[Sinus injuries caused by giant cells: giant cell granuloma and giant cell tumor coexisting with Paget's disease of the cranium].
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BACKGROUND: From both epidemiologic and pathologic viewpoints, gangliogliomas exhibiting components of giant cell glioblastomas are extraordinary neoplasms. We report herein the case of a 6-year-old girl who presented initially with a World Health Organization grade IV anaplastic ganglioglioma (a mixed ganglion cell tumor-giant cell glioblastoma). Despite aggressive management, the patient died of disease in a relatively short period. METHODS: Formalin-fixed, paraffin-embedded tissue blocks were sectioned at 5 microm for histochemical and immunohistochemical analyses. Hematoxylin-eosin-stained sections and immunohistochemically stained sections from the primary and secondary resections were reviewed. Reactivity for glial fibrillary acidic protein, neurofilament protein, synaptophysin, and Ki67 nuclear antigen was evaluated. RESULTS: Histologically, 2 distinct cell populations were noted on both the primary and secondary resections. The primary resection revealed a neoplasm having a predominant glial component consistent with a glioblastoma. Interspersed were dysmorphic ganglion cells supporting a diagnosis of ganglioglioma. The second resection (following therapy) demonstrated a much more prominent dysmorphic ganglion cell component and a subdued glial component. CONCLUSION: Although immunohistochemical analysis clearly distinguished the 2 tumor cell populations, the identification of Nissl substance in neurons proved to be equally helpful. Although other cases of grade III gangliogliomas and rare cases of grade IV gangliogliomas have been reported, the present case is exceptional in that, to our knowledge, it is the only report of a patient who presented initially with a composite grade IV ganglioglioma and who was clinically followed up to the time of death. This case allows direct comparison between the histologic findings in a giant cell glioblastoma and a ganglioglioma and documents the aggressive biologic behavior of this complex neoplasm.
Marked cellular reactions in the urine appeared after subcutaneous vaccination with inactivated influenza virus vaccine. Inclusion-bearing epithelial cells increased in 16 cases from 2.4 to 9.6% and erythrocytes from 2.5 to 16.2 per visual field. Pathological values for inclusion-bearing cells were found in 5 of 18 cases (28%), spherical giant cells in 3 (17%), and an abnormal number of erythrocytes in 7 (39%). Killed virus, lacking the capability of replication, thus gave rise both to the formation of inclusions and to fusion of cells within the epithelium of the kidneys and of the urinary tract, and also to haematuria. There was a striking resemblance to the reaction in 34 cases of uncomplicated influenza A2, but the inclusion-provoking effect of the vaccination dose was clearly weaker and the erythrocyturia somewhat less pronounced. As a rule the cellular changes after the vaccination quickly reverted to normal, but there were examples of elevated values still existing after 6 months. Two patients had a high inclusion content and haematuria persisting for 3 and 4 years, one of whom following influenza A2. Influenza and influenza vaccinations may be the cause of certain instances of chronic benign haematuria.
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Immunohistochemical investigation of PCNA and Ki-67, two diverse nuclear proteins essential to the cell cycle, was undertaken in archival, formalin-fixed and paraffin-embedded specimens of giant cell fibroma (GCF) and peripheral giant cell granuloma (PGCG++). GCF multinucleated cell nuclei were mostly PCNA+, although there was variability in staining intensity. This indicates heterogeneity in nuclear PCNA metabolism of GCF multinucleated cells, and it is possible that the most intensely stained nuclei have passed through the cell cycle more recently compared to the less immunoreactive nuclei. However, the absence of Ki-67 immunoreactivity in GCF multinucleated cells, and absence of mitoses in GCF multinucleated cells, suggests that cell cycling in the absence of cytokinesis is not involved in GCF multinucleated cell formation. Alternatively, GCF multinucleated cells possibly form by fusion of mononuclear cells previously identified as fibroblasts, although this theory cannot be confirmed by the data presented in this study, and the histogenesis of GCF multinucleated cells remains unclear. In contrast, absence of either PCNA or Ki-67 immunoreactivity in PGCG multinucleated cells is consistent with an osteoclast lineage and formation from differentiated mononuclear cells.
Alterations of cell cycle regulatory proteins, especially those that regulate G1 to S transition, have been implicated in the pathogenesis of a wide variety of human tumors. In previous studies we showed that that there is overexpression of cyclin D1 protein predominately in the giant cell component of giant cell tumors of bone. The purpose of this study was to investigate the mechanisms that may be responsible for cyclin D1 accumulation in giant cell tumors. Giant cell tumors have high levels of cyclin D1 mRNA and the giant cell-enriched population of these tumors have significantly more mRNA and protein expression of cyclin D1 than the mononuclear cell population. The giant cells also expressed higher levels of p21 protein and more p21 bound to cyclin D1 than the mononuclear cells. It is possible that p21 may be contributing to the cyclin D1 accumulation that occurs in the giant cells and perhaps even giant cell formation in these tumors. Additional studies are required to confirm the role of p21 in the pathogenesis of these tumors.
To clarify the histogenesis of giant cells appearing in giant cell tumors of bone (GCTB), an ultrastructural and cytochemical study of six cases was performed with both acid phosphatase (ACPase) and tartrate-resistant acid phosphatase (TRACPase) as marker enzymes. TRACPase is considered a specific marker for osteoclasts. ACPase was demonstrated in the macrophagelike stromal cells, the multinucleated giant cells, and the infiltrating macrophages. The enzyme reaction was localized in lysosomal dense bodies and Golgi areas. Intense TRACPase activity was demonstrated in the multinucleated giant cells, whereas a weak reaction was found in the macrophagelike stromal cells. The multinucleated giant cells and macrophagelike stromal cells resembled osteoclasts with regard to the subcellular localization of TRACPase. The present results suggest that the giant cells in GCTB are indeed derived from osteoclasts.
OBJECTIVES: To compare the morphology of foreign body and Langhans giant cells in the two different inflammatory phases of giant cell arteritis (GCA). METHODS: Electron microscopy was performed on 6 positive temporal arterial biopsies. Light microscopy and immunocytochemistry for macrophage-associated antigen (KP1) and alpha-smooth muscle actin (alpha-SMA) were performed on 16 positive biopsies. RESULTS: A focal granulomatous reaction with foreign body giant cells was found only in association with the internal elastic membrane (IEM) in atrophic arterial segments, which often displayed calcification of the IEM. Diffuse invasion of lymphocytes and monocytes/macrophages affected non-atrophic as well as atrophic arterial segments. Within such segments Langhans giant cells were found in all layers of the wall. Electron microscopy of biopsies displaying the focal foreign body reaction revealed that large cells devoid of lysosomes but with cytoplasmic densities, tightly packed cytoplasmic filaments and numerous micropinocytotic vesicles formed clusters close to calcified parts of the internal elastic membrane. Furthermore, foreign body giant cells were surrounded by large cells devoid of lysosomes. Lysosomes tended to concentrate in central parts of the foreign body giant cells. In the diffusely inflamed arteries, the Langhans giant cells were surrounded by mononuclear cells rich in lysosomes. The lysosomes in the Langhans giant cells were more evenly distributed than in foreign body giant cells. Immunocytochemistry of biopsies displaying the focal granulomatous reaction revealed an uneven, often central immunoreactivity for the macrophage marker (KP1) in the foreign body giant cells, and immunostaining for alpha-smooth muscle antigen (alpha-SMA) showed their poor delineation from the surrounding vascular smooth muscle cells. The Langhans giant cells in the diffusely inflamed arteries displayed a strong even cytoplasmic immunoreactivity for KP1 and a distinct delineation from the smooth muscle cells in the alpha-SMA staining. CONCLUSION: Differences in terms of distribution, light microscopy, immunocytochemistry and electron microscopy between the two types of giant cells in GCA indicate a difference in their function as well as their histogenesis.
Interleukin-6 (IL-6) is a multifunctional cytokine whose role in osteoclastic bone resorption has not been clearly defined. Therefore, we have used giant cells, which express many features of osteoclasts, from giant cell tumors of bone as a model to examine the role that IL-6 may play in human osteoclastic bone resorption. We found that conditioned medium from 24-h cultures of highly purified giant cells (10(6)/ml) contained large amounts of IL-6 (37.9 +/- 8.8 ng/ml), similar to the amount of IL-6 produced by tumor stromal cells (29.8 +/- 11.5 ng/ml). Giant cells and stromal cells from giant cell tumors expressed IL-6 mRNA, as indicated by polymerase chain reaction analysis and in situ hybridization studies, and immunohistochemical techniques demonstrated that the giant cells expressed IL-6 receptors. The addition of a neutralizing antibody to IL-6 significantly decreased the area of dentine resorbed by purified giant cells in a dose-dependent manner, and the addition of IL-6 to cultures of purified giant cells pretreated with anti-IL-6 restored the resorbing capacity of the giant cells. These data suggest that IL-6 may act as both an autocrine and a paracrine factor for human osteoclasts and play an important role in the bone-resorbing capacity of these cells.
The origin of the stromal, stellate and multinucleate cells in oral giant cell fibroma is unclear. Sixteen giant cell fibromas were stained immunocytochemically for keratin (MNF 116), vimentin, S-100 protein, neurofilaments, glial fibrillary acidic protein, alpha-smooth muscle actin, desmin, CD31 (PECAM-1), CD68, Factor XIIIa and prolyl 4-hydroxylase (5B5). In all cases positive staining was found with vimentin and prolyl 4-hydroxylase, indicating a functional fibroblast phenotype. Reactivity for Factor XIIIa was seen in two cases and in only one was a small number of giant cells stained, suggesting that the majority of oral giant cell fibromas are unrelated to the histologically similar fibrous papule of the nose or facial angiofibroma.
Giant cell reactions (giant cell reparative granulomas) are uncommon lesions that predominantly involve the small bones of the hands and feet. In 1980, only 13 cases of this entity had been described. Three patients with similar giant cell reactions were identified from the Mayo Clinic files, and an additional 27 patients were collected from the consultation files of one of the authors. Clinical information and follow-up data for these 30 patients suggest that the biologic behavior and, therefore, treatment of giant cell reactions differ from those of true giant cell tumors in the small bones of the hands and feet.
Giant cell tumor of bone (GCT) is a local aggressive neoplasm of bone characterized by expansive osteolytic lesions at the epiphysis of long bones. Bisphosphonates have been used to prevent bone resorption in secondary osteolytic tumors because of their strong anti-osteoclastic action. The authors studied the apoptosis and ultrastructural changes induced in osteoclast-like giant cells of GCT, following treatment with the aminobisphosphonate pamidronate in 16 patients with GCT of bone. Transmission electron microscopy (TEM) was used to identify ultrastructural changes, indicative of apoptosis, in the cytoplasm and the nucleus of the giant cells. Significant changes were observed in tumor samples from all 16 patients. In the cytoplasm these changes were characterized by abundant large tubular vesicles containing a central electrodense core scattered through the cytoplasm. In addition, mitochondria in the sections from pamidronate-treated patients appeared to be edematous when compared with sections from untreated patients. Nuclear changes in the giants cells were characterized by the formation of dense chromatin material scattered throughout the nucleus. The TUNEL labeling assay indicated that the mean pretreatment apoptotic index of 7.8% increased to 53% following pamidronate treatment. This was statistically significant (p<.001) and correlated well with the ultrastructural changes noted on TEM. The formation of abundant tubular vesicles in giant cells following bisphosphonate treatment may reflect disturbed vesicular trafficking and may affect the bone resorbing activity of giant cells.
By means of tissue culture, electron microscopy, cytochemistry, indirect immunofluorescence and immunohistochemistry, the multinucleated giant cells(MGCs) in 12 giant cell tumors of bone (GCT) were studied in contrast with osteoclasts (OCs), foreign body giant cells (FGCs) and inflammatory giant cells (IGCs). The findings in the majority of MGCs were identical with those in OCs, suggesting that they most probably derived from the same precursor. Continuous in vitro culture revealed two kinds of MGCs, which were designated preliminarily as short-lived MGCs and long-lived MGCs for their difference in morphology and in several biological features, which suggests two kinds of MGCs exist in GCT. We conclude that the short-lived conform to the typical MGCs known generally to the pathologists, while the long-lived are deemed to be closely related to the neoplastic elements of the tumor.
We report a case of a neuroendocrine tumor of the jejunum metastatic to the liver in a 26-year-old woman. Light and electron microscopy of this tumor revealed a poorly differentiated neoplasm composed of clusters of round to polygonal cells compatible with a diagnosis of neuroendocrine tumor. In the absence of identifiable silver-staining granules or immunocytochemical demonstration of a specific hormone product in tumor cells, this tumor cannot be further classified among the various neuroendocrine tumors that may arise in this location. However, interspersed among tumor cells was a distinct population of multinucleate giant cells having an appearance similar to benign osteoclasts. Enzyme histochemistry for 5'-nucleotidase, acid phosphatase, and nonspecific esterase each showed a dichotomous staining pattern for the small tumor cells and giant cells and suggest that the giant cells are not tumor derived, but represent a second, presumably reactive, cell population.
The behaviour of multinucleated giant cells (GCs), obtained from a giant cell tumour of the tibia and cultured on glass coverslips or on devitalized bone slices, was studied using light and electron microscopy. Monitoring the GCs on bone slices by phase-contrast microscopy revealed that they had removed calcified bone matrix resulting in excavation of lacunae, with subsequent lateral extension and perforation of the bone slices. Electron microscopy demonstrated for the first time that the GCs responsible for exavating lacunae had two specific membrane modifications, ruffled border and clear zone, and showed basically similar cytoplasmic fine structures to those of osteoclasts. Fluorescence images of the GCs on glass and on bone after rhodamine-conjugated phalloidin staining revealed that most of the GCs had an intensely fluorescent peripheral band composed of a number of F-actin dots called podosomes. Some GCs showed unusual arrangements of podosomes suggesting abortive attempts at GC formation. We have demonstrated that the band structure of the GCs cultured on bone is intimately involved in bone resorption. Two stromal cell types could be recognized. The predominant type, which seemed to be the only neoplastic element because of its proliferative capability, showed quite different fine structural and cytoskeletal features from the GCs. The other type, which was much less frequent and seemed not to proliferate, had morphological similarities to the GCs, and seemed to be their precursor. Importantly GCs cultured on bone and the osteoclasts share common structures for adhesion to and resorption of bone, strongly supporting the view that the GCs of the giant cell tumour of bone are potentially active bone resorbers and can be regarded as osteoclasts.
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