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The fine structural localization of nonspecific alkaline phosphatase was elucidated in two giant cell tumors of bone using lead as capturing ion and beta-glycerophosphate as substrate in the incubation solution. Lead phosphate precipitate--indicating presence of alkaline phosphatase--was demonstrated on the plasma membranes, and the membranes bordering vesicles and vacuoles of presumed endocytotic nature, in giant cells and type 1 stromal cells (fibroblast-like cells). The findings support the view that stromal cells type I and giant cells are histogenetically related.

A comparative electrone microscopic investigation of osteogenic sarcomas and giant-cell bone tumors has revealed the ultrastructural differences between a mononuclear component of the giant-cell tumor and the most frequently observed type of osteogenic sarcoma cells (a well-developed ergastoplasma in cells of osteogenic sarcoma and moderately developed one- in the giant-cell tumor of bones, different rate of development of the mitochondrial apparatus, the character of nuclei) that indicates different genesis of these two tumor types. In giant-cell bone tumors a definite ultrastructural similarily between some mono- and multinuclear cells (a large number of mitochondrial, similar character of nuclei) may speak in favour of the common source of their development and explains the high activity of oxidoreduction enzymes in them revealed histochemically.

Clinical and pathologic features of five low-grade mucoepidermoid and a similar number of squamous cell carcinomas of breast are presented. Three of each were retrieved from 55 cases of invasive breast cancer previously assessed to exhibit squamous metaplasia. Although the estimated incidence of low-grade mucoepidermoid cancers is approximately 0.2%, they may be more frequent, masquerading under designations of squamous metaplasia or intracystic carcinomas. All patients with low-grade mucoepidermoid cancer, and the two recorded previously, were free of recurrence for 4-10 years. No high-grade mucoepidermoid cancers were found. Squamous cell cancers frequently have a phyllode configuration (carcinoma phyllodes). Two examined by electron microscopy revealed a commonality of ultrastructural features with similar tumors of other sites. None exhibited glandular differentiation or tinctorial evidence of mucin secretion. One squamous cell carcinoma contained both malignant epithelial and banal, osteoclast-like, stromal giant cells. Only the latter were identified in tissue culture. This experience and review of the literature prompted a nosologic characterization of giant cell lesions of breast. One patient with squamous cell carcinoma succumbed because of her disease; the remainder are either free of or alive with recurrence at 4 and 10 years.

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.

Four cases of malignant giant cell tumor of soft parts (MGCT) were studied ultrastructurally. Most of the cells in three cases were identified as undifferentiated mesenchymal cells and mononuclear monohistiocytic cells. The osteoclastlike cells seemed to arise from fusion of monohistiocytic cells. Immature fibroblastic cells, occasionally containing filaments with densities, were also present. They were scarce in three cases and predominant in the fourth. It was concluded that MGCT is a mesenchymal sarcoma with a bimorphic--monohistiocytic and fibroblastic--differentiation. MGCT is therefore considered a special variant of malignant fibrous histiocytoma.

Cells were disaggregated from osteoclastomas, and the response of the giant cells to calcium-regulating hormones, prostaglandin (PG)E1 and dibutyryl cyclic AMP (dbcAMP) was observed by phase-contrast time-lapse video microscopy. The pattern and nature of their response was very similar to that previously found to be characteristic of osteoclasts: calcitonin (CT), PGE1 and dbcAMP induced cytoplasmic quiescence, while parathyroid hormone (PTH) showed no influence on cytoplasmic motility or behaviour. The cells were also cultured on slices of devitalized cortical bone for 5 or 18 h. After this time the giant cells were associated with the appearance in the scanning electron microscope of characteristic resorption pits, the volume of which was calculated by computer-assisted morphometric and stereophotogrammetric techniques after removal of cells. Calcitonin caused a dramatic reduction in the volume of bone resorbed by these isolated cells compared with control cultures, while PTH was without significant effect. This result supports the view that PTH does not increase bone resorption in intact bone through a direct effect on osteoclasts. PGE1, which stimulates bone resorption when added to intact bone, paradoxically reduced resorption in our cultures. It thus appears possible that PGE1 acts as a direct inhibitor of osteoclastic bone resorption but has an additional effect on other cells in bone, which are induced by PGE1 to cause osteoclastic stimulation.

A malignant giant cell tumor of the carpal bones metastatic to the lung in a 23-year-old woman is described. Findings from ultrastructural and cell marker studies support the concept that this tumor is of histiocytic origin.

In vitro cell culture techniques were used to identify and characterize the individual cell types present in human giant cell tumors of bone. Three major cell types were identified based on morphologic characteristics, patterns of specific cell surface antigens, presence of receptors for hormones, and cell products. One population consisted of mononuclear cells that expressed monocyte-macrophage markers. These cells lacked receptors for skeletal hormones and did not persist in culture. Distinct from these cells was a population of mononuclear cells that proliferated in culture and most likely represented the neoplastic element of the tumor. These cells phenotypically resembled connective tissue stromal cells, i. e., they did not express macrophage surface antigens and they produced collagens (Types I and III). They also possessed receptors for parathyroid hormone. The final population of tumor cells consisted of multinucleated giant cells. These cells lacked monocyte-macrophage surface antigens and possessed receptors for calcitonin, a phenotypic marker for osteoclasts. These studies illustrate that in vitro cell culture techniques can be employed to identify and characterize the cell populations of tumors of skeletal tissues, and demonstrate the usefulness of these cell culture models for investigating the biology of bone tumors.

A case of giant cell tumor (GCT) of the distal femur in a 56-year-old man is reported in association with Paget's disease. The case is unique in that is is the first report of GCT arising in a patient with this disease in which the neoplasm arose in a bone that did not show radiologic evidence of Paget's disease. This case also represents the first example of such an association in which viral-like inclusion bodies are seen in the osteoclast of the tumor. The fact that similar inclusion bodies are seen in the osteoclast of patients with Paget's disease and in their GCT implies a cause-and-effect etiologic relationship rather than mere coincidence. The implications are that a slow-virus infection is involved in the pathogenesis of Paget's disease and in giant cell tumors occurring in patients with this disease.

Comparative ultrastructural and histoenzymological study of 10 osteogenic (4 osteosarcomas), osteolytic (3 benign giant cell tumours, 2 malignant osteoclastomas) and fibrosarcomatous osseous tumours of the jaw emphasised the analogies between osteoblasts and fibroblastic stromal cells of giant cell tumours. These two cell types, with their abundant granular ergastoplasm, secrete a collagen interstitial fibrillary substance which is capable of secondary calcification. Their enzyme activities, with regard to oxidative mechanisms and protein synthesis are identical. Osteogenic activity as assessed by ATPase and alkaline phosphatase, more marked than in osteosarcomas, is also found in the stroma of benign giant cell tumours. With regard to the plasmodes characteristic of giant cell tumours, they are certainly original from both a morphological and enzymological standpoint : richness in mitochondria and lysosomes, intensity of oxidative reactions (B.O.H.B.D. +++). Nevertheless, the morphological appearances seen would be more in favour of their stromal origin than in their arising from monocytes-macrophages coming from the blood.

An ultrastructural study of 13 cases of typical giant cell tumor of bone (GCT) revealed the presence of virus-like intranuclear inclusions (INI), morphologically identical to those reported in Paget's disease of bone. In two giant cells of two different patients, INI were found only after careful survey of a great number of cells. This finding, coupled with the scarcity of GCT with similar inclusions reported in the literature, reveals the extreme rarity of this finding and leaves open to discussion the specificity of these INI even in Paget's disease, as well as the possible etiological significance in giant cell tumor of bone.

Eleven benign giant cell tumors of bone were studied in the electron microscope, and the fine structural localization of acid phosphatase was elucidated. Three distinct cell types are always present in these tumors: stromal cells type 1; stromal cells type 2; and multinucleated giant cells. Small mononuclear cells may also occur, but are not likely to be actively participating in the neoplastic process. The range of variability in the fine structure of the different cell types constituting this tumor has been established. Variations in appearances include: a) presence of nuclear pseudoinclusions in stromal cells type 1 and multinucleated giant cells; b) aberrations in the structure of the rough surfaced endoplasmic reticulum in the same cell types; c) occurrence of ruffled borders, ectoplasmic layers and cytoplasmic labyrinths containing acid phosphatase in the giant cells. Some giant cells show evidence of marked phagocytic activity and contain large and numerous residual bodies carrying acid phosphatase. The significance of the interrelations between the different cell types are discussed and the possible role of stromal cells type 2 in immunological mechanisms directed against the tumor cells are mentioned.

We report two cases of giant cell tumor of bone (osteoclastoma) associated with Paget's disease. One appeared on the left cubitus in a 68-year-old male patient while the second involved the right maxillary sinus in a 79-year-old woman. Histopathological study was completed by ultrastructural and immunocytological studies. They were demonstrated to contain intranuclear virus-like filamentous inclusions in the osteoclasts. However, we cannot obtain positive response with antisera against measles virus and respiratory syncitial virus. These data are confronted to the hypothesis for a viral aetiology of Paget's disease and giant cell tumor of bone, associated or not to Paget's disease.

A clinico-pathologic study of a 69-year-old woman with a malignant giant cell tumor of the uterus compatible with malignant giant tumor of soft tissues is presented. The diagnosis was based mainly on light- and electron-microscopic findings, including the demonstration of phagocytic activity of the neoplastic cells. The tumor metastasized to the lung and the patient died a short time after clinical onset. The classification of uterine sarcomas and the differential diagnosis are briefly discussed.

We report the fourth case of an osteoclastoma-like giant cell tumour of the renal pelvis. A special feature was that although thorough sampling of the tumour showed an osteoclastoma-like pattern throughout, it was intimately associated with carcinoma in situ change of the adjacent transitional epithelium and this provides further support for the view that these tumours are of epithelial derivation. However, immunohistological and ultrastructural studies failed to reveal epithelial features within the tumour cells and the possible significance of this finding is discussed.

The intranuclear tubulo-filaments appearing in giant cells were studied ultrastructurally in a giant cell tumour of bone arising in a patient with Paget's disease. Serial sections have shown the presence of invaginating nuclear membrane around these apparent intranuclear tubulo-filaments, thus segregating these structures from the nuclear substance proper. Further sectioning showed clear continuity between these tubulo-filaments and the rest of the cytoplasmic contents. It is found that these apparent intranuclear tubules represent pseudo-inclusions rather than true intranuclear inclusions.

The origin and characteristics of so-called stromal cells (stromal cell) and the osteoclast-like giant cell series of 19 cases of giant cell tumor (G.C.T.) of bone were studied. Immunohistochemically, two interesting cases were found. The stromal cells of one case were alpha-1-antitrypsin positive and those of the other case were alpha-1-antichymotrypsin positive. The histiocytic stromal cells of the latter case seemed to be surely neoplastic since they showed mild to moderate cell atypism. There were foci consisting of fibroblastic cells or osteoid and osteoblasts within the tumor. Those cells in the foci were apparently continuous with the surrounding stromal cells, and they were, therefore, also considered to be neoplastic. These findings strongly indicate that the stromal cells originate from the undifferentiated mesenchymal cells in the bone marrow and may differentiate to osteoblastic, fibroblastic, and histiocytic cells. All cells of these three series were not stained for a high stable form of acid phosphatase (SAPhase). SAPhase activity was demonstrated only in osteoclast-like giant cells and some mononuclear cells, which are recently believed to be non-neoplastic. Therefore, the cell atypia of SAPhase negative stromal cells is considered to have a prognostic value.

In multinuclear cells of giant cell tumours of long bones studied in biopsies and histiotypic cultures the centrioles were found to be grouped at a distance from the nuclei, forming a giant centrosphere made of diplosomes in equal number to that of the nuclei. This arrangement renders the possibility of new mitotic activity highly unlikely. By contrast, close contacts between multinuclear cells and stromal cells together with the collapse of membranes between cells in contact and the centriolar arrangement represent arguments in favour of genesis by fusion from mononuclear cells of stromal type, in common with many polykaryons. The multinuclear cells of these tumours would appear to represent only the final stage in the evolution of certain mononuclear cells.

In a case of giant cell tumour of bone, electron microscopy revealed filamentous inclusions within the nuclei of all the giant cells. Although not invariably present in such tumours, their similarity with the nucleocytoplasmic inclusions seen in osteoclasts in Paget's disease is underlined. This raises interesting questions as to their nature and the histogenesis of these disorders.

Five cases of a rare peculiar type of mammary carcinoma with osteoclast-like stromal giant cells are reported. The tumors are characterized by a large number of multinucleated giant cells in intimate association with the epithelial neoplastic cells. The light and electron microscopic observations confirm the earlier reports about the origin of the giant cells from mononuclear histiocytes as a local response to some tumoral products. In 3 patients a preoperative fine-needle aspiration biopsy was carried out and the cytomorphology of these tumors is described to alert cytopathologists who encounter this entity in the routine breast mass aspiration biopsy.

Five cases of mammary carcinoma with osteoclast-like giant cells are reported. This study as well as review of the literature underline characteristic features of this rare histological type of carcinoma: a round well-circumscribed dense nodule of benign appearance on mammograms in half of the cases; brown colour of tumour specimens; stromal hypervascularity; negativity of epithelial, vascular and most histiocytic immunohistochemical markers in giant cells; positivity of leucocyte common antigen and vimentin in giant cells. Giant cells most probably originate from the fusion of histiocytic type mononucleated stromal cells, but results of immunohistochemical stainings cannot actually bring formal arguments to support this hypothesis.

An unusual malignant thyroid neoplasm with a morphologic resemblance to giant cell tumor of the bone is reported in a patient who presented with a rapidly growing thyroid mass and a history of pre-existing goiter. The light and electron microscopic studies disclosed areas of differentiated follicular carcinoma with gradual transition to undifferentiated carcinoma. Pleomorphic spindle-shaped cells and giant cells were accompanied by numerous osteoclast-like multinucleated giant cells. Desmosomes and interdigitating cell surfaces were apparent in the differentiated as well as undifferentiated areas on electron microscopy. These findings support an epithelial rather than a mesenchymal origin for this neoplasm.

The cytogenesis of giant cell tumors of bone was studied in 6 cases by combined electron microscopical, histochemical and autoradiographical investigations. Electron microscopy identified two different types of mononuclear stromal cells: fibroblast-like cells with spindly shape and numerous membranes of the granular ER occur together with macrophages bearing many large lysosomes and a prominent Golgi apparatus. Enzyme histochemical results reflect the same diversity: One portion of mononuclear cells exhibits strong alpha-naphthyl acetate esterase (ANAE) activity, known as a marker for cells of the mononuclear phagocyte system, while the other, fibroblast-like cell type is ANAE negative. Tumor giant cells contain numerous membranes of granular ER, mitochondria, and a few isolated lysosomes. They lack the typical brush border of osteoclasts. Moderate to strong ANAE activity of these giant cells reflects their belonging to the mononuclear phagocyte system. Consequently, the giant cell tumor of bone consists of two different cell types, i.e. fibroblast-like cells and cells of the mononuclear phagocyte system, and so is appraised as a fibrohistiocytic tumor. A new inference from our autoradiographic findings is that tritiated thymidine is incorporated only by mononuclear cells, but not by giant cells. Electron microscopical autoradiography demonstrated that among the mononuclear cells, only fibroblasts are found to proliferate, but not macrophages. Thus, the giant cell tumor of bone is seen as a neoplasm of fibroblastic cells with a strong reactive infiltration of cells from the mononuclear phagocyte system.

A 15-year-old white boy with a giant cell fibroblastoma of the skin of the abdomen is described. Giant cell fibroblastoma is a rare soft tissue neoplasm that most commonly occurs in children as a small, painless mass in the dermis and subcutaneous tissue. Although local recurrences have been reported, no metastases have occurred. Giant cell fibroblastoma must be differentiated from other spindle cell neoplasms.

Giant cell tumor is considered to be a lesion which behaves locally in an aggressive fashion and has a high local recurrence rate. Several physical adjuvant methods have been employed to reduce the local recurrence rate including cryosurgery with liquid nitrogen, phenol instillation, and the use of methylmethacrylate. In laboratory conditions, the authors applied a CO2 laser beam to eliminate traces of residual tumor tissue. As a mode of physical adjuvant treatment, use of the laser seems to be a promising technique for local tumor control.

Distinction between lesions of the jaws containing giant cells can be difficult. This study reports the results of the study of the ultrastructure of 30 patients with Paget's disease in comparison with a patient diagnosed as having malignant giant cell tumor of the mandible. The ultrastructure of the malignant giant cell tumor of the mandible was found to contain nuclear inclusions morphologically identical with the 12-15 nm tubules characteristic of the nuclei of osteoclasts in Paget's disease of bone. No clinical or laboratory signs of Paget's disease was found in this patient. A search of the literature failed to produce reports of identical nuclear inclusions in soft tissue giant cell tumors, osteosarcomas, reparative granulomas containing giant cells or in osteitis fibrosa cystica. Such nuclear inclusions have been reported in benign giant cell tumors of bone, one another in malignant giant cell tumor and cases of polymyositis. These observations raise the question of a possible virus associated with the tumor since there are recent reports of immunological evidence for the presence of a virus in Paget's disease, and viruses have been suspected in polymyositis.

The biologic behavior of central giant cell lesions of the jaws ranges from quiescent to aggressive with destructive expansion. To date, these variations have not been explained by the findings of routine histologic examination. This retrospective clinicopathologic study of giant cell lesions was performed to search for histologic correlates of biologic behavior. Lesions in 17 patients were classified clinically as nonaggressive (group I) or aggressive (group II). In general, group II lesions affected children at an earlier age, were larger at the time of diagnosis, and recurred more frequently. The following histologic parameters were assessed: fractional surface area occupied by giant cells (FSA), relative size index of giant cells (RSI), stromal characteristics, mitotic index, inflammatory cells, and hemosiderin content. Histologic differences between the two groups were not as clear as the differences in biologic behavior. However, aggressive lesions had a higher RSI, and recurrent giant cells lesions had a higher RSI and FSA; these parameters warrant further study. In addition, electron microscopic differences in a small number of aggressive and nonaggressive lesions were documented.

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.

Clinicopathologic, enzyme histochemical, and electron microscopic findings in 207 cases (208 lesions) of giant cell tumor of tendon sheath (GCTTS) are presented. The GCTTS could be divided into two groups according to the anatomic location, the first occurring in the digits (digit group, 182 cases) and the second, in the larger joints (large joint group, 25 cases). In the majority of cases of the digit group, the tumor occurred in one of the fingers (158 cases), whereas in the large joint group, the tumor was common in the ankle (10 cases) and knee joints (8 cases). The lesion was more common in women (67%) than in men (33%). Microscopically, the GCTTS in both groups consisted of a mixture of abundant histiocyte-like, foam, and multinucleated giant cells of the osteoclast type. However, worthy of special mention were the large clefts or wide pseudoglandular spaces lined by synovial cells and that were more striking in the large joint group than in the conventional digit group. The component cells had functional properties of macrophages, as determined in the enzyme histochemical study. Electron microscopically, the tumors consisted essentially of histiocyte-like, fibroblast-like, and intermediate cells, together with myofibroblasts.

A peculiar configuration of endoplasmic reticulum (ER) was observed by electron microscopy in some mononuclear cells from a malignant giant cell tumor of bone that had been removed from a cervical vertebral body in a 54-year-old female. The unusual ER consisted of looped, smooth tubules, which originated from poorly developed rough ER present in the tumor cells. The tubular structures were approximately 23 nm in diameter and contained paracrystalline material. The curvilinear tubular ER closely resembles the vermiform tubular structures that have been observed mainly in histiocytes from different clinical forms of histiocytosis X.

An unusual giant cell tumor of the breast of a 72 year old man is reported. The microscopic and ultrastructural features of the tumor are presented in detail. Unusual and previously unreported myofibroblastic an myoepithelial differentiation of the spindle cell component is described. The possible histogenesis of the tumor is discussed.

We present a case report of osteoclast-type giant cell tumor of the pancreas and review the literature concerning this rare neoplasm, the histogenesis of which is uncertain. Electron microscopic features have suggested stromal, histiocytic, and epithelial origins to different investigators. Analysis of the present case supports and epithelial origin, with positive immunocytochemical staining for carcinoembryonic antigen and for low molecular weight keratin in the mononuclear and in some osteoclastlike giant cells. These tumor cells did not stain for mesenchymal markers (lysozyme, alpha 1-antitrypsin, alpha 1-antichymotrypsin, S100 protein). Zymogen granules, desmosomes, and zonulae occludentes were identified ultrastructurally and further support an epithelial derivation.