Malignant phyllodes tumor of the breast with expression of osteonectin and vinculin

Phyllodes tumor is a very rare neoplasm which accounts for 2.5% of all fibroepithelial lesions of the breast. The mesenchymal component of a malignant phyllodes tumor frequently contains heterologous components. We report a case of malignant phyllodes tumor. The patient was a 40-year-old woman with a lump on the left breast. Histological examination revealed the lump to be a malignant phyllodes tumor with foci of liposarcomatous differentiation. The mesenchymal tumor cells, including those in the liposarcomatous components, were found to express vimentin, osteonectin and vinculin. However, they showed no immunoreaction to CAM 5.2, desmin, alpha-smooth muscle actin (ASMA), neuron-specific enolase (NSE) nor S-100. Ultrastructurally, the mesenchymal tumor cells were found to have abundant cytoplasmic organelles, but there was no evidence showing their differentiation to myofibroblasts. Further studies will be necessary to elucidate the significance of vinculin and osteonectin expression in malignant phyllodes tumor.     

Neuroendocrine Carcinoma of the Skin (Merkel Cell Carcinoma): Ultrastructural and Immunohistochemical Demonstration of Neurofilaments

In this study we characterized a skin tumor that grew in the temporal region of a 69-year-old woman. On the basis of tumor morphology, a metastasis from a small cell carcinoma of the lung was initially suggested, but X-ray and bronchoscopic studies were negative. The tumor recurred twice within a year, yet no tumors were found elsewhere in the body. Ultrastructurally, cytoplasmic organelles compatible with neuroendocrine storage granules and perinuclear aggregates of intermediate-sized (8–10 nm) filaments were found in many tumor cells. Indirect immunofluorescence microscopy revealed neurofilament-type intermediate filaments in the tumor cells but no keratin-or vimentin-type filaments. Our results further demonstrate neural properties of this tumor type, which is generally considered to have its origin from Merkel cells, the cutaneous neuroendocrine cells.     

Neuroendocrine Carcinoma of the Skin (Merkel Cell Carcinoma): Ultrastructural and Immunohistochemical Demonstration of Neurofilaments

In this study we characterized a skin tumor that grew in the temporal region of a 69-year-old woman. On the basis of tumor morphology, a metastasis from a small cell carcinoma of the lung was initially suggested, but X-ray and bronchoscopic studies were negative. The tumor recurred twice within a year, yet no tumors were found elsewhere in the body. Ultrastructurally, cytoplasmic organelles compatible with neuroendocrine storage granules and perinuclear aggregates of intermediate-sized (8-10 nm) filaments were found in many tumor cells. Indirect immunofluorescence microscopy revealed neurofilament-type intermediate filaments in the tumor cells but no keratin-or vimentin-type filaments. Our results further demonstrate neural properties of this tumor type, which is generally considered to have its origin from Merkel cells, the cutaneous neuroendocrine cells.     

Prognostic indicators for survival in stage I carcinoma of the lung: a histologic study of 47 surgically resected cases

In a previous study of 91 consecutive lung cancer cases, we reported that tumor stage was the only significant predictor of survival, with all 5-yr survivors having Stage I disease. Approximately half of the 47 Stage I cases survived 5 yr, so the present study was initiated to determine which histologic features were predictive of survival for Stage I cases. An average of 10 slides per case was evaluated independently by three pathologists, and each slide was subjectively scored using previously agreed criteria for the following parameters: vascular or lymphatic invasion; anaplasia; mitotic rate; inflammatory host response; and the presence or absence of necrosis, tumor giant cells, a central scar, mucin production, benign giant cell reaction, or desmoplasia. Survival was also correlated with patient's age, sex, tumor (T) and nodal (N) status, tumor cell type, and histologic heterogeneity. All three observers found the extent of tumor necrosis to be a significant negative predictor of survival (P less than 0.05). One observer found tumor giant cells to be an adverse factor, another observer found scar carcinomas to have worse survival, and a third observer found lymphocytic inflammatory host response to be a positive predictor and venous invasion to be a negative predictor of survival (P less than 0.05). All other parameters showed no significant correlation with survival. The finding of some parameters which correlated with survival according to one but not the other two observers indicates that the results of studies of histologic prognostic indicators by a single observer may not be valid for other pathologists attempting to use the same subjective criteria.     

Testicular Stromal Tumor: Ultrastructural,Immunohistochemical, and Gel Electrophoretic Evidence of Epithelial Differentiation

A testicular tumor, removed from a 52-year-old man, was composed of uniform spindle cells and abundant interposed collagen, and was histologically diagnosed as a stromal tumor. Electron microscopy revealed cords of cells sometimes surrounded by a basal lamina. Desmosome-like junctions were found between some cells, and immunostaining for desmoplakins was positive. Immunofluorescence studies also showed cytokeratin-positivity in most and vimentin-positivity in some of the tumor cells. The presence of typical simple epithelial cytokeratins of M, 40000, 45000 and 52000 was revealed by the western blotting method.

Cytokeratin positivity in the tumor cells suggests the epithelial nature of this mesenchymal-looking tumor. The tumor might arise from cytokeratin-positive epithelial elements of the testis or its covering mesothelium, but the histogenesis remains unresolved. Our findings suggest that some of the so-called testicular stromal tumors may in fact be of epithelial nature by presenting features typical of epithelial differentiation.     

Testicular Stromal Tumor: Ultrastructural, Immunohistochemical, and Gel Electrophoretic Evidence of Epithelial Differentiation

A testicular tumor, removed from a 52-year-old man, was composed of uniform spindle cells and abundant interposed collagen, and was histologically diagnosed as a stromal tumor. Electron microscopy revealed cords of cells sometimes surrounded by a basal lamina. Desmosome-like junctions were found between some cells, and immunostaining for desmoplakins was positive. Immunofluorescence studies also showed cytokeratin-positivity in most and vimentin-positivity in some of the tumor cells. The presence of typical simple epithelial cytokeratins of M, 40000, 45000 and 52000 was revealed by the western blotting method.

Cytokeratin positivity in the tumor cells suggests the epithelial nature of this mesenchymal-looking tumor. The tumor might arise from cytokeratin-positive epithelial elements of the testis or its covering mesothelium, but the histogenesis remains unresolved. Our findings suggest that some of the so-called testicular stromal tumors may in fact be of epithelial nature by presenting features typical of epithelial differentiation.     

Evaluation of ENU-induced gliomas in rats: nomenclature, immunochemistry, and malignancy

Rats developed mixed gliomas, oligodendrogliomas, and a few astrocytomas in response to transplacental ethylnitrosourea. The neoplastic cell composition of mixed gliomas must be defined; this study required a 20-80% admixture of neoplastic astrocytes and oligodendroglia for the diagnosis of mixed glioma. A battery of immunoantibodies, including Leu-7, S-100, and vimentin, were helpful in classifying rat gliomas, and the histologic features of each tumor type are described. Other brain tumor characteristics that may decide the outcome of carcinogenicity studies include incidence, multiplicity, latency, fatality, size, and malignancy. The size of tumors was determined by measuring their 3-dimensional volumes. Brain tumor volume was found to be highly correlated with malignancy and fatality. Systematic evaluation of the malignancy of brain tumors is an important but often overlooked adjunct method of measuring the effectiveness of a carcinogen. A system to estimate malignancy, one that grades 9 tumor characteristics and weights, each according to clinical outcome, was developed. It was found that mixed gliomas grew larger, had a shorter latency, and were significantly more malignant than were other gliomas.     

Widely invasive solitary fibrous tumor of the sphenoid sinus,cavernous sinus,and pituitary fossa

Solitary fibrous tumor is a spindle cell tumor first described in the pleura, but also found in multiple extrathoracic sites including the meninges, orbit, nasal and paranasal sinuses. No cases have been previously reported in the cavernous sinus or pituitary fossa. We present the case of a 54-year-old woman who presented with progressive amaurosis. On imaging studies, a widely infiltrative lesion involving the pituitary fossa, sphenoid sinus, cavernous sinus, carotid artery, medial temporal, ethmoid, and pterygoid bones, and extending into the nasopharynx was discovered; impression was a malignant tumor originating in the pituitary fossa. At surgery, the tumor was only partially resectable because of extensive bony invasion and encasement of the carotid artery, and was found to compress but not invade the pituitary gland. Histology showed a spindle cell proliferation with a dense, hyalinized collagenous stroma and dilated vascular spaces, some showing a staghorn-like appearance. Areas of cellular pleomorphism and increased cellularity were present, but few mitoses were identified. Immunohistochemistry showed strong positivity with CD34, factor XIIIa, CD99, and Bcl-2. There was scattered cyclin D1, mib-1, and p53 positivity. Muscle, epithelial, vascular, and melanocytic markers were negative. These results led to the diagnosis of solitary fibrous tumor. The size, extensive invasion, and bony destruction indicated a tumor with at least low malignant potential. The occurrence of solitary fibrous tumors in the pituitary fossa and sinuses of the head and neck is rare, but must be considered in the differential diagnosis of spindle cell lesions in these regions.     

The role of the THY1 gene in human ovarian cancer suppression based on transfection studies

In our recent studies, the expression of the THY1 gene encoding a 25-28 kDa glycoprotein located at 11q23-q24, was found to be associated with complete tumor suppression of the ovarian cancer cell line SKOV-3 after the transfer of chromosome 11. These studies raised the possibility that THY1 maybe a candidate tumor suppressor gene for ovarian cancer. To investigate this, the complete cDNA sequence for THY1 was cloned and transfected into SKOV-3 ovarian cancer cells. The expression of THY1 in the transfectants was confirmed by Northern blot analysis, immunocytochemistry, and flow cytometry. Both SKOV-3-THY1 and SKOV-3-null cells were inoculated subcutaneously into severe combined immunodeficiency (SCID) mice to determine in vivo tumorigenicity. THY1 transfectants formed tumors, but overall tumor growth rate and tumor size was significantly reduced compared with their null counterparts. To further correlate THY1 expression with tumorigenicity, the THY1 antisense was transfected into the nontumorigenic clone, 11(C)9-8, which resulted in restoration of tumorigenicity. These data indicate that THY1 expression alone cannot suppress tumorigenicity; however, abrogation of THY1 expression from nontumorigenic cells can restore tumorigenesis. Taken together, the data suggest that THY1 is necessary but not sufficient to suppress ovarian tumorigenicity. Therefore, THY1 can be designated as a putative tumor suppressor gene for human ovarian cancer.     

Intracardiac ectopic thyroid

The case of a patient with an intracardiac ectopic thyroid is reported. A lesion was found in a 25-year-old man and was diagnosed by two-dimensional echocardiography as a right intraventricular tumor. An operation was performed. Histologic and ultrastructural studies showed that the tumor was a thyroid mass. The origin of intracardiac ectopic thyroids is probably to be found in disturbances occurring early in embryogenesis.     

ADCC in aging rats with methylcholanthrene-induced sarcoma (MC-Sa)

Investigations on the relationship between the aging of the immune system and the tumor growth are the trigger of our studies. The purpose of the present paper was to determine a relation between cytotoxic activity of the spleen lymphocytes in ADCC assay and the MC-induced sarcoma growth in adult and aging rats. In ADCC assay the mouse leukemia L1210 labeled with Cr and sensitized with rabbit anti-L1210 serum was used as target cells. In aging rats with MC-Sa tumors the lymphocyte activity in ADCC was increased or remained unchanged in the comparison with normal animals. On the contrary, in adult rats with MC-Sa tumors ADCC activity was decreased. In comparative studies between the groups of adult and aging rats a reverse relationship between the tumor growth and the lymphocyte activity in ADCC was found. In aging rats the level of ADCC was higher than in adults, but the tumor growth was slower. We suggest that ADCC phenomenon may be involved in an antitumor response, especially effective in aging rats.     

Autoimmune response induced by dendritic cells exerts anti-tumor effect in murine model of leukemia

An autoimmune response can be induced with the application of dendritic cells (DCs), offering a viable tumor vaccine for cancer immunotherapy. Previous studies have shown that DC-based tumor vaccines in animal tumor models can inhibit tumor growth and induce autoantibodies transiently without clinical or histological features of autoimmunity. The present study aimed to investigate the role of immune response induced by dendritic cells-based therapy, especially anti-ds DNA antibodies in tumor inhibition. In this study, high titers of anti-ds DNA antibodies were induced after injecting syngeneic dendritic cells into BALB/c mice. In addition, mice immunized with DCs showed the inhibition of RL ♂ 1, BALB/c leukemia cell line, tumor growth, and prolonged survival times of tumor mice but no significant difference was found in specific CTL response and NK cell activity when compared to those of the control group. Anti-ds DNA monoclonal antibodies can recognize RL ♂ 1 cells but not normal cells by FACS analysis. Monoclonal anti-ds DNA antibody was demonstrated to be able to lyse tumor cells via complement mediated reaction in vitro and also exhibits the anti-tumor effects when the antibody was injected into tumor-implanted mice. The data suggested that immunization with dendritic cells can induce autoimmune response, which might exert anti-tumor activity in vivo.     

Dextran conjugated dendritic nanoconstructs as potential vectors for anti-cancer agent

The purpose of the present investigation was to evaluate the potential of surface engineered polypropylene imine (PPI) dendrimers as nanoscale drug delivery units for site-specific delivery of a model anti-cancer agent, doxorubicin·hydrochloride (DOX). Dextran conjugated PPI dendrimers were synthesized, characterized and further loaded with DOX. The developed formulation was characterized by Fourier transform infrared spectroscopy (FTIR), nuclear magnetic resonance (NMR) and transmission electron microscopic (TEM) studies. Dendrimer formulation was evaluated for in vitro drug release and haemolytic studies under various pH conditions. Cell uptake and cytotoxicity studies were performed on A549 cell lines using MTT cell proliferation assay. In vivo studies were conducted for evaluation of various pharmacokinetic parameters and tissue distribution pattern. In vitro, formulation displayed initial rapid release of the drug followed by rather slow release. Further, the dextran conjugated dendrimer formulation was found to be least haemolytic but more cytotoxic as compared to free drug. Cell uptake studies depicted that the formulation was preferably taken up by the tumor cells when compared to free drug. The conjugation of oxidized polyaldehyde dextran imparts macromolecular nature to the dendritic carrier, consequently the formulation was found to selectively enter highly porous mass of tumor cells at the same time precluding normal tissues. Thus it was concluded that the drug loaded dendrimer formulation would selectively localize in the tumor mass, increasing the therapeutic margin of safety while reducing the side effects associated with anti-cancer agents.     

Calretinin expression in human normal and neoplastic tissues: a tissue microarray analysis on 5233 tissue samples

Calretinin is a calcium-binding protein expressed in different normal and neoplastic tissues. Early studies suggested that calretinin is a useful marker to differentiate adenocarcinomas from malignant mesotheliomas of the lung, but subsequent work has shown that calretinin can be expressed in several other tumor types. To systematically investigate the epidemiology of calretinin expression in normal and neoplastic tissues, we used tissue microarrays (TMAs) to analyze the immunohistochemically detectable expression of calretinin in 5233 tissue samples from 128 different tumor categories and 76 different normal tissue types. At least 1 case with weak expression could be found in 74 of 128 (58%) different tumor types and 46 entities (36%) had at least 1 tumor with strong positivity. In normal tissues, a particularly strong expression was found in Leydig cells of the testis, neurons of the brain, theca-lutein and theca interna cells of the ovary, and mesothelium. In tumors, strong calretinin expression was most frequently found in malignant mesotheliomas (6 of 7), Leydig cell tumors of the testis (5 of 5), adenomas of adrenal gland (5 of 9), and adenomatoid tumors (4 of 9). In summary, calretinin is frequently expressed in many different tumor types. Metastases of various different origins must be included in the differential diagnosis of calretinin-positive pleura tumors.     

Host-mediated effectors of tumor invasion: role of mast cells in matrix degradation

The role of collagenolytic enzymes in tumor invasion and metastasis has been emphasized, but the source of enzyme activity has remained unclear. Degradation of stromal connective tissue is a common feature of invasive neoplasia, and host-tumor cell interactions are probably important for localized collagenolysis. We have examined the role of mast cells in malignant cell invasion using cells derived from the rat mammary adenocarcinoma 13762NF. Histologic studies have shown increased numbers of mast cells at the zone of tumor invasion. Mast cell products and conditioned medium from such cells stimulated the production of collagenolytic enzymes by stromal fibroblasts as well as certain subpopulations of tumor cells in vitro. The tumor cell response to mast cell-mediated stimulation of collagenolysis appears to be related to the metastatic potential of the tumor cell. A subpopulation of host fibroblasts derived from the invading tumor zone was also found to be more responsive to mast cell factors than normal fibroblasts, as judged by collagenase production. Thus the mast cell has the potential to induce collagenolytic activity from both host fibroblasts and tumor cells.     

Kaposiform hemangioendothelioma of the thymus

Kaposiform hemangioendothelioma is a rare pediatric neoplasm that presents most commonly in the soft tissues. We report the case of a 1-month-old infant who presented with stridor and was found to have a diffusely infiltrating tumor in the thymus that extended into the pericardium and up the carotid sheaths. Histologic examination revealed a vascular tumor infiltrating among the lobules of the lymphocyte-depleted thymus. The lesion had features of both a capillary hemangioma and Kaposi sarcoma. Immunoperoxidase studies on formalin-fixed, paraffin-embedded tissue demonstrated the neoplastic endothelial cells to be positive for vascular markers CD31 and CD34. Antibody to factor VIII-related antigen labeled feeding vessels, but failed to stain the lobules of tumor. Although these tumors have been treated in a fashion similar to capillary hemangiomas in the past, it may be important to differentiate Kaposiform hemangioendotheliomas because of their association with Kasabach-Merritt syndrome and recent success with more aggressive chemotherapy regimens.     

A region close to Tp53 shows LOH in familial breast cancer

The proportions of mutation of BRCA1 and BRCA2 detected in familial breast cancer vary in different regions. Most breast cancer families in Sweden cannot be explained by mutations in the known major susceptibility genes. Our previous studies have found a high frequency of LOH in the Tp53 region in familial breast cancer suggesting a putative tumor suppressor gene in this region, and the Tp53 gene was excluded as predisposing gene in these families by mutation screening. In order to identify other candidate tumor suppressor genes responsible for familial breast cancer, we performed LOH analysis in 98 paired tumor and blood samples from 91 breast cancer families using 11 microsatellite markers on chromosome 17p. Two loci with high frequency of LOH were found. One spanned the Tp53 gene, the other was distal to Tp53. Linkage studies were performed on 17p with 11 microsatellite markers in 102 breast cancer families with no detectable mutations in the BRCA1 and BRCA2 gene. The linkage analysis did not further support any of the regions suggested by the LOH study. However, since the Tp53 gene is already known to predispose to breast cancer as well as being involved in tumor progression, it is possible that also this region, close but distal to Tp53 contains a gene involved in familial and/or sporadic breast cancer development similar to Tp53.     

Electron microscopy in tumor diagnosis: Indications for its use in the immunohistochemical Era

The electron microscope reveals much more information on tumor cell structure than can be obtained with the light microscope, and some of the data are useful in diagnostic studies. In this review, major contributions of electron microscopy in the main tumor categories are discussed. To select between immunocytochemistry and electron microscopy, the probable contributions of each in the context of the particular case must be assessed. Usually, electron microscopy will only be requested after a battery of immunostaining procedures has been performed and found to be insufficient, but there are occasions when ulstrastructural study is logically the first choice after routine light microscopy. It is worth taking tissue for possible electron microscopy from any tumor that is known or anticipated to be a diagnostic problem.     

Pleomorphic hyalinizing angiectatic tumor of soft parts: Case Report with unusual ganglion-like cells and review of the literature

Pleomorphic hyalinizing angiectatic tumor (PHAT) is a recently described, non-metastasizing tumor of uncertain lineage. This tumor distributes equally between the genders and has a predilection for the subcutaneous soft tissue, particularly in lower extremity, other locations are rare. Based on the recent literature, PHAT is suspected to encompass the morphological spectrum with other tumors such as myxoinflammatory fibroblastic sarcoma (MIFS) and hemosiderotic fibrolipomatous tumor (HFLT), although cytogenetic data remain inconsistent. We report a case of PHAT that arose in the upper arm with unusual morphology which showed ganglion-like cells similar to Reed-Sternberg-like cells found in MIFS. The tumor had strong immunohistochemical expression of CD34, CD99, and was negative for S-100. The ganglion-like cells were positive for both CD34 and CD68 but negative for CD30. The translocation between chromosome 1 and 10, a frequent finding of MIFS and HFLT, was not identified by FISH excluding the possibility of hybrid PHAT and MIFS. We conclude FISH can be a potential useful tool to separate PHAT with atypical morphology from hybrid tumor in doubted cases. Due to the rarity of PHAT and lack of consistent pathogenetic signatures, more cases and further studies will be needed to elucidate the pathogenesis and nature of this tumor.     

Ultrastructural Descriptions of Heterotypic Aggregation between Eosinophils and Tumor Cells in Human Gastric Carcinomas

A histological variant of gastric adenocarcinoma, characterized by an intense tumor-associated tissue eosinophilia (TATE), has been occasionally reported in the literature. The purpose of this ultrastructural study was to determine the interactions between frequently occurring eosinophils and tumor cells in gastric carcinoma characterized by TATE. Fresh tumor tissue of 92 gastric carcinomas was processed for both light and electron microscopic examination. Intense TATE was found in 7 out of 92 (7.6%) gastric carcinomas (6 of intestinal-type and 1 of diffuse-type). Electron microscopy, selectively performed in 7 cases with intense TATE, revealed eosinophils, singly or in groups, in contact with damaged or necrotic tumor cells. Activated eosinophils showing piecemeal degranulation were also found in intimate contact with viable tumor cells, characterized by plasma membrane caveolar invaginations. The authors regard this close morphological relationship as in vivo evidence for possible cross-talk between eosinophil and viable tumor cell, a conclusion that has already been drawn from experimental studies, but until now inadequately supported by ultrastructural observations in a human tumor.