics, with that in children requiring re-evaluation because of its similarities to pleomorphic xanthoastrocytoma.     

Cytogenetic and molecular genetic analyses of giant cell glioblastoma multiforme reveal distinct profiles in giant cell and non-giant cell subpopulations

We have comparatively analyzed mechanisms associated with chromosomal and microsatellite instability in giant cell glioblastoma multiforme (gcGBM) and classic GBM. This included microsatellite instability (MSI), loss of expression of four major mismatch repair (MMR) proteins, aberrations of five chromosomes, EGFR copy number, and TP53 mutations. MSI was more frequent among gcGBM (30 vs. 7.8%, P = 0.054). TP53 mutations were more commonly observed in gcGBM (83.3%), whereas EGFR was amplified in just one gcGBM (8.3%). By tumor cell phenotype-specific cytogenetic analysis of gcGBM, increased chromosome copy numbers were identified in 72-84% of giant cells but in only 4-14% of nongiant cells; in classic GBM, intermediate frequencies were noted (11-49%). Chromosome 10 deletions were found in nongiant cells of all gcGBM cases but in only approximately 45% of the cell population in classic GBM. The present study shows a distinct pattern of cytogenetic alterations in nongiant and giant cell phenotypes in gcGBM and suggests that multinuclear giant cells evolve from nongiant tumor cells at an early tumor stage. Furthermore, the data point to differences in the profile of chromosomal and microsatellite instability in gcGBM and classic GBM that might underscore the distinct pathological features of both tumor subtypes.     

A case of giant cell glioblastoma: a mimicker of a cerebral metastasis

We report a rare case of giant cell glioblastoma that was difficult to distinguish from cerebral metastasis. The MRI finding was a ring-enhancing well-circumscribed solitary brain tumor that was very similar to cerebral metastasis. Even when MRI results were considered together with the findings by magnet resonance spectroscopy and perfusion-weighted MRI, it was hard to distinguish between giant cell glioblastoma and cerebral metastasis before surgery. When we find a solitary ring-enhancing intracranial mass with little tendency of invasion, we need to consider the possibility of giant cell GBM as a differential diagnosis.     

Genetic profile of 22 pancreatic carcinoma cell lines

The K-ras, p53, p16 and DPC4 genes are among those most frequently altered in pancreatic ductal carcinoma. We analyzed 22 cell lines for alterations in these genes by direct sequence analysis and methylation-specific polymerase chain reaction. These cell lines showed mutations in K-ras and p53 at frequencies of 91% and 95%, respectively. Alterations in p16INK4a were found in all cases and included nine homozygous deletions, seven mutations and promoter methylation in six cases. Eight cell lines (36%) had an alteration of DPC4, including one mutation and seven homozygous deletions. The most typical mutational profile involved K-ras, p53, and p16INK4a, concurrently aberrated in 20 cases (91%). Eight cell lines had alterations in all four genes. Inactivation of DPC4 was always accompanied by alteration of all of the other three genes. This comprehensive data regarding the cumulative genetic alterations in pancreatic carcinoma cell lines will be of great value for studies involving drug sensitivity or resistance that may be associated with inactivation of a particular gene or molecular pathway.     

A serially transplantable human giant cell glioblastoma that maintains a near-haploid stem line

We have karyotyped a human giant cell glioblastoma removed from an 11-year-old girl and have established from it a subcutaneously transplantable line in athymic nude mice. The original tumor contained near-haploid cells with 25 or 26 chromosomes, including two copies of #1, (7 or 7p+) and #18. There were also hyperdiploid (49-52) cells that were tetraploid for these same three chromosome types; doubled versions of the hyperdiploid population were also seen. The stemline of the mouse-grown tumor was 26,X, +1, +7p+, +18 in the first passage and has remained consistently near-haploid through ten serial in vivo passages. Growth stabilization has occurred with an average latency of less than 3 months. This transplantable line is available for evaluating chemotherapeutic responsiveness of human giant cell glioblastoma and for studying near-haploidy in solid human tumors.     

Malignant melanoma mimicking giant cell variant of glioblastoma multiforme: a case report and review of literature

We present a case of metastatic malignant melanoma in a patient initially diagnosed with glioblastoma multiforme, giant cell variant. A forty year old female presented to our institution for a re-resection of a recurrent right parietal lobe mass, presumed to be recurrent glioblastoma multiforme. PET scan during preoperative evaluation revealed a 3 cm left lower lobe lung mass. Metastatic glioblastoma to lung was considered in the differential diagnosis. Resection of the brain mass revealed a highly pleomorphic giant and spindle cell lesion with an immunophenotype strongly supportive of melanoma. Immunostains for melanocytic markers were subsequently performed on the lung biopsy specimen, and demonstrated diffuse staining of the atypical cells, supporting the diagnosis of malignant melanoma in the lung. This case demonstrates the importance of considering melanoma in the differential in any tumor with high grade features.     

Genetic profile of gliosarcomas

There are distinct genetic pathways leading to the glioblastoma, the most malignant astrocytic brain tumor. Primary (de novo) glioblastomas develop in older patients and are characterized by epidermal growth factor (EGF) receptor amplification/overexpression, p16 deletion, and PTEN mutations, whereas secondary glioblastomas that progressed from low-grade or anaplastic astrocytoma develop in younger patients and frequently contain p53 mutations. In this study, we assessed the genetic profile of gliosarcoma, a rare glioblastoma variant characterized by a biphasic tissue pattern with alternating areas displaying glial and mesenchymal differentiation. Single-strand conformation polymorphism followed by direct DNA sequencing revealed p53 mutations in five of 19 gliosarcomas (26%) and PTEN mutations in seven cases (37%). Homozygous p16 deletion was detected by differential polymerase chain reaction in seven (37%) gliosarcomas. The overall incidence of alterations in the Rb pathway (p16 deletion, CDK4 amplification, or loss of pRb immunoreactivity) was 53%, and these changes were mutually exclusive. Coamplification of CDK4 and MDM2 was detected in one gliosarcoma. None of the gliosarcomas showed amplification or overexpression of the EGF receptor. Thus gliosarcomas exhibit a genetic profile similar to that of primary (de novo) glioblastomas, except for the absence of EGFR amplification/overexpression. Identical PTEN mutations in the gliomatous and sarcomatous tumor components were found in two cases. Other biopsies contained p16 deletions, an identical p53 mutation, or coamplification of MDM2 and CDK4 in both tumor areas. This strongly supports the concept of a monoclonal origin of gliosarcomas and an evolution of the sarcomatous component due to aberrant mesenchymal differentiation in a highly malignant astrocytic neoplasm.     

Genetic pathways to primary and secondary glioblastoma

Glioblastoma is the most frequent and most malignant human brain tumor. The prognosis remains very poor, with most patients dying within 1 year after diagnosis. Primary and secondary glioblastoma constitute distinct disease subtypes, affecting patients of different age and developing through different genetic pathways. The majority of cases (>90%) are primary glioblastomas that develop rapidly de novo, without clinical or histological evidence of a less malignant precursor lesion. They affect mainly the elderly and are genetically characterized by loss of heterozygosity 10q (70% of cases), EGFR amplification (36%), p16(INK4a) deletion (31%), and PTEN mutations (25%). Secondary glioblastomas develop through progression from low-grade diffuse astrocytoma or anaplastic astrocytoma and manifest in younger patients. In the pathway to secondary glioblastoma, TP53 mutations are the most frequent and earliest detectable genetic alteration, already present in 60% of precursor low-grade astrocytomas. The mutation pattern is characterized by frequent G:C-->A:T mutations at CpG sites. During progression to glioblastoma, additional mutations accumulate, including loss of heterozygosity 10q25-qter ( approximately 70%), which is the most frequent genetic alteration in both primary and secondary glioblastomas. Primary and secondary glioblastomas also differ significantly in their pattern of promoter methylation and in expression profiles at RNA and protein levels. This has significant implications, particularly for the development of novel, targeted therapies, as discussed in this review.     

应用RAPD技术检测肺巨细胞癌转移细胞株的遗传学改变

目的：用ＲＡＰＤ技术检测人肺巨细胞癌高低转移细胞株的遗传改变。方法：人肺巨细胞癌细胞系高转移细胞株ＰＬＡ－８０１Ｄ和低转移株ＰＬＡ－８０１Ｃ,用１００条各１０个碱基的随机引物经ＰＣＲ扩增,扩增产物在含溴化乙锭的１．５％琼脂糖凝胶中电泳,紫餐透射仪上观察照相。结果：１００条引物绝大多数能扩增出明显的条带,多数引物产生的条带在高低转移株之间无差异,表现为单态性;其中１７条引物产生多态性,表现为带的有无     

Clinicopathologic profile of 470 giant cell tumors of bone from a cancer hospital in western India

Over 20 years, 470 cases of giant cell tumor of bone diagnosed at a tertiary cancer hospital were analyzed. Male predominance (57%), predilection for bones around the knee joint (42%), and occurence in the 21- to 30-year-old age group (49.1%) with 6% being in the immature skeleton are well known facts. Accurate diagnosis was possible in 66% and 88% of cases on radiology and biopsy, respectively. Tumors measured 6 to 20 cm and, in 402 cases, showed “usual” histology comprising uniformly scattered multinucleate giant cells amidst mononuclear stromal cells, together imparting a syncitium-like appearance. Presence of osteoid, hemorrhage, and aneurysmal bone cyst–like areas; spindle cells in sheets (devoid of giant cells); or storiform pattern and intravascular osteoclasts were less common. The less common histologic features posed diagnostic difficulty in the setting of a small biopsy. Treatment included intralesional curettage (33.19%), marginal excision (4.2%), wide excision (31%), or radical surgeries (14.25%). Recurrences seen in 170 cases were multiple in 47 cases. Metastases largely to the lung were recorded in 24 cases. The histology of all the tumors, namely, primary, recurrent, or metastatic was identical. Statistical analysis using the computer software SPSS (SPSS Inc, Chicago, Ill)was performed with particular reference to the unusual histologic features vs recurrence and metastasis by χ² test. The only statistically significant factors were occurrence in the axial skeleton vs appendicular skeleton (P = .001) and primary treatment elsewhere vs at this hospital (P = .045), each of these being associated with increased frequency for local recurrence but not metastasis.     

Origin of giant cells in osteoclast-like giant cell tumors of the pancreas

To clarify the origin of giant cells in osteoclast-like giant cell tumors (OGCTs) of the pancreas, we performed microscopical, immunohistochemical, and K-ras gene mutation analyses with a microdissection approach in 3 cases, featuring 4 cellular components (osteoclast-like giant cells [OGCs], pleomorphic large cells [PLCs], mononuclear cells, and ductal carcinoma cells). Two cases had abundant OGCs, and 1 case contained large number of both OGCs and PLCs. In each, none of the microdissected OGCs contained any K-ras gene mutation while they were positive for a histiocytic marker (CD-68). In contrast, PLCs, when present, frequently harbored K-ras gene mutations and were negative for CD-68. In all cases, mononuclear cells, a mixture of histiocyte-like and atypical, from microscopic and immunohistochemical viewpoints, also frequently showed K-ras alteration. Histiocyte-like mononuclear cell was equipped with a regular and oval nucleus similar to those in OGCs and was positive for CD-68. Atypical mononuclear cell showed an irregular, pleomorphic, or sometimes bizarre nucleus similar to those in PLCs and was negative for CD-68. All of the K-ras gene mutations found in PLCs and mononuclear cells were the same as in the ductal carcinoma cells within the same tumor. Thus, OGCs differ in origin from ductal cells and are strongly suggested to be nonneoplastic and of mesenchymal origin, whereas PLCs, which harbor K-ras gene mutations, are neoplastic and presumably derived from ductal carcinoma cells. Moreover, mononuclear cells may be classified into 2 types, histiocyte-like and atypical.     

Osteoclast-like giant cell tumor of the pancreas: immunophenotypic similarity to giant cell tumor of bone

An immunophenotype was performed on an osteoclast-like giant cell tumor of the pancreas using a panel of antibodies to epithelial and leukocyte antigens. Several antibodies to cytokeratin and carcinoembryonic antigen were negative in the tumor. Osteoclast-like cells were positive for CD4, CD13, CD45, CD68, CD71, and vimentin, but negative for lysozyme and HLA-DR. Mononuclear tumor cells were positive for CD4, CD11c, CD13, CD14, CD45, CD68, CD71, HLA-DR, and vimentin, but negative for lysozyme. The phenotype is similar to that previously described for giant cell tumor of bone. The osteoclast-like cell phenotype is also similar to that reported for normal osteoclasts. The findings support a nonepithelial origin for osteoclast-like giant cell tumor of the pancreas, and suggest a derivation similar to giant cell tumor of bone.     

Osteoclast-type giant cell tumour of the pancreas

Summary Two cases of osteoclast-type giant cell tumour of the pancreas (OGTP) are presented and compared with similar tumours of other locations and pancreatic carcinomas. One of the tumours was analyzed by immunohistochemical methods. The mononuclear stromal cells and osteoclast-like giant cells, which characterize this very rare neoplasm, reacted with an antibody against vimentin, but were not decorated by antibodies against lysozyme, alpha-1-ACHT, alpha-1-AT. Pleomorphic mononuclear cells in osteoid additionally contained osteonectin and could thus be identified as osteoblasts. Only the tumour glands stained positively with panepithelial keratin antibodies and antibodies against the keratin polypeptides 7, 18, 19. These results demonstrate for the first time the mesenchymal differentiation of the OGTP, which in some cases is also able to form epithelial structures. The immunohistochemical reactions and the characteristic morphology of the tumour show the OGTP to be an entity which must be differentiated from pancreatic carcinoma, especially from its giant cellular subtype.     

Osteoclastoma-like giant cell tumor of the lung

Osteoclastoma-like giant cell tumor of lung. A case of osteoclastoma-like giant cell tumor of the lung is reported. This is an unusual tumor too described in the heart, thyroid, skin, soft tissues and pancreas. AA. studied the tumor's structure and are of opinion that it concerns a primitive nonepithelial neoplasm of the lung.     

Osteoclast-like giant cell tumor of the liver

A 66-year-old male with osteoclast-like giant cell tumor of the liver that arose in the non-cirrhotic liver is presented. The liver tests were almost normal, and plasma levels of alpha-fetoprotein and carcinoembryonic antigen were within normal limits. The findings of liver scan by 99mTc phytate, celiac angiography, and CT scans are described for the first time for this rare neoplasm, showing a large, unresectable liver tumor. Histologically, the tumor mainly consisted of osteoclast-like giant cells and mononuclear cells, which were focally arranged in a vaguely trabecular pattern and sarcomatous pattern. By an electromicroscopic study, however, no definitive evidence was obtained whether it arose from epithelial cells or nonepithelial cells. Various clinicopathological features were described and compared with previously reported cases including two cases arising in the liver.     

Osteoclast-like giant cell tumour of the gallbladder

Summary We describe a rare carcinoma of the gallbladder containing osteoclast-like giant cells. Well-differentiated adenocarcinoma was found in the mucosa of the fundus, and osteoclast-like giant cells were present mainly in a haemorrhagic mass protruding from the mucosal surface. The metastatic hepatic tumour was composed chiefly, if not exclusively, of osteoclastoma-like cells, but minute carcinomatous elements were also present. There was an apparent transition between the giant cells and tubular structures in both the gallbladder tumour and hepatic tumour. However, ultrastructural study did not reveal any evidence of epithelial differentiation in the giant cells. Immunohistochemical studies suggested that the mononuclear and giant cells were mesenchymal and histiocytic in nature (vimentin and factor XIII a positive). A few exceptional giant cells transforming from the fine tubular structure were positive for epithelial membrane antigen. In conclusion, the osteoclast-like giant cell tumour component was thought to represent mesenchymal metaplasia in pre-existent adenocarcinoma.