bromochloroacetic-acid and Bone-Neoplasms

In the past decade, several emerging bone and soft tissue neoplasms of the head and neck region have been described in the literature, including GLI1-altered mesenchymal tumors, (intraosseous) rhabdomyosarcoma with TFCP2 fusion, and adamantinoma-like Ewing sarcoma. This review provides a summary of the clinical features, histologic characteristics, immunoprofile, key diagnostic features, and differential diagnoses of these emerging entities. Notably, all three entities show epithelioid morphology and cytokeratin immunopositivity, highlighting the need to consider these mesenchymal neoplasms in the differential diagnoses of cytokeratin-positive epithelioid tumors in the head and neck region. Appropriate workups including detection of the characteristic molecular alterations are essential for the correct diagnosis.

Topics: Biomarkers, Tumor; Bone Neoplasms; DNA-Binding Proteins; Head and Neck Neoplasms; Humans; Keratins; Los Angeles; Sarcoma, Ewing; Soft Tissue Neoplasms; Transcription Factors

Benign notochordal tumors (BNCT) and chordomas are primary bone tumors of the spine with a predominant localization in the sacrum and clival region followed by the vertebral bodies. Besides the most common variant (NOS [not otherwise specified] with hepatoid or renal carcinoma cell-like differentiation) chordomas with chondroid, and polymorphic to anaplastic morphology are described. An unfavorable variant are pediatric chordomas with a loss of INI-1. BNCT and chordomas are characterized by the following immunohistological profile: vimentin+, cytokeratin+/-, epithelial membrane antigen (EMA)+/-, S100 protein+/-, brachyury+. This profile helps to distinguish these tumors from other lesions such as chondrosarcoma, chordoid meningioma, and metastases of carcinoma.

Topics: Bone Neoplasms; Child; Chondrosarcoma; Chordoma; Humans; Keratins; S100 Proteins

Myoepithelial tumors (METs) of bone (BMETs) are a rare but distinct tumor entity. METs that are cytologically benign are termed myoepitheliomas; METs with malignant histologic features are called myoepithelial carcinomas. BMETs have a wide age range, may involve any part of the skeleton, and have a variable spindle cell and epithelioid morphology. Bone tumors to be considered in the differential diagnosis are discussed. Additional techniques are indispensable to correctly diagnose BMETs. By immunohistochemistry, BMETs often express cytokeratins and/or EMA together with S100, GFAP, or calponin. Half of BMETs harbor EWSR1 (or rare FUS) gene rearrangements with different gene partners.

Topics: Biomarkers, Tumor; Bone Neoplasms; Calcium-Binding Proteins; Calponins; Diagnosis, Differential; Gene Rearrangement; Glial Fibrillary Acidic Protein; Humans; Immunohistochemistry; Keratins; Microfilament Proteins; Myoepithelioma; rab GTP-Binding Proteins; RNA-Binding Protein EWS

Parachordoma is an extremely uncommon soft-tissue tumor, which mainly occurs in the deep soft-tissue of the distal parts of the limbs, such as deep fascia, muscle tendon, synovial or soft-tissue closed to the bone. Nevertheless, the literature reports about parachordoma on the thoracic wall were scarce. The clinical and imaging manifestation has a non-specific appearance. In this article, we reported one case of parachordoma of the thoracic wall that we met in clinical works and reviewed the literature.

Topics: Adult; Bone Neoplasms; Humans; Keratins; Male; Radiography; Ribs; S100 Proteins; Soft Tissue Neoplasms; Vimentin

Primary small cell neuroendocrine carcinoma of the vagina is extremely rare, and its clinical behavior is aggressive. To our knowledge, 22 patients with this tumor have been reported in the English literature to date.. To investigate 3 patients with this tumor clinically and pathologically.. The pathology database at the University of Texas Medical Branch at Galveston was searched, and 3 cases of primary small cell neuroendocrine carcinoma of the vagina were found. The histologic, immunohistochemical, and ultrastructural profiles of the tumors were investigated. The medical charts of the patients were reviewed, and the patients were followed up.. Women with the diagnosis of primary small cell neuroendocrine carcinoma of vagina.. All 3 patients presented with advanced disease, and 2 patients died within 4 months of the initial diagnosis. One 38-year-old patient was newly diagnosed, and her clinical outcome had not yet been determined. The histologic features of all 3 tumors were similar to those of their pulmonary counterpart. All cases were positive for cytokeratin, chromogranin A, and synaptophysin. The expression pattern of thyroid transcription factor 1 was examined in all 3 patients, of whom 2 were negative and 1 was positive with negative clinical and radiologic thyroid or pulmonary findings. Ultrastructural evaluation showed scattered intracytoplasmic electron-dense neurosecretory granules.. Primary small cell neuroendocrine carcinoma of the vagina has histologic, immunohistochemical, and ultrastructural features similar to those of its pulmonary counterpart. Because thyroid transcription factor 1 can be positive, it should not be used to differentiate primary from metastatic disease. The current therapies have usually resulted in poor outcomes, and new therapeutic modalities should be explored.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Brachytherapy; Carcinoma, Small Cell; Chromogranin A; Chromogranins; Cisplatin; Combined Modality Therapy; Etoposide; Fatal Outcome; Female; Hemorrhage; Humans; Keratins; Middle Aged; Neoplasm Proteins; Nuclear Proteins; Radioisotope Teletherapy; Synaptophysin; Thyroid Nuclear Factor 1; Transcription Factors; Vaginal Diseases; Vaginal Neoplasms

The tumor secretion markers used most in the daily practice are reviewed, emphasizing the physiological aspects having great practical usefulness. Likewise, the possible value of other recently described substances which could be introduced into the daily practice in the near future is explained.

Topics: Antigens, Neoplasm; Biomarkers, Tumor; Bone Marrow; Bone Neoplasms; Breast Neoplasms; Cell Adhesion Molecules; Female; Forecasting; Humans; Keratins; Neoplasm Proteins; Proto-Oncogene Proteins

Topics: Antibodies, Monoclonal; Biomarkers, Tumor; Bone Neoplasms; Carcinoembryonic Antigen; Esophageal Neoplasms; Humans; Keratins; Lymphatic Metastasis; Neoplasm Metastasis; Reverse Transcriptase Polymerase Chain Reaction

Ewing's sarcoma, a highly malignant neoplasm, is characterized by an 11;22 translocation [t(11;22) (q24;q12)], resulting in the fusion of genes FLII and EWS. Adamantinoma of extragnathic bones, a low-grade malignant neoplasm with epithelial features, is not typically considered in the differential diagnosis of Ewing's sarcoma. In this study, three osseous Ewing's sarcomas with histological, immunohistochemical, or ultrastructural epithelial features were subjected to reverse transcription-polymerase chain reaction and sequencing studies for the Ewing's sarcoma molecular rearrangement. (Two of the three cases were originally described as adamantinomas or nontypical Ewing's sarcoma before the availability of genetic characterization.) In addition, traditional cytogenetic analysis and a unique combined interphase molecular cytogenetic/ immunocytochemical approach with bicolor 11;22 translocation breakpoint flanking probes (cosmids) and pancytokeratin antibodies were performed on one neoplasm. At(11;22) (q24;q12) was found in one neoplasm and a type II EWS/FLI-1 fusion transcript was detected in all three neoplasms. The combined genetic/immunocytochemical approach revealed the presence of the 11 ;22 translocation in the nuclei of cytokeratin immunoreactive cells. These genotypic and phenotypic findings delineate a novel Ewing's sarcoma histologic variant, "adamantinoma-like Ewing's sarcoma."

Topics: Adolescent; Bone Neoplasms; Cytogenetics; Desmosomes; Diagnosis, Differential; Humans; In Situ Hybridization, Fluorescence; Intermediate Filaments; Keratins; Male; Neoplasms, Glandular and Epithelial; Oncogene Proteins, Fusion; Proto-Oncogene Protein c-fli-1; Radiography; Reverse Transcriptase Polymerase Chain Reaction; RNA-Binding Protein EWS; RNA, Neoplasm; Sarcoma, Ewing; Transcription Factors

Chondrosarcoma of bone is a well recognized, relatively common clinicopathologic entity. Morphologically distinct soft tissue chordoid sarcoma (CS), or extraskeletal myxoid chondrosarcoma, is a relatively rare tumor that has generally been documented in extraosseous soft tissues.. The clinical and pathologic features of two patients with biopsy-proven CS from the pathology files of the Mayo Clinic and St. Thomas's Hospital were evaluated. Routine hematoxylin and eosin-stained slides were reviewed in both cases. Sections from both were examined immunohistochemically using the avidin-biotin-peroxidase technique and employing commercially available antibodies to the following antigens: S-100 protein, cytokeratin (AE1/AE3), epithelial membrane antigen (EMA), CD31, and factor VIII. Appropriate positive and negative controls were utilized throughout these procedures. Cytogenetic analysis was performed on fresh samples obtained from one tumor. Clinical data were obtained from the patients' medical records.. The two cases of primary CS of bone arose from the right distal femur and right scapula, respectively, in 2 men ages 48 and 76 years, respectively. Morphologically, the tumors were lobulated, multinodular, and comprised of a uniform population of rounded to slightly spindled cells. Nuclei were hyperchromatic with inconspicuous nucleoli and surrounded by clear, vacuolated to eosinophilic cytoplasm. Neoplastic cells were arranged in anastomosing chords, strands, and, less often, nests and pseudopapillary structures embedded in an abundant, mostly hypovascular, mucinous matrix. Foci of hemorrhage and cystic degeneration were present in both tumors. No well developed hyaline cartilage or neoplastic osteoid was observed. Immunohistochemically, one neoplasm showed focal positivity for S-100 protein but was uniformly negative for cytokeratin (AE1/AE3), factor VIII, and CD31. The other tumor showed no immunopositivity with cytokeratin, EMA, or S-100 protein. Cytogenetic analysis in the latter tumor revealed a nonrandom reciprocal chromosomal translocation, t(9;22)(q22-31;q11-12). Both patients developed local recurrences and widespread distant metastases. Wide surgical excision was the primary mode of therapy. One patient died of tumor.. Skeletal CS is an extraordinarily rare neoplasm with a distinct morphology. Although follow-up data were limited to only four examples, including two from the literature, the clinical course appears worse than that for usual chondrosarcoma of bone. Wide surgical resection appears to represent the best mode of therapy. The role of chemotherapy and radiation therapy has not been clearly defined.

Topics: Aged; Biopsy; Bone Neoplasms; Cell Nucleolus; Cell Nucleus; Chondrosarcoma; Chromosomes, Human, Pair 22; Chromosomes, Human, Pair 9; Cytogenetics; Cytoplasm; Factor VIII; Femur; Hemorrhage; Humans; Immunoenzyme Techniques; Immunohistochemistry; Keratins; Male; Middle Aged; Mucin-1; Neoplasm Recurrence, Local; Platelet Endothelial Cell Adhesion Molecule-1; S100 Proteins; Scapula; Translocation, Genetic; Vacuoles

Two cases of tumors of the posterior portion of the petrous bone are presented. Both resulted in significant loss of hearing and caused extensive bone destruction. Microscopically, they corresponded to papillary adenomatous tumors with few histologically aggressive features. Immunohistochemical studies were done, and a positive reaction was obtained with the antibodies against the cytokeratins, Leu-7 and neuronal-specific enolase. A diagnosis of adenocarcinoma of the endolymphatic sac was made. These are rare tumors known for their long clinical prodrome and their local aggressiveness. Increased awareness will allow for earlier diagnosis and treatment.

Topics: Adenocarcinoma; Adenoma; Adolescent; Adult; Bone Neoplasms; CD57 Antigens; Endolymphatic Sac; Female; Humans; Immunohistochemistry; Keratins; Phosphopyruvate Hydratase; Temporal Bone; Tomography, X-Ray Computed

The tumor designated by Stout and Murray as "hemangiopericytoma" (HPC) more than 50 years ago continues to represent a source of uncertainty and disagreement among pathologists. In particular, questions exist regarding the synonymity of a hemangiopericytomatous growth pattern--defined by a monomorphic population of compact polygonal or bluntly fusiform cells and a branching stromal vascular pattern with a "staghorn" configuration--and the presence of a reproducible biological entity. It has been shown repeatedly that these same histologic features may be observed at least focally in a diversity of neoplasms, including "true" hemangiopericytomas, synovial sarcomas, mesenchymal chondrosarcomas, infantile fibrosarcomas, malignant fibrous histiocytomas, malignant peripheral nerve sheath tumors, leiomyosarcomas, endometrial stromal sarcomas, solitary fibrous tumors, myofibromas, malignant mesotheliomas, thymomas, sarcomatoid carcinomas, malignant melanomas, and "phosphaturic mesenchymal tumors." Despite their potential sharing of the microscopic attributes in question, such neoplasms have individualistic clinical features and can also be distinguished from one another by specialized pathologic analyses. HPC is "defined" in that context by reactivity for vimentin, with or without CD34 and CD57, but it lacks other immunodeterminants of epithelial, neural, and myogenous differentiation. Paradoxically, this phenotype is indeed associated with the presence of myogenous-type cytoplasmic filaments in ultrastructural evaluations of HPC. Other lesions that may resemble "true" HPC--but which possess dissimilar subcellular and clinical characteristics--include solitary fibrous tumors, hemangiopericytomalike tumors of the sinonasal tract, and "infantile (congenital) hemangiopericytomas." Such observations suggest that the hemangiopericytoma is both a pathologic entity and a morphological pattern, and they emphasize the utility of adjuvant pathologic studies in this diagnostic context.

Topics: Actins; Bone Neoplasms; CD57 Antigens; Diagnosis, Differential; Hemangiopericytoma; Humans; Keratins; Meningioma; Myofibromatosis; Nasopharyngeal Neoplasms; Reticulin; Sarcoma, Synovial; Soft Tissue Neoplasms; Stromal Cells

In a 52-year-old Caucasian man osteopoikilosis had been misdiagnosed roentgenologically 2 years before his death. Gradually he developed Cushing's syndrome and ultimately superior vena caval obstruction. At autopsy a primary thymic carcinoid with extensive osteoblastic bone metastasis was found. Immunohistochemically the tumor was shown to be positive for adrenocorticotropic hormone (ACTH), cytokeratin (KL1), neuron-specific enolase, synaptophysin, chromogranin and glucagon. Remarkably the tumour was negative for serotonin despite high urinary hydroxyindolacetic acid levels. Bilateral hyperplasia of the adrenal cortex was found. The adenohypophysis showed a considerable reduction of ACTH-producing cells and numerous Crooke's cells with a characteristic immunohistochemical pattern.

Topics: Adrenal Cortex; Adrenocorticotropic Hormone; Bone Neoplasms; Carcinoid Tumor; Cushing Syndrome; Diagnostic Errors; Humans; Keratins; Male; Middle Aged; Osteopoikilosis; Phosphopyruvate Hydratase; Radiography; Thymus Neoplasms; Vena Cava, Superior

In view of the still disputed relationship between adult adamantinoma and osteofibrous dysplasia in children, a unique case of adamantinoma, indicating a direct relationship between the two lesions, is presented with a review of the literature. The patient was a six-year-old boy who complained of pain and swelling in the left lower leg. Roentgenographs showed a loculate osteolysis surrounded by sclerosis within the cortex of the tibial shaft that would be typical of osteofibrous dysplasia. Although an osteofibrous-dysplastic component predominated histologically, some small islands of epithelial cells were scattered throughout the lesion. Immunohistochemically, the tumor cells of these epithelial islands gave a constant positive reaction for cytokeratin as well as vimentin, while the stromal cells in the osteofibrous dysplasia-like lesion were positive for vimentin only. This type of lesion is recorded in the Bone Tumor Registry of Westphalia at a rate of 8.3% for osteofibrous dysplasia, and of 25% for adamantinoma. A review of the literature, yielding reports with remarkable uniformity on 14 cases beyond the present one, suggests the existence of a separate clinicopathologic entity to be called juvenile intracortical adamantinoma with predominant osteofibrous dysplasia-like features, and which might be a regressing form of adamantinoma specific in childhood.

Topics: Ameloblastoma; Bone Neoplasms; Child; Fibrous Dysplasia of Bone; Humans; Immunohistochemistry; Keratins; Male; Tibia; Vimentin

Carcinosarcomas of the prostate gland are exceedingly rare, and previous reports exist on only seven of these neoplasms. The authors studied two such tumors, which occurred in 63- and 69-year-old patients. One of them had osseous metastases develop, which were treated unsuccessfully by irradiation and diethylstilbestrol therapy. The other patient is free of disease 15 months after radical prostatectomy. Both tumors contained an intimate mixture of carcinoma and sarcoma; patient 1 displayed foci of chondrosarcoma, osteosarcoma, and leiomyosarcoma, whereas patient 2 exhibited areas of chondrosarcoma, osteosarcoma, rhabdomyosarcoma, and angiosarcoma. The phenotypic nature of these tissues was confirmed by immunohistochemical studies, showing reactivity for vimentin, S-100 protein, desmin, actin, myoglobin, or Ulex europaeus I agglutinin. Conversely, the sarcomatous components lacked prostate-specific antigen, epithelial membrane antigen, and cytokeratin, whereas carcinomatous elements expressed these three markers. The authors' data support the existence of true carcinosarcomas of the prostate, that is, malignant neoplasms with conjoint epithelial and mesenchymal differentiation. The question of whether prostatic carcinosarcoma is an entity that is totally distinct from sarcomatoid or metaplastic carcinoma remains problematic.

Topics: Actins; Aged; Antigens, Neoplasm; Biomarkers, Tumor; Bone Neoplasms; Carcinosarcoma; Desmin; Humans; Keratins; Male; Membrane Glycoproteins; Middle Aged; Mucin-1; Prostatic Neoplasms; S100 Proteins; Vimentin

Keratin protein immunohistochemistry is a powerful diagnostic tool whose role has already been firmly established in many surgical pathology laboratories. Recent studies of the biology of keratin proteins have defined the heterogeneity of keratin protein expression among various epithelial tissues and their tumors and provide the basis for understanding the immunoreactivity of epithelial tumors with various keratin antibodies. Successful execution of the procedure requires attention to technical details such as the fixation of tissue, use of proteolytic enzymes such as trypsin for formalin-fixed tissues, and the choice of the appropriate antibody and controls. Broadly reactive polyclonal and monoclonal antibodies to keratins have been remarkably useful in identifying poorly differentiated and undifferentiated carcinomas. Monoclonal antibodies of restricted specificity and monospecific antibodies to keratin are under development and may prove helpful in defining the organ of origin of metastatic carcinomas. Keratin protein immunohistochemistry supplements existing information used by pathologists in diagnosis, and the immunohistochemical results should be interpreted in the light of the clinical findings, gross and microscopic pathology, and the results of any other special studies.

Topics: Animals; Antibodies; Antibodies, Monoclonal; Bone Neoplasms; Carcinoid Tumor; Carcinoma; Humans; Immunoassay; Keratins; Neoplasms; Sarcoma; Soft Tissue Neoplasms

A 10-year-old female American Pit Bull dog was diagnosed with metastatic undifferentiated carcinoma of the scapula. Immunohistochemistry showed positive immunoexpression for cytokeratins (AE1/AE3, 34BE12, CK7) and vimentin, confirming squamous cell carcinoma. No evidence of nodules was found in the complete physical examination and imaging procedures conducted. The patient was diagnosed with carcinoma of unknown primary origin. Amputation and adjuvant chemotherapy with doxorubicin and piroxicam were performed, but the patient died of respiratory failure after 737 days of diagnosis. Necropsy confirmed undifferentiated carcinoma infiltrating the lungs and kidneys, and showing the same immunoexpression as the tumor in the scapula. Amputation associated with chemotherapy extended the overall survival time of this patient.

Topics: Amputation, Surgical; Animals; Biomarkers, Tumor; Bone Neoplasms; Carcinoma, Squamous Cell; Dogs; Drug Therapy; Female; Immunohistochemistry; Keratins; Kidney Neoplasms; Lung Neoplasms; Neoplasms, Unknown Primary; Scapula; Vimentin

Metastatic pituitary carcinoma to bone is rare. In this report, we present a case of a 59-year-old female with recurrent pituitary adenoma of the sparsely granulated somatotroph subtype with metastasis to a few bony sites 10 years later. Needle core biopsy (NCB) with touch preparations was performed on a 5 mm lesion in left ilium. Diff-Quik stained NCB touch preparation slides showed a few loosely cohesive epithelial polygonal cells that were arranged in nests or acini, or singly, had scant vacuolated cytoplasm and eccentrically located round nuclei (plasmacytoid) with slight nuclear pleomorphism, fine granular chromatin, conspicuous nucleoli, and smooth nuclear membrane. Trilineage hematopoietic cells of bone marrow were also appreciated in the background. H&E stained core sections showed fragments of bone and bone marrow with nests of bland epithelial cells with similar cytomorphology as seen in NCB touch preparation slides. The tumor cells were immunoreactive for juxtanuclear dot-like staining of pan-cytokeratin (CAM 5.2 and AE1/AE3) (a specific feature), neuroendocrine markers (CD56, synaptophysin, and chromogranin. Additionally, scattered cells were immunoreactive for growth hormone. Molecular test showed that tumor cells were negative for the promoter methylation of O-6-Methylguanine-DNA Methyltransferase (MGMT). Final diagnosis of metastatic pituitary carcinoma was rendered. Morphology of metastatic pituitary carcinoma, its differential, clinical presentation and treatment were discussed. Diagn. Cytopathol. 2017;45:645-650. © 2017 Wiley Periodicals, Inc.

Topics: Adenocarcinoma; Anion Exchange Protein 1, Erythrocyte; Biomarkers; Biomarkers, Tumor; Biopsy, Large-Core Needle; Bone Neoplasms; CD56 Antigen; Chromogranin A; Female; Gene Expression; Growth Hormone; Humans; Ilium; Keratins; Middle Aged; Pituitary Neoplasms; Synaptophysin

Primary intraosseous myoepithelial tumours, including carcinomas are rare tumours. The concept of histopathological spectrum of these tumours is evolving. We describe clinicopathological and immunohistochemical features of five myoepithelial carcinomas, including molecular cytogenetic results in one case. There were five male patients within age-range of 8-40 years (median = 26). Four tumours occurred in the long bones, including two tumours, each, in the femur and fibula, respectively, while a single tumour occurred in the proximal phalanges. Tumour size (n = 3 cases) varied from 5.6 to 8.6 cm. On radiological imaging, most tumours appeared as expansile, lytic and destructive lesions. Two tumours appeared as sclerotic lesions. Two cases were referred with diagnoses of chondrosarcomas and a single case was referred with two different diagnoses, including an adamantinoma and an osteosarcoma. Histopathological examination in all these cases showed multinodular tumours comprising mostly polygonal cells, exhibiting moderate nuclear atypia and interspersed mitotic figures within a stroma containing variable amount of myxoid, chondroid, hyalinised and osteoid-like material. Three tumours revealed prominent squamous differentiation. By immunohistochemistry, tumour cells were positive for EMA (5/5), pan CK (AE1/AE3) (3/3), CK5/6 (4/4), CK MNF116 (1/1), S100 protein (5/5) and GFAP (3/5). The first tumour revealed EWSR1 rearrangement. The first patient, 10 months after tumour resection and a simultaneous lung metastatectomy, is free-of-disease (FOD). The second patient, 11 months after tumour resection is FOD. The third and fourth patients underwent wide resections and are on follow-up. The fifth patient underwent resections, including a lung metastatectomy. Primary intraosseous myoepithelial carcinomas are rare and mimic conventional primary bone tumours. Some primary intraosseous myoepithelial carcinomas display EWSR1 rearrangement. Squamous differentiation may be considered as an addition to their evolving histopathological spectrum. Immunohistochemical stains constitute as a necessary tool for arriving at the correct diagnosis in such cases, which has treatment implications. Surgical resection remains the treatment mainstay.

Topics: Adamantinoma; Adolescent; Adult; Biomarkers, Tumor; Bone Neoplasms; Calmodulin-Binding Proteins; Child; Chondrosarcoma; Diagnosis, Differential; E2F6 Transcription Factor; Femur; Fibula; Finger Phalanges; Gene Expression; Glial Fibrillary Acidic Protein; Humans; Immunohistochemistry; Keratins; Male; Mutation; Myoepithelioma; RNA-Binding Protein EWS; RNA-Binding Proteins; S100 Proteins

Ewing sarcoma family tumors (EFTs) of the head and neck are rare and may be difficult to diagnose, as they display significant histologic overlap with other more common undifferentiated small blue round cell malignancies. Occasionally, EFTs may exhibit overt epithelial differentiation in the form of diffuse cytokeratin immunoexpression or squamous pearls, resembling the so-called adamantinoma-like EFTs and being challenging to distinguish from bona fide carcinomas. Furthermore, the presence of EWSR1 gene rearrangement correlated with strong keratin expression may suggest a myoepithelial carcinoma. Herein, we analyze a series of 7 adamantinoma-like EFTs of the head and neck, most of them being initially misdiagnosed as carcinomas because of their anatomic location and strong cytokeratin immunoexpression, and subsequently reclassified as EFT by molecular techniques. The tumors arose in the sinonasal tract (n=2), parotid gland (n=2), thyroid gland (n=2), and orbit (n=1), in patients ranging in age from 7 to 56 years (mean, 31 y). Microscopically, they departed from the typical EFT morphology by growing as nests with peripheral nuclear palisading and prominent interlobular fibrosis, imparting a distinctly basaloid appearance. Moreover, 2 cases exhibited overt keratinization in the form of squamous pearls, and 1 sinonasal tumor demonstrated areas of intraepithelial growth. All cases were positive for CD99, pancytokeratin, and p40. A subset of cases showed synaptophysin, S100 protein, and/or p16 reactivity, further confounding the diagnosis. Fluorescence in situ hybridization assays showed EWSR1 and FLI1 rearrangements in all cases. Our results reinforce that a subset of head and neck EFTs may show strong cytokeratin expression or focal keratinization, and are therefore histologically indistinguishable from more common true epithelial neoplasms. Thus, CD99 should be included in the immunopanel of a round cell malignancy regardless of strong cytokeratin expression or anatomic location, and a strong and diffuse CD99 positivity should prompt molecular testing for the presence of EWSR1 gene rearrangements.

Topics: 12E7 Antigen; Adamantinoma; Adolescent; Adult; Antigens, CD; Biomarkers, Tumor; Biopsy; Bone Neoplasms; Calmodulin-Binding Proteins; Cell Adhesion Molecules; Cell Differentiation; Child; Diagnosis, Differential; Female; Gene Rearrangement; Head and Neck Neoplasms; Humans; Immunohistochemistry; In Situ Hybridization, Fluorescence; Keratins; Male; Middle Aged; Myoepithelioma; Neuroectodermal Tumors, Primitive, Peripheral; Predictive Value of Tests; Proto-Oncogene Protein c-fli-1; RNA-Binding Protein EWS; RNA-Binding Proteins; Sarcoma, Ewing; Tissue Array Analysis; Young Adult

Topics: Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Biopsy; Bone Neoplasms; Carcinoma, Small Cell; Chromogranin A; Fatal Outcome; Head and Neck Neoplasms; Humans; Keratins; Liver Neoplasms; Lung Neoplasms; Male; Middle Aged; Prostate-Specific Antigen; Prostatic Neoplasms; Scalp; Skin Neoplasms; Tomography, X-Ray Computed

Clear cell chondrosarcoma is a rare cartilaginous bone tumor, and little is known about its pathology. We investigated the immunohistochemical expression profiles of cytokeratins (CAM5.2, AE1/AE3, CK7, CK8, CK18, and CK20), epithelial membrane antigen, SRY (sex-determining region Y)-box 9, type II collagen, runt-related transcription factor 2, and osteocalcin in clear cell chondrosarcoma and compared them with those in chondroblastoma, conventional chondrosarcoma, and osteosarcoma. Of 5 cases of clear cell chondrosarcoma, 3 demonstrated positive staining for AE1/AE3 and some form of cytokeratin in the clear cell component. Of the 5 cases, 4 strongly expressed SRY (sex-determining region Y)-box 9 in the clear cell component but weakly expressed it in the cartilaginous component. Of the 5 cases of clear cell chondrosarcoma, 3 expressed runt-related transcription factor 2 in both the clear cell and cartilaginous components, but no expression of osteocalcin was detected. In chondroblastoma, 8 of 13 cases expressed AE1/AE3, and other cytokeratins, such as CK7 (4/13), CK8 (6/13), CK18 (8/13), and CK20 (3/13), demonstrated a similar staining extensity pattern between the cellular and cartilaginous components. Clear cell chondrosarcoma and chondroblastoma have similar immunohistochemical features in that they both express epithelial and chondrogenetic markers. On the other hand, tumor cells of clear cell chondrosarcoma have no osteoblastic immunohistochemical expression in comparison with chondroblastoma.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Biomarkers, Tumor; Bone Neoplasms; Cell Differentiation; Child; Chondroblastoma; Chondrosarcoma; Core Binding Factor Alpha 1 Subunit; Female; Humans; Immunohistochemistry; Keratins; Male; Middle Aged; Mucin-1; SOX9 Transcription Factor; Young Adult

We describe the clinicopathological, immunohistochemical, and molecular features of 3 primary juxtacortical myoepithelioma/mixed tumor of bone. The patients were 2 males (13 and 23 years of age) and a 15-year-old female. The juxtacortical lesions were all located in the femur, and were surgically removed, 2 with wide margins and one with marginal margins. This latter tumor recurred locally 18 months later. The 3 patients were free of disease at 6 to 17 months follow-up. Histologically, all lesions showed a prominent multinodular architecture, and were formed by epithelioid and stellate elements, organized in solid sheets, or embedded in myxoid or chondroid matrix. Areas of osteoid formation were also observed. One tumor had the appearance of classical mixed tumor, showing aspects of duct formation and focal squamous differentiation. Immunohistochemically, all cases were positive for cytokeratins, epithelial membrane antigen, and S100 protein. The expression of other myoepithelial markers, including p63, glial fibrillary acid protein and calponin was more limited. No rearrangement of Ewing sarcoma region 1 (EWSR1) and fused in sarcoma (FUS) genes was observed by fluorescent in situ hybridization. To our knowledge, this is the first report of primary myoepitheliomas of bone arising at juxtacortical sites. These lesions must be distinguished from other benign and malignant bone and cartilage-forming surface tumors, including periosteal chondroma and chondrosarcoma, juxtacortical chondromyxoid fibroma, and periosteal and paraosteal osteosarcoma. The clinicoradiologic presentation and their histological and immunohistochemical features are distinctive enough to allow the separation from these entities.

Topics: Adolescent; Biomarkers, Tumor; Bone Neoplasms; Disease-Free Survival; DNA, Neoplasm; Female; Femur; Humans; In Situ Hybridization, Fluorescence; Keratins; Male; Mucin-1; Myoepithelioma; Neoplasms, Complex and Mixed; Radiography; Recovery of Function; Retrospective Studies; S100 Proteins; Treatment Outcome; Young Adult

Muscle-invasive bladder cancer is associated with a high frequency of metastasis, and bone is the most common metastatic site outside the pelvis. To clarify its organ-specific characteristics, we generated a successive bone metastatic T24-B bladder cancer subline following tail vein injection of metastatic T24-L cells. Compared with parental T24-L cells, epithelial-like T24-B cells displayed increased adhesion but decreased migration or invasion abilities as well as up-regulation of cytokeratins and down-regulation of vimentin, N-cadherin and MMP2. Mechanically, phosphatidylinositol 3-kinase (PI3K)/Akt targets glycogen synthase kinase-3β (GSK3β)/β-catenin to control ZEB1 gene transcription, and then subsequently regulates the expression of cytokeratins, vimentin and MMP2. Importantly, ZEB1 is essential for bladder cancer invasion in vitro and distant metastasis in vivo, and ZEB1 overexpression was highly correlated with the expression of those downstream markers in clinical tumor samples. Overall, this study reveals a novel mechanism facilitating metastatic bladder cancer cell re-colonization into bone, and confirms the significance of mesenchymal-to-epithelial transition (MET) in formation of bone metastasis.

Topics: Animals; beta Catenin; Bone Neoplasms; Cadherins; Cell Line, Tumor; Down-Regulation; Epithelial-Mesenchymal Transition; Female; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Homeodomain Proteins; Humans; Keratins; Matrix Metalloproteinase 2; Mice; Mice, Nude; Phosphatidylinositol 3-Kinase; Proto-Oncogene Proteins c-akt; Signal Transduction; Transcription Factors; Transcription, Genetic; Transplantation, Heterologous; Up-Regulation; Urinary Bladder Neoplasms; Vimentin; Wnt Proteins; Zinc Finger E-box-Binding Homeobox 1

Topics: Biomarkers, Tumor; Bone Neoplasms; Calcium-Binding Proteins; Calponins; Chondroblastoma; Diagnosis, Differential; Humans; Immunohistochemistry; Keratins; Magnetic Resonance Imaging; Male; Membrane Proteins; Microfilament Proteins; Middle Aged; Mixed Tumor, Malignant; S100 Proteins; Soft Tissue Neoplasms; Vascular Neoplasms

Epithelial marker expression has been reported in Ewing's sarcoma family of tumors (ESFT). However, cytokeratin (CK), epithelial membrane antigen (EMA), and carcino embryonic antigen (CEA) prevalence has not been assessed thoroughly in a large series of genetically confirmed ESFT. The aim of the present study is to confirm the presence of epithelial markers in a large group of ESFT tested genetically for any of their specific gene fusions and the differential diagnosis with other small round cell tumors. To establish the prevalence of epithelial markers, we then performed immunohistochemical studies with antibodies CK (AE1/AE3), CK8/18, CK34β12, EMA, E-cadherin, and CEA on 415 genetically confirmed ESFT. Immunoreactivity to cytokeratin, EMA, and CEA was present in 19.2%, 6.6%, and 20.8% of cases, respectively. There was no significant association between epithelial markers and histological subtypes, but the atypical variant of ESFT expressed these markers in a high proportion compared with the peripheral neuroectodermal tumors and the conventional variant. The present findings confirm that epithelial marker expression in ESFT, including EMA and CEA, does not rule out a diagnosis of ESFT, and the integration of clinical, radiological, histopathological, immunohistochemical, and molecular genetic findings should form the basis for the diagnosis of bone and soft tissue sarcomas, especially in tumors with atypical or unusual phenotype.

Topics: Biomarkers, Tumor; Bone Neoplasms; Carcinoembryonic Antigen; Humans; Immunohistochemistry; Keratins; Mucin-1; Sarcoma, Ewing; Tissue Array Analysis

Adamantinoma is one of the rarest primary bone tumors and is almost exclusively found in the tibia. Because of its scarcity, there are only a handful of reported cases of adamantinoma diagnosed by fine needle aspiration (FNA). We report a case of a 30-year-old woman seen at The Johns Hopkins Hospital for a 2.5-cm lytic lesion in the distal diaphysis of the tibia. A computed tomography-guided FNA of the lesion revealed a moderately cellular lesion consisting of a biphasic admixture of epithelioid cells seen singly and in fragments. These cells had round to oval nuclei with pale chromatin and well-formed nuclear grooves. The other population had more elongated nuclei and spindled appearance. An immunostain for cytokeratin was positive, supporting the diagnosis of adamantinoma. Due primarily to its rarity, the diagnosis of adamantinoma on FNA can be challenging and must be made in the context of its characteristic clinical and radiographic setting.

Topics: Adamantinoma; Adult; Biomarkers, Tumor; Biopsy, Fine-Needle; Bone Neoplasms; Bone Transplantation; Female; Humans; Immunohistochemistry; Keratins; Tibia

Adamantinomas of the long bones are low-grade malignant tumours. They seem to be related to osteofibrous dysplasia with a mesenchymal-to-epithelial transformation. We report a case of an adamantinoma with a revertant sarcomatoid transformation that showed a complete loss of epithelial differentiation. It corresponded to a 41-year-old male presented with an 8-cm multilobated lesion in the centre of the distal tibia. On the en bloc resection specimen, areas of classic adamantinoma were found but most of the tumor corresponded to a high-grade neoplasm with 2 histologic patterns: one made up by epithelial nests with a basaloid arrangement and positive for pankeratins and so-called glandular keratins, and a second sarcomatoid component, negative for these epithelial markers. Five months after surgery the patient had a massive relapse that consisted solely of the second sarcomatous component also negative for epithelial antibodies.Three cases of adamantinomas with sarcomatoid transformation of the epithelial component have been described but the tumours still preserved an epithelial immunophenotype. However, our case represents the extreme end of the sarcomatoid dedifferentiation of a classic adamantinoma with complete sarcomatoid transformation and total loss of epithelial markers. To our knowledge this has not been described previously.

Topics: Adamantinoma; Adult; Biomarkers; Biomarkers, Tumor; Bone Neoplasms; Cell Transformation, Neoplastic; Humans; Keratins; Male; Mesoderm; Neoplasms, Second Primary; Phenotype; Sarcoma; Tibia; Treatment Outcome

Occasional reports indicated cytokeratin (CK) protein expression (mainly by immunohistochemistry) in malignant melanoma (MM) and suggested an association with unfavorable clinical parameters. However, the mRNA expression of CK and its clinicopathologic significance in MM has not been specifically evaluated. We investigated the mRNA and protein expression of nine CKs in melanoma cell lines and tissues, in particular the prognostic significance of CK18 mRNA expression. Reverse transcription (RT)-PCR (CK6-10, 14 and 18-20), in-situ hybridization (ISH) (CK18), and western blotting (CK18 and pan-cytokeratin AE1/AE3) were performed on MM cell lines A375, A875, M14, and SK-MEL-1. Eighty MM tissue samples were analyzed by ISH and immunohistochemistry for CK18 expression. The mRNA of CK6-8, 10, 14, 18, and 19 (but not CK9 and 20) was detected in one to four of the melanoma cell lines by RT-PCR. CK18 was detected in all four cell lines by RT-PCR, ISH, and western blotting. CK18 mRNA ISH was positive in three of 30 (10.0%), 10 of 25 (40.0%), and 12 of 25 (48.0%) of primary cutaneous, primary mucosal, and metastatic melanomas, respectively (overall positivity: 25 of 80, 31.3%). CK18 immunostaining was only observed focally in eight of 80 (10.0%) of MM tissue samples, and AE1/AE3 immunostaining was altogether negative. Significantly, CK18 mRNA ISH positivity (but not protein immunohistochemistry) was associated with poorer prognosis by both univariate analysis (P<0.001) and multivariate analysis (relative risk=5.430, 95% confidence interval 2.246-13.128, P<0.001). CK18 mRNA could be identified in one-third of melanoma tissue samples and is an adverse prognostic factor. ISH is superior to immunohistochemistry for analyzing CK18 expression in MM.

Topics: Blotting, Western; Bone Neoplasms; Brain Neoplasms; Cell Line, Tumor; Gene Expression Regulation, Neoplastic; Humans; Immunoenzyme Techniques; In Situ Hybridization; Kaplan-Meier Estimate; Keratin-18; Keratins; Lymphatic Metastasis; Melanoma; Neoplasm Proteins; Prognosis; Proportional Hazards Models; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; RNA, Neoplasm; Skin Neoplasms

Previous studies showed that intercellular communication by gap junctions has a role in bone formation. The main connexin involved in the development, differentiation, and regulation of bone tissue is connexin (Cx) 43. In addition, Cx46 is also expressed, mostly localized within the trans-Golgi region. Alterations in the expression pattern and aberrant location of these connexins are associated with oncogenesis, demonstrating a deficient gap junctional intercellular communication (GJIC) capacity in neoplastic tissues. In this study, we evaluated normal and neoplastic bone tissues regarding the expression of Cx43 and Cx46 by immunofluorescence, gene expression of these connexins by real-time PCR, and their correlation with cell proliferation index and deposition of collagen. Fourteen neoplastic bone lesions, including 13 osteosarcomas and 1 multilobular tumor of bone, were studied. The mRNA levels of Cx43 were similar between normal and neoplastic bone tissue. In normal bone tissue, the Cx43 protein was found mainly in the intercellular membranes. However, in all bone tumors studied here, the Cx43 was present in both cell membranes and also aberrantly in the cytoplasm. Regarding only tumor samples, we determined a possible inverse correlation between Cx43 expression and cellular proliferation, although a positive correlation between Cx43 expression and collagen deposition was also noted. In contrast, Cx46 had lower levels of expression in neoplastic bone tissues when compared with normal bone and was found retained in the perinuclear region. Even though there are differences between these two connexins regarding expression in neoplastic versus normal tissues, we concluded that there are differences regarding the subcellular location of these connexins in normal and neoplastic dog bone tissues and suggest a possible correlation between these findings and some aspects of cellular proliferation and possibly differentiation.

Topics: Animals; Bone Neoplasms; Cell Proliferation; Connexin 43; Connexins; DNA, Neoplasm; Dog Diseases; Dogs; Female; Gene Expression Regulation, Neoplastic; Immunohistochemistry; Keratins; Male; Microscopy, Fluorescence; Osteocalcin; Osteonectin; Osteosarcoma; Proliferating Cell Nuclear Antigen; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Vimentin

In prostate cancer, androgen blockade strategies are commonly used to treat osteoblastic bone metastases. However, responses to these therapies are typically brief, and the mechanism underlying androgen-independent progression is not clear. Here, we established what we believe to be the first human androgen receptor-negative prostate cancer xenografts whose cells induced an osteoblastic reaction in bone and in the subcutis of immunodeficient mice. Accordingly, these cells grew in castrated as well as intact male mice. We identified FGF9 as being overexpressed in the xenografts relative to other bone-derived prostate cancer cells and discovered that FGF9 induced osteoblast proliferation and new bone formation in a bone organ assay. Mice treated with FGF9-neutralizing antibody developed smaller bone tumors and reduced bone formation. Finally, we found positive FGF9 immunostaining in prostate cancer cells in 24 of 56 primary tumors derived from human organ-confined prostate cancer and in 25 of 25 bone metastasis cases studied. Collectively, these results suggest that FGF9 contributes to prostate cancer-induced new bone formation and may participate in the osteoblastic progression of prostate cancer in bone. Androgen receptor-null cells may contribute to the castration-resistant osteoblastic progression of prostate cancer cells in bone and provide a preclinical model for studying therapies that target these cells.

Topics: Animals; Bone Neoplasms; Cell Line, Tumor; Fibroblast Growth Factor 9; Gene Expression Regulation, Neoplastic; Humans; Immunohistochemistry; Karyotyping; Keratins; Male; Mice; Mice, SCID; Middle Aged; Neoplasm Metastasis; Neoplasm Transplantation; Orchiectomy; Organ Culture Techniques; Osteoblasts; Osteogenesis; Prostatic Neoplasms; Receptors, Androgen; Transplantation, Heterologous; Vimentin

Topics: Bone Neoplasms; Chondroblastoma; Fibroma; Humans; Immunohistochemistry; Keratins; Tibia

Adamantinoma of the long bones is a rare primary bone tumor of uncertain embryogenesis. It tends to involve the tibia almost exclusively. We report on adamantinomas occurring in a 16-year-old male patient, with synchronous tibial and fibular lesions. Histologically, there were characteristic clusters of epithelial cells in a fibrous background, forming a keratin cyst. Immunohistochemically, these cells were strongly positive for cytokeratin. This keratin cyst formation is quite an unusual finding in classic adamantinoma.

Topics: Adamantinoma; Adolescent; Bone Cysts; Bone Neoplasms; Diagnosis, Differential; Fibula; Humans; Keratins; Magnetic Resonance Imaging; Male; Neoplasms, Multiple Primary; Tibia

As a result of overlapping morphologic and immunohistochemical features, it can be difficult to distinguish synovial sarcoma, malignant peripheral nerve sheath tumor, and Ewing sarcoma/primitive neuroectodermal tumor in core biopsies. To analyze and compare immunohistochemical profiles, we stained tissue microarrays of 23 synovial sarcomas, 23 malignant peripheral nerve sheath tumors, and 27 Ewing sarcomas with 22 antibodies potentially useful in the differential diagnosis, and analyzed the data with cluster analysis. Stain intensity was scored as none, weak, or strong. For CD99, tumors with membranous accentuation were independently categorized. Cluster analysis sorted five groups, with like tumors clustering together. Synovial sarcoma clustered into two groups: one cytokeratin and EMA positive (n = 11), the other mostly cytokeratin negative, EMA positive, bcl-2 positive and mostly CD56 positive (n = 9). Malignant peripheral nerve sheath tumor clustered into two groups: one S100 positive, with nestin and NGFR positivity in most (n = 10), the other mostly S100 negative, and variably but mostly weakly positive for nestin and NGFR (n = 11). Ewing sarcomas clustered into a single group driven by membranous CD99 staining. Thirteen cases failed to cluster (outliers), while three Ewing sarcomas clustered into groups of other tumor types. Paired antibodies for each tumor type determined by visual assessment of cluster analysis data and statistical calculations of specificity, sensitivity, and predictive values showed that EMA/CK7 for synovial sarcoma, nestin/S100 for malignant peripheral nerve sheath tumor, and membranous CD99/Fli-1 for Ewing sarcoma yielded high specificity and positive predictive values. Cluster analysis also highlighted aberrant staining reactions and diagnostic pitfalls in these tumors. Hierarchical cluster analysis is an effective method for analyzing high-volume immunohistochemical data.

Topics: 12E7 Antigen; Antigens, CD; Biomarkers, Tumor; Bone Neoplasms; CD56 Antigen; Cell Adhesion Molecules; Cluster Analysis; Diagnosis, Differential; Humans; Immunohistochemistry; Keratins; Mucin-1; Nectins; Nerve Sheath Neoplasms; Nerve Tissue Proteins; Proto-Oncogene Protein c-fli-1; Receptors, Nerve Growth Factor; S100 Proteins; Sarcoma, Ewing; Sarcoma, Synovial

Epithelioid angiosarcoma of the bone is a rare tumor and is a diagnostic challenge. Here we present an autopsy case of a 62-year-old man with multifocal osteolytic lesions in the extremities and the pelvis. The initial diagnosis of a tibial biopsy was poorly differentiated adenocarcinoma. On the occasion of autopsy, a fungating thrombotic nodule was found at the anterior wall of the right atrium, and small hemorrhagic infarcts with tumor thrombi were found in the lung. Histologically, the above lesions were identical to the former tibial biopsy and they showed large eosinophilic epithelioid cells with irregular ovoid nuclei and prominent eosinophilic nucleoli. Rare intracytoplasmic lumina were identified. Immunohistochemically, the tumor cells were positive for cytokeratins (CAM5.2 and AE1/AE3), CD31, factor VIII-related antigen, and vimentin. This case showed angiotropic spread of the tumor only to the right atrium and the lung, with no solid mass in other organs. Multicentric epithelioid angiosarcoma of the bone is a pitfall in pathological diagnoses, especially if a strong radiological impression of metastatic carcinoma is provided. Therefore, pathologists should be aware of this rare variant.

Topics: Adenocarcinoma; Biomarkers, Tumor; Biopsy; Bone Neoplasms; Diagnosis, Differential; Epithelioid Cells; Fatal Outcome; Hemangiosarcoma; Humans; Immunohistochemistry; Keratins; Male; Middle Aged; Neoplasm Invasiveness; Neoplasms, Multiple Primary; Platelet Endothelial Cell Adhesion Molecule-1; Tibia; Vimentin; von Willebrand Factor

Ewing's sarcoma/primitive neuroectodermal tumor (EWS/PNET) is an aggressive neoplasm of bone and soft tissue. Histologically, it is characterized by the presence of small round blue cells, which usually express MIC-2 and FLI-1 immunohistochemically. The most specific feature for diagnosis, however, is cytogenetic or molecular evidence of a consistent abnormality, the t(11;22)(q24;q12), or variants thereof. The immunohistochemical expression of keratins in a significant proportion of these cases has been highlighted in several recent studies. The ultrastructural features of these keratin-positive tumors have not, however, been characterized in detail. In this study we analyzed the ultrastructural features of 12 well-documented EWS/PNETs that stained strongly for pankeratin by immunohistochemistry. Ultrastructurally, the tumor cells contained a few organelles, which included a small number of mitochondria, poorly developed Golgi complexes, free ribosomes, and inconspicuous rough-endoplasmic reticulum. Rudimentary cell junctions were seen in 2 tumors while prominent junctions were observed in the remaining 10. Five tumors contained intracytoplasmic filaments, and definite tonofibrils were identified in 2. Well-developed basal lamina around tumor cells were also demonstrated in 2 tumors. Follow-up information was available for all cases. Seven patients died of disease, 2 are alive with disease, and 3 have no current evidence of disease. The cohort includes 5 patients with a type-1 translocation, which has been associated with a better prognosis in some studies; 4 of these patients have died of their disease, and 1 is alive with recurrent disease. This study shows that keratin-positive EWS/PNETs have evidence of epithelial differentiation ultrastructurally, and may possibly represent a more aggressive subset of the EWS/PNET group of tumors.

Topics: Adolescent; Adult; Biomarkers, Tumor; Bone Neoplasms; Child; Fatal Outcome; Female; Humans; Immunohistochemistry; Keratins; Male; Microscopy, Electron, Transmission; Neuroectodermal Tumors, Primitive, Peripheral; Oncogene Proteins, Fusion; Proto-Oncogene Protein c-fli-1; Reverse Transcriptase Polymerase Chain Reaction; RNA-Binding Protein EWS; RNA, Neoplasm; Sarcoma, Ewing; Soft Tissue Neoplasms; Transcription Factors

Peripheral primitive neuroectodermal tumor (PNET)/Ewing's sarcoma (ES) of the central nervous system is extremely rare and should be differentiated from central PNET and other small blue round cell tumors. We describe a case of a meningeal peripheral PNET/ES of the spinal cord in an 11-year-old boy. Immunohistochemically, the small blue round cell tumor showed expression of epithelial markers and of CD99, thus posing an important differential diagnostic problem with a poorly differentiated synovial sarcoma. Fluorescence in situ hybridization revealed rearrangement of the EWS gene, as seen in peripheral PNET/ES. Peripheral PNET/ES does occur in the central nervous system, but its diagnosis can be extremely difficult on morphologic and immunohistochemical grounds alone. Genetic analysis plays a key role in its distinction from other small blue round cell tumors.

Topics: Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Bone Neoplasms; Child; Diagnosis, Differential; Humans; Keratins; Laminectomy; Male; Meninges; Mucin-1; Neuroectodermal Tumors, Primitive; Sarcoma, Ewing; Sarcoma, Synovial; Spectral Karyotyping; Spinal Cord; Spinal Cord Neoplasms; Vimentin

Androgen-dependent prostate cancer (PrCa) xenograft models are required to study PrCa biology in the clinically relevant in vivo environment.. Human PrCa tissue from a femoral bone metastasis biopsy (BM18) was grown and passaged subcutaneously through male severe combined immune-deficient (SCID) mice. Human mitochondria (hMt), prostate specific antigen (PSA), androgen receptor (AR), cytokeratin-18 (CK-18), pan-cytokeratin, and high molecular weight-cytokeratin (HMW-CK) were assessed using immunohistochemistry (IHC). Surgical castration was performed to examine androgen dependence. Serum was collected pre- and post-castration for monitoring of PSA levels.. BM18 stained positively for hMt, PSA, AR, CK-18, pan keratin, and negatively for HMW-CK, consistent with the staining observed in the original patient material. Androgen-deprivation induced tumor regression in 10/10 castrated male SCID mice. Serum PSA levels positively correlated with BM18 tumor size.. BM18 expresses PSA and AR, and rapidly regresses in response to androgen withdrawal. This provides a new clinically significant PrCa model for the study of androgen-dependent growth.

Topics: Androgens; Animals; Bone Neoplasms; Humans; Keratins; Male; Mice; Mice, SCID; Neoplasm Transplantation; Neoplasms, Hormone-Dependent; Prostate-Specific Antigen; Prostatic Neoplasms; Receptors, Androgen; Transplantation, Heterologous

Malignant bone tumors with epithelial differentiation are extremely rare. Only one case of primary malignant bone tumor with distinct squamous cell carcinoma and chondrosarcoma has ever been reported. Reported herein is a case of primary malignant bone tumor with distinct squamous cell carcinoma and chondrosarcoma, so-called carcinosarcoma of bone, arising in the femur of a 53-year-old man. The tumor was located within the femur and was diagnosed by curettage as a well-differentiated chondrosarcoma. No primary tumor was detected in any other organ. Within a few months the tumor had rapidly grown toward the soft tissue, and hemipelvectomy was performed. Examination of the surgical specimen revealed that the tumor was mainly composed of undifferentiated spindle sarcoma cells with scattered foci of chondrosarcoma and of squamous cell carcinoma with keratin pearl formation. The patient died approximately 6 months postoperatively. At autopsy multiple metastases were detected in the heart, both lungs, muscles, and lymph nodes. Interestingly, the chondrosarcoma and squamous cell carcinoma components were observed in several metastatic foci. The tumors in both the previously reported case and the present case contained components of chondrosarcoma and squamous cell carcinoma with keratin pearl formation, and this combination of histological features may be a unique characteristic of carcinosarcoma of bone.

Topics: Bone Neoplasms; Carcinoma, Squamous Cell; Chondrosarcoma; Fatal Outcome; Humans; Immunohistochemistry; Keratins; Male; Middle Aged; S100 Proteins; Vimentin

The human epidermal growth factor receptor (EGFR) is reportedly overexpressed in 15-20% of breast carcinomas. EGFR overexpression is associated with reduced survival and is inversely correlated with expression of estrogen receptor (ER). This study assessed EGFR expression in breast carcinomas with squamous differentiation. The immunohistochemical (IHC) expression of EGFR was evaluated in 39 breast carcinomas with squamous differentiation (30 pure squamous, 6 adenosquamous, 3 carcinosarcomas) by use of the pharmDx assay (clone 2-18C9, DakoCytomation). Cases were considered positive if at least 10% of the cells showed 1+ positivity in the squamous component. Squamous differentiation was confirmed with IHC for CK5-6 (clone D5/16B4, DakoCytomation). ER, PR, and HER2 status as well as clinical information regarding treatment and outcome were correlated. As a control, a tissue microarray comprising 280 lymph node positive breast carcinomas was evaluated with the same EGFR assay. The 39 patients ranged in age from 33 to 77 years (mean 52). The tumors measured 1.3-30 cm (mean 4.8). Sentinel or full axillary lymph node dissection was performed in 28 patients. Fourteen patients had positive lymph nodes. At the time of initial diagnosis, 3 patients had distant metastasis. Follow-up was available for 16 patients (mean 45 months). Disease-free survival at 3 years was 70%. Among the 39 tumors 87% (34) were positive for EGFR (p<0.0001). Sixty-nine percent (27 of 39) showed >50% 2+ EGFR staining. EGFR-positive tumor cells (showing squamous morphology) were also found in 1 bone, 1 lung, and 8 of 11 lymph node metastases available for evaluation. All 11 lymph nodes showed squamous differentiation. All but 1 of the EGFR+ tumors examined were ER and PR negative. Six EGFR-positive tumors were HER2 positive. No statistically significant differences in HER2 status, size, lymph node status and disease-free survival were observed between EGFR+ and EGFR- cases, but the number of EGFR-negative tumors was quite small. Nine of 280 (3%) of lymph node-positive invasive carcinomas on the tissue microarray were EGFR+; review of the initial diagnostic slides failed to reveal squamous features in all but 1 of the 9 EGFR+ tumors. Breast carcinomas with squamous differentiation are a distinct subgroup of breast tumors with a very high frequency of EGFR positivity. Breast carcinomas of this type would be ideal candidates for a trial with EGFR inhibitors.

Topics: Adult; Aged; Bone Neoplasms; Breast Neoplasms; Carcinoma, Adenosquamous; Carcinoma, Squamous Cell; Carcinosarcoma; Cell Differentiation; ErbB Receptors; Follow-Up Studies; Humans; Immunohistochemistry; Keratins; Lung Neoplasms; Lymph Nodes; Lymphatic Metastasis; Middle Aged; Neoplasm Staging; Receptor, ErbB-2; Receptors, Estrogen

Intraosseous benign notochordal cell tumors are recently recognized conditions that may undergo malignant transformation to classic chordomas. This study attempts to define the morphologic and immunohistochemical characteristics of 34 benign notochordal cell tumors by contrasting them with classic chordomas and the notochordal vestiges in fetal intervertebral discs. Benign notochordal cell tumors were characterized by well-demarcated though unencapsulated sheets of adipocyte-like vacuolated and less vacuolated eosinophilic cells within axial bones. The round nuclei were mildly polymorphic but bland. The tumor cells often contained cytoplasmic eosinophilic hyaline globules and lack any intercellular myxoid matrix or necrosis. The involved bone trabeculae were often sclerotic without evidence of bone destruction. The histologic features were different from those of both notochordal vestiges in fetal intervertebral discs and classic chordomas. There was overlap in immunohistochemical reactivity of benign notochordal cell tumors and chordomas, but notochordal vestiges failed to demonstrate cytokeratin 18 positivity. A more appropriate term for the lesions is "benign notochordal cell tumor" rather than "notochordal rest" or "notochordal hamartoma" as they are not rests and do not fulfill the definition of hamartoma. Benign notochordal cell tumors do not need any surgical procedure and must be adequately recognized to prevent unnecessary operations.

Topics: Adult; Aged; Aged, 80 and over; Bone Neoplasms; Chordoma; Female; Humans; Immunohistochemistry; Intervertebral Disc; Keratins; Male; Middle Aged; Notochord

We analyzed the expression of proteases and the clinicopathologic significance in non-skull base chordoma (NSBC). By using immunohistochemical techniques, we studied the expression of matrix metalloproteinase (MMP)-1, MMP-2, MMP-9, cathepsin B (CatB), and urokinase plasminogen activator (uPA) in 29 NSBCs and compared these data with clinicopathologic parameters and the expression of cell differentiation markers. Expression of MMP-1 (P = .092), MMP-2 (P = .041), and CatB (P = .058) was associated with nuclear pleomorphism, a previously described adverse prognostic indicator. Expression of cytokeratin 8 correlated with that of MMP-1 (P = .005), MMP-2 (P = .002), and uPA (P = .032). Patients with higher MMP-2 expression had a poorer prognosis than those with lower MMP-2 expression (P = .013). We believe that NSBCs with nuclear pleomorphism or stronger epithelial character have a higher invasive ability than those without. In addition, high MMP-2 expression was an indicator of an unfavorable clinical outcome in NSBC.

Topics: Adult; Aged; Aged, 80 and over; Bone Neoplasms; Cathepsin B; Chordoma; Humans; Immunohistochemistry; Keratins; Matrix Metalloproteinases; Middle Aged; Prognosis; Survival Analysis; Urokinase-Type Plasminogen Activator

We report a urachal adenocarcinoma metastatic to both ovaries in a 50-year-old Japanese woman. Pelvic examination and imaging studies revealed a large cystic tumor occupying the pelvis and another cystic tumor between the umbilicus and the urinary bladder. A laparotomy was performed. Histopathological examination revealed a urachal tumor that was a well-differentiated invasive mucinous adenocarcinoma; the overlying urothelium was intact. The right and left ovarian tumors were well-differentiated mucinous adenocarcinomas. The urachal and ovarian tumors were immunoreactive for cytokeratin 20 and carcinoembryonic antigen, but negative for cytokeratin 7. The patient is alive with lymph node and bone metastases 6 months postoperatively. This is the eighth reported case of an adenocarcinoma of the bladder with ovarian metastasis.

Topics: Adenocarcinoma, Mucinous; Adult; Bone Neoplasms; Carcinoembryonic Antigen; Female; Humans; Immunohistochemistry; Intermediate Filament Proteins; Keratin-20; Keratin-7; Keratins; Lymphatic Metastasis; Ovarian Neoplasms; Urachus; Urinary Bladder Neoplasms

We have developed a series of novel mammary epithelial cell lines from tumors arising in strain 129 mice, with the ultimate goal of evaluating the role of host factors in the development of bone metastases. Mammary tumors were induced in mice with subcutaneously implanted medroxyprogesterone acetate (MPA) pellets followed by administration of DMBA by oral gavage. Mammary tumor development was efficient in the 129 strain and was independent of osteopontin (OPN) expression. Epithelial cell lines were isolated from these tumors; surprisingly, these cells did not form tumors upon inoculation into the mammary fat pad of syngeneic mice, even when MPA was present. One OPN-deficient cell line was selected for further study; full transformation of these cells required expression of both polyoma middle T and activated ras. These doubly transfected cells, 1029 GP+Er3, grew in soft agar, and formed hormone-independent tumors efficiently in the mammary fat pad that spontaneously metastasized to several soft tissue sites but not to the bone. Derivatives of these cells were isolated from tumors arising in the fat pad and from a lung metastasis (r3T and r3L, respectively): these cells formed tumors more rapidly in the fat pad than the parental GP+Er3 cells. Upon left ventricle injection, the r3T and r3L cells formed osteolytic bone metastases in 129 mice, with few metastases seen in other organs. These tumors filled the marrow cavity, and caused extensive destruction of both cortical and trabecular bone. Intriguingly, in an alternative syngeneic host, (129xC57B1/6) F1, osteolytic bone metastases were not seen on x-ray; instead extensive liver metastasis was present in these mice, indicating that genetic factors in these two strains regulate tumor cell homing and distribution during metastasis. These cell lines provide an important new tool in the study of bone metastasis, particularly in elucidating the role of host factors in the development of these lesions, as the 129 mouse strain is frequently used for genetic manipulations in the mouse.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Antigens, Polyomavirus Transforming; Antineoplastic Agents, Hormonal; Bone Neoplasms; Carcinogens; Cell Transformation, Neoplastic; Epithelial Cells; Female; Genes, ras; Heart Ventricles; Humans; Keratins; Liver Neoplasms, Experimental; Male; Mammary Neoplasms, Experimental; Medroxyprogesterone Acetate; Mice; Mice, Inbred C57BL; Mice, Inbred Strains; Mice, Knockout; Neoplastic Cells, Circulating; Osteolysis; Osteopontin; Retroviridae; Sialoglycoproteins; Transfection; Tumor Cells, Cultured

The objective was to elaborate a method of immunohistochemical diagnosis of bone micrometastases and to apply this procedure in operated patients with the non-small cell form of lung cancer. By means of a cocktail of cytokeratin mixtures and individual cytokeratins the immunohistochemical profile of the primary pulmonary focus is assessed. Bone micrometastases are evaluated from the bone marrow of a sampled costal segment. A total of 30 bone marrow samples were examined. For further evaluation 17 patients remained in the group. Isolated segments with a marked positivity of cytokeratins were observed in four instances. The yield of bone marrow from costal segment is very good. The initial results are encouraging for further research.

Topics: Biomarkers, Tumor; Bone Neoplasms; Carcinoma, Non-Small-Cell Lung; Humans; Immunohistochemistry; Keratins; Lung Neoplasms

Desmoplastic mesothelioma is a rare subtype of diffuse malignant mesothelioma, and is often difficult to distinguish from reactive pleural fibrosis because of associated extensive collagen fibrosis. An 82-year-old woman with a severe cough was revealed to have pleural effusion and diffuse pleural thickening on the right side. Antibiotics were ineffective, and a compression fracture of the ninth and tenth thoracic vertebral bodies was recognized on X-ray. Autopsy revealed a diffuse pleural thickening with hyalinized collagen tissue in the central part of the pleura. However, the peripheral part of the fibrous tissue was composed of spindle and polygonal cell proliferation that were immunohistochemically positive for antibodies against cytokeratin and vimentin. In addition, the ninth and tenth thoracic spines were infiltrated by similar cells. The condition was diagnosed as desmoplastic mesothelioma with bone metastases. Asbestos bodies were detected in the thickened pleura and fibrosed alveolar septa, and it was suggested retrospectively that the patient had been exposed to asbestos. Thus, autopsy analyses of fibrous pleurisy are necessary to detect a desmoplastic variant of mesothelioma of the pleura and its association with asbestos exposure.

Topics: Aged; Aged, 80 and over; Asbestos, Crocidolite; Bone Neoplasms; Fatal Outcome; Female; Humans; Keratins; Mesothelioma; Pleural Neoplasms; Radiography, Thoracic; Vimentin

Bone vascular tumors are very rare. Epithelioid types are described according to their architecture, their degree of vascular differentiation, and their cytonuclear atypia. The include epithelioid hemangioma, epithelioid hemangioendothelioma, and angiosarcoma. We report a case of L4 corpus vertebral bone epithelioid hemangioma. The patient was a 25-year-old man with a tumor that recurred twice. The lesion was characterized by a vascular lumen lined by cells with regular nuclei and inflammatory infiltrates. Capillaries were lined by prominent epithelioid endothelial cells, associated with CD31+ and cytokeratin-.

Topics: Adult; Bone Neoplasms; Epithelium; Hemangioma; Humans; Immunohistochemistry; Keratins; Lumbar Vertebrae; Male; Neoplasm Recurrence, Local; Platelet Endothelial Cell Adhesion Molecule-1

To clarify the clinicopathological profile of osteosarcomas showing an intensely positive immunoreaction for cytokeratin.. Clinicopathological and immunohistochemical features were analysed in 131 patients with non-metastatic, conventional osteosarcoma, treated in Akita University and National Cancer Centre in Tokyo between 1972 and 1999.. Six patients (4.5%; mean age, 32 years; four men, two women) had osteosarcomas showing intense cytokeratin expression. Tumours were located on the long bones of the extremities in five patients and the ilium in one. Osteoid formations were found in biopsied specimens in all cases. Three tumours were classified as osteoblastic osteosarcoma, two as fibroblastic, and one as chondroblastic. In three tumours classified as the osteoblastic subtype, epithelioid features were prominent, and four tumours showed pronounced cellular pleomorphism. In contrast to the expression of cytokeratin, epithelial membrane antigen was negative in all cases. Surgery with a wide excisional margin was performed in six patients. Preoperative and postoperative chemotherapy was given to five of the six patients, but the effects of these agents were negligible. Three of the six patients developed lung metastases, whereas the other three patients have remained well with no evidence of local recurrence or distant metastasis.. Osteosarcoma with intense immunoreaction for cytokeratin was rare. The clinicopathological features were similar to those of patients with conventional osteosarcoma, except for a higher age, chemotherapy resistance, histological epithelioid features, and pleomorphism. This study indicates that osteoid formation and negative expression of epithelial membrane antigen are key features in the differentiation from metastatic carcinoma.

Topics: Adolescent; Adult; Aged; Biomarkers, Tumor; Bone Neoplasms; Diagnosis, Differential; Epithelioid Cells; Female; Humans; Immunohistochemistry; Keratins; Magnetic Resonance Imaging; Male; Middle Aged; Osteosarcoma

We present the clinical, histologic, immunohistochemical, and ultrastructural findings of four cases of non-functioning oncocytic adrenocortical carcinomas. The patients' ages ranged from 39 to 71 years. There was no sex predilection. Large yellow-tan tumors (8.5 to 17.0 cm), well demarcated from the adjacent kidney, were seen with a thin rim of normal adrenal gland along one edge. One tumor invaded the inferior vena cava and extended up to the level of the right atrium, and another metastasized to bone. The other two tumors had similar morphologic features and therefore were considered carcinomas. Histologic sections of all four cases showed a diffuse proliferation of polygonal neoplastic cells with large nuclei containing prominent nucleoli and abundant granular and eosinophilic cytoplasm. Occasional mononuclear and binucleated giant cells were noted in one case. There were rare mitotic figures (less than one per 10 high power fields). All tumors were immunoreactive for cytokeratins (AE1/AE3 and CAM5.2). Inhibin was focally expressed by one tumor and its bone metastasis. Ultrastructurally, the cytoplasm of the neoplastic cells was packed with innumerable mitochondria. Cytologic atypia or mitotic rate cannot reliably predict the biologic behavior of oncocytic adrenocortical neoplasms. Large tumor size (4/4), extracapsular extension (3/4), blood vessel invasion (2/4), necrosis (4/4), and metastasis (1/4) are features of malignancy for oncocytic adrenocortical carcinomas. The treatment of these tumors is complete surgical excision.

Topics: Adenoma, Oxyphilic; Adrenal Cortex Neoplasms; Adrenocortical Carcinoma; Adult; Aged; Bone Neoplasms; Cytodiagnosis; Female; Humans; Immunohistochemistry; Inhibins; Keratins; Male; Microscopy, Electron; Middle Aged

The authors describe a tumor that had the histologic and ultrastructural features and immunohistochemical profile of an axial chordoma, but arose in the distal ulna. A skeletal survey failed to show any other site of involvement. The tumor was resected, and the patient remains free of disease 2 1/2 years later. Rare tumors with the histologic features of chordoma have been reported in appendicular locations. Chordoma periphericum, a tumor that has the potential to metastasize, needs to be distinguished from parachordoma because no classic parachordoma has been reported to disseminate.

Topics: Adult; Biomarkers, Tumor; Bone Neoplasms; Chordoma; Disease-Free Survival; Humans; Immunoenzyme Techniques; Intercellular Junctions; Keratins; Magnetic Resonance Imaging; Male; Neoplasm Proteins; Organelles; Radiography; S100 Proteins; Ulna

Metastatic carcinoma of unknown primary is a common problem, accounting for up to 10-15% of all solid tumours at presentation. Proper identification of the site of origin has prognostic and therapeutic significance. Prior immunohistochemical methods to identify the site of origin have been useful in a limited number of cases. Differential cytokeratin staining may be useful in this setting, particularly in identifying metastases from lung cancer. We have identified 144 cases of metastatic carcinoma of unknown primary to bone, lung or liver at Brigham and Women's Hospital between 1 January 1997 and 1 July 1998. Cytokeratin (CK) 7 and CK20 were used in 75 of these cases to narrow down the possible sites of the primary tumours. All of these cases were ambiguous as to the site of the primary tumour. Forty-five cases were CK7+/CK20-, 15 cases were CK7-/CK20-, 9 cases were CK7-/CK20+ and 6 cases were CK7+/CK20+. Three of the cases were selected for detailed presentation and discussion as well as a discussion of the pertinent literature. Overall, the CK7+/CK20- phenotype favours a lung primary, the CK7+/CK20+ phenotype strongly favours transitional cells (urothelial) carcinoma, the CK7-/CK20+ phenotype favours colorectal carcinoma, while the CK7-/CK20- profile is not helpful.

Topics: Biomarkers; Bone Neoplasms; Humans; Immunohistochemistry; Intermediate Filament Proteins; Keratin-20; Keratin-7; Keratins; Liver Neoplasms; Lung Neoplasms; Neoplasms, Unknown Primary

Plasmacytomas are localized neoplastic proliferations of monoclonal plasma cells. When multifocal, the process is referred to as multiple myeloma. These lesions exhibit a pattern of antigen expression and cytomorphology that usually leads to a ready diagnosis. However, potentially troublesome variations in immunophenotype occur. We describe a case of a plasmacytoma from a patient who presented with sudden onset of pain and a lytic lesion of the left proximal humerus. Hematoxylin and eosin-stained sections showed a lymphoproliferative lesion composed of large lymphoid cells, some with plasmacytoid and immunoblastic features. The lesion also showed significant mitotic activity. Immunohistochemical staining was positive for CD45 (LCA), CD56 (N-CAM), CD43 (MT1), and cytokeratin CAM5.2. There was also clonal staining for lambda light chains. In addition, flow cytometric analysis showed positivity for myeloid markers such as CD13, CD33, CD38, and CD138. Significant negative markers include CD20 (L26), CD45RO (UCHL-1), and CD79alpha. The unusual phenotypic features of this plasmacytoma illustrate potential diagnostic pitfalls. It is important to fully study such lesions to correctly classify them, because this has significant impact on prognosis and management.

Topics: Antigens, Differentiation, T-Lymphocyte; Antigens, Neoplasm; Bone Neoplasms; Humans; Humerus; Immunophenotyping; Keratins; Plasmacytoma

To examine the expression of the p63 protein in normal, preneoplastic, and neoplastic human prostatic tissue. The p63 gene, a member of the p53 gene family, is expressed in the basal epithelial cells of multiple organs. Irregularities in p63 expression have been associated with epithelial carcinogenesis.. We performed immunohistochemistry with an anti-p63 antibody on specimens from radical prostatectomies, prostate needle biopsies, and metastatic prostate adenocarcinoma. We analyzed p63 expression in regions of normal prostate, benign prostatic hyperplasia, proliferative inflammatory atrophy (PIA), high-grade intraepithelial neoplasia, and adenocarcinoma.. Basal epithelial cells in normal, benign prostatic hyperplasia, and high-grade intraepithelial neoplasia tissue stained intensely for the p63 polypeptide, but the vast majority of adenocarcinoma specimens from 233 patients-66 (94%) of 70 radical prostatectomies, 132 (89%) of 148 prostate needle biopsies, and 14 (93%) of 15 metastases-did not. In tumors in which the adenocarcinoma cells were positive, the staining intensity was weak and occurred in less than 1% of the cells. Tumors that stained positive for p63 were more likely to be high grade than those that did not (P <0.0001). Basal cells in PIA expressed p63, but these cells were sparsely distributed relative to the basal cells in the normal glands. Luminal cells in PIA were, in general, negative for p63.. In contrast to normal and preneoplastic prostatic tissue, the vast majority of prostate adenocarcinomas do not express p63. Therefore, p63 immunohistochemistry represents a potential novel adjuvant method for facilitating the pathologic diagnosis of prostate cancer in prostate needle biopsies. The selective expression of p63 in normal basal cells, coupled with the finding that p63 null mice fail to develop prostates, provides strong evidence that the basal cells represent prostatic epithelial stem cells. In addition, these findings suggest that p63 may protect prostatic epithelial cells against neoplastic transformation and support the hypothesis that intermediately differentiated cells in the luminal epithelium of PIA are the targets of neoplastic transformation in the prostate.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Biopsy, Needle; Bone Neoplasms; Cell Differentiation; DNA-Binding Proteins; Epithelium; Genes, Tumor Suppressor; Humans; Immunohistochemistry; Keratins; Lymphatic Metastasis; Male; Membrane Proteins; Middle Aged; Phosphoproteins; Precancerous Conditions; Prostate; Prostatic Hyperplasia; Prostatic Neoplasms; Stem Cells; Trans-Activators; Transcription Factors; Tumor Suppressor Proteins

Clear cell (CRCC), papillary (PRCC) and chromophobe (CHRC) renal cell carcinoma (RCC) are the three most frequent subtypes of RCC. The rate and distribution of their metastatic lesions have not been well documented. We compared metastatic RCC according to subtype and primary tumor characteristics to better understand their behavior and to aid in the diagnosis of metastatic RCC. Pathology reports and clinical charts related to 283 CRCC, 48 PRCC and 13 CHRCC, including their respective sarcomatoid variants, were reviewed. A hundred and thirty-seven CRCC, 5 PRCC and 1 CHRCC with metastases were identified. CRCC and non-CRCC (PRCC and CHRCC) had different patterns of metastasis and primary tumor growth. CRCC metastases were predominantly distributed in lungs, bone, brain, lymph nodes, and adrenal glands. The associated primary CRCC measured 1.5 to 15 cm, were of all grades and stages, and were often associated with invasion of small or large veins. Three PRCC had regional lymph node metastases, 1 PRCC had both regional and mediastinal lymph node metastases. Bone metastasis was present in 1 case each of PRCC and CHRCC. One PRCC with metastasis solely to regional nodes measured 4 cm. The other 4 cases of PRCC with regional lymph node and/or distant metastases as well as the CHRCC with distant metastases were greater than 8 cm in diameter. In metastasizing and non-metastasizing non-CRCC, invasion of small veins was rare and invasion of renal veins was not seen. We cannot comment with any certainty on the metastatic behavior of CHRCC. In our experience, PRCC tend to loco-regional invasion with lymph node spread. They have a low potential for vascular invasion and distant metastases that likely occur only at late stages of the disease. CRCC has a propensity for vascular invasion and may be associated with distant metastasis at an early stage. Therefore, metastatic RCC at a distant location are most likely to be of CRCC origin than PRCC origin.

Topics: Adrenal Gland Neoplasms; Aged; Bone Neoplasms; Brain Neoplasms; Carcinoma, Renal Cell; Female; Humans; Immunoenzyme Techniques; Keratins; Kidney Neoplasms; Lung Neoplasms; Lymphatic Metastasis; Male; Middle Aged; Neoplasm Staging; Survival Rate; Vimentin

Serum pyridinoline cross-linked carboxy-terminal telopeptide of type I collagen (ICTP) is a metabolite of type I collagen comprising 90% or more of organic substances in bone. Its usefulness as a marker of bone metastasis from malignant tumors is expected.. We measured ICTP to evaluate its clinical usefulness for diagnosis of bone metastasis in 140 patients with lung cancer. For comparison, serum carcinoembryonic antigen (CEA), cytokeratin 19 fragment (CYFRA 21-1), gastrin-releasing peptide precursor (ProGRP), alkaline phosphatase and calcium were simultaneously measured. ICTP was measured by double-antibody radioimmunoassay.. ICTP was significantly higher in patients with bone metastasis from lung cancer than in the group without bone metastasis, patients with other pulmonary diseases or healthy control subjects and showed excellent sensitivity and specificity, indicating that this marker is highly useful for complementary diagnosis of bone metastasis from lung cancer. Moreover, the survival duration was significantly shorter in the ICTP-positive group than in the ICTP-negative group, suggesting that ICTP can be a prognostic factor in lung cancer.. It is suggested that measurement of ICTP is worthwhile as a serological diagnostic method of bone metastasis from lung cancer. Moreover, since repeated measurements are possible, this measure was considered very helpful in complementary diagnosis of bone metastasis and also as a standard to determine the timing of examinations such as bone scintigraphy.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Alkaline Phosphatase; Antigens, Neoplasm; Biomarkers; Biomarkers, Tumor; Bone Neoplasms; Calcium; Carcinoembryonic Antigen; Carcinoma, Large Cell; Carcinoma, Small Cell; Carcinoma, Squamous Cell; Collagen; Collagen Type I; Female; Gastrointestinal Hormones; Humans; Keratin-19; Keratins; Lung; Lung Diseases; Lung Neoplasms; Male; Middle Aged; Peptide Fragments; Peptides; Prognosis; Recombinant Proteins; Sensitivity and Specificity; Survival Rate

To elucidate the precise origin and characteristics of the epithelial components of osteofibrous dysplasia (OF) and adamantinoma (AD), the expression of transforming growth factor (TGF)-beta1, beta2 and beta3 and cytokeratin (CK) subtypes were studied in five cases of AD and 18 cases of OF by immunohistochemistry. CK1 was expressed in 10 out of 18 OF cases; CK5 was expressed in one OF case; CK14 was positively stained in 10 cases of OF; CK19 was positively stained in 16 OF cases; CK1 was expressed in three out of five AD cases; CK5 was expressed in one case of AD; CK14 was positively stained in four AD cases; and CK19 was positively stained in five AD cases. In OF, TGF-beta1, beta2 and beta3 were expressed in both fibroblasts and osteoblasts. In AD, TGF-beta1, beta2 and beta3 were expressed in both epithelial and fibrous components. These results suggest that epithelial components of AD and OF share epidermal characteristics, CK1, express basal cell phenotype and cytokeratins 5, 14 and 19. In addition to these epithelial characteristics, strong immunoreactivity for TGF-beta poses the possibility of TGF-beta promotion of basal cell phenotype expression for the epithelial components in OF and AD.

Topics: Adolescent; Adult; Bone Neoplasms; Child; Child, Preschool; Female; Fibrous Dysplasia, Monostotic; Fibula; Humans; Immunoenzyme Techniques; Keratins; Male; Middle Aged; Neoplasms, Glandular and Epithelial; Phenotype; Tibia; Transforming Growth Factor beta

Considering the current need to improve cost-effectiveness in cancer patient management, a prospective study was undertaken in order to define the optimal combination of bone scan and tumour marker assays in breast and lung cancer strategies, as has been done in the case of prostate cancer. All patients with breast or lung cancer referred to the Nuclear Medicine Department of the Grenoble Teaching Hospital between December 1995 and April 1997 were included. A blood sample was drawn in each case for marker assay (CA15-3 or CEA and CYFRA 21-1) on the same day as the bone scan. Two hundred and seventy-five patients were included: 118 with lung cancer and 157 with breast cancer. With regard to lung cancer, no information useful for guiding bone scan prescription was obtained through CEA and CYFRA 21-1 assays. For breast cancer, the results suggest that in asymptomatic patients, a CA15-3 level of less than 25 U/ml (upper normal value chosen as the threshold) is strongly predictive of a negative bone scan; by contrast, high tumour marker levels are predictive of neoplastic bone involvement. When a doubtful bone scan is obtained in a patient with breast cancer, a normal marker level makes it highly probable that bone scan abnormalities are not related to malignancy.

Topics: Aged; Aged, 80 and over; Antigens, Neoplasm; Biomarkers, Tumor; Bone and Bones; Bone Neoplasms; Breast Neoplasms; Breast Neoplasms, Male; Carcinoembryonic Antigen; Female; Humans; Keratin-19; Keratins; Lung Neoplasms; Male; Middle Aged; Mucin-1; Predictive Value of Tests; Prospective Studies; Radionuclide Imaging; Radiopharmaceuticals; Technetium Tc 99m Medronate

Breast cancer affects approximately one woman in twelve and kills more women than any other cancer. If detected early, patients have a five year survival rate of 66%, but once metastatic disease has developed, there is no effective treatment. About 70% of patients with metastatic disease have bone involvement, while lungs and liver are the other common targets. Bone metastases cause severe pain, pathological fractures and hypercalcaemia and thus are a significant clinical problem. The development of new therapies for metastatic breast carcinoma depends on a better understanding of the mechanism of homing of the tumour cells to bone, liver and lungs and the factors required for their growth in these organs. Research on mechanisms of breast cancer metastasis, particularly to bone, has relied on in vitro studies or on tumour models in which the inoculation route is designed to promote delivery of tumour cells to a specific organ. Metastases in bone are achieved by inoculation into the right ventricle of the heart. To our knowledge there has been no report of a model of metastatic spread from the mammary gland to distant sites which reliably includes bone. In this paper, we describe our recent development of a novel murine model of metastatic breast carcinoma. The new model is unique in that the pattern of metastatic spread closely resembles that observed in human breast cancer. In particular, these murine breast tumours metastasise to bone from the primary breast site and cause hypercalcaemia, characteristics not normally found in murine tumours, but common in human disease. Furthermore, in a preliminary characterisation of this model, we show that secretion of parathyroid hormone-related protein, a role for which has been implicated in breast cancer spread to bone, correlates with metastasis to bone. This model therefore provides an excellent experimental system in which to investigate the factors that control metastatic spread of breast cancer to specific sites, particularly bone. The special advantage of this system is that it involves the whole metastasis process, beginning from the primary site. Existing models consider mechanisms that pertain to growth of tumour once the site has been reached. An understanding of the regulation of these factors by potential therapeutic agents could lead to improvement in therapies designed to combat metastatic disease. For the first time, this development will allow exploration of the molecular basis of site-specific m

Topics: Animals; Bone Neoplasms; Calcium; Female; Immunohistochemistry; Infusions, Intravenous; Keratins; Mammary Neoplasms, Experimental; Mice; Mice, Inbred BALB C; Parathyroid Hormone-Related Protein; Proteins; Radioimmunoassay; Tumor Cells, Cultured

The detection of cytokeratin-positive bone marrow cells has been considered a prognostic factor in numerous malignant tumors. We investigated whether this was also valid for localized prostate cancer. Bone marrow aspirates were taken prior to radical prostatectomy from 169 consecutive patients with pT1/2 pNO G1-3 adenocarcinoma of the prostate. The immunocytochemical detection of cytokeratin no. 18 (CK 18)-positive cells using monoclonal antibody CK 2 was interpreted as micrometastasis. Repeat marrow aspirations were performed at 6 months postoperatively and once a year thereafter. The patients were re-examined over a period of at least 10 and a maximum of 72 months (median 32 months). An increase in prostate specific antigen > or = 0.5 ng/ml was considered a biochemical "relapse". One hundred and fifty-four patients had evaluable bone marrow aspirates, of which 74.7% were CK 18-negative and 25.3% positive. The latency period for biochemical relapse was 1481 days (median) in the CK 18-negative group and 1106 days (median) in the CK 18-positive group. This difference was not statistically significant. The CK 18-positive aspirates (n = 39) showed one positive cell in 20 cases, two positive cells in 8 and three or more positive cells in 11 cases. The preoperative number of cells had no statistically significant effect upon the onset of biochemical relapse. Only patients with three or more CK 18-positive cells tended to have a poorer prognosis. One hundred and thirteen patients had evaluable bone marrow aspirates pre- and postoperatively. Postoperative persistence or occurrence of CK 18-positive cells did not affect the outcome of the disease. The detection of CK 18-positive cells in bone marrow does not influence the prognosis of patients with localized prostate cancer within a period fo 32 months (median). Solely a subgroup of patients showing a large preoperative number of CK 18-positive cells seems to tend to an unfavorable course of the disease. Thus, further studies are necessary aiming at a more detailed characterization of these cells.

Topics: Aged; Antibodies, Monoclonal; Bone Marrow; Bone Neoplasms; Epithelial Cells; Humans; Immunohistochemistry; Keratins; Life Tables; Male; Middle Aged; Predictive Value of Tests; Prognosis; Prostatectomy; Prostatic Neoplasms; Time Factors

Thirty-five chordomas and more than 100 other tumors that have to be considered in the differential diagnosis, were immunohistochemically analyzed using a panel of antibodies including those to subsets of keratins (K), HBME-1, a monoclonal antibody recognizing an unknown antigen on mesothelial cells, and neuroendocrine markers. The patterns of immunoreactivities in chordoma were compared with those in renal cell carcinoma, colorectal mucinous adenocarcinoma, pituitary adenoma, skeletal chondrosarcoma, and extraskeletal myxoid chondrosarcoma (ESMC). Chordomas were consistently positive for keratin cocktail AE1/AE3, and for the individual keratins K8 and K19, and nearly always positive for K5, but they showed negative or only sporadic reactivity for K7 and K20. The keratin K8 and K19 reactivity was retained in those chordomas showing solid sheets of epithelioid, spindle cells, or cartilaginous metaplasia, and in one of two cases showing overtly sarcomatous transformation. In comparison, keratins were never present in skeletal chondrosarcoma, although K8 and to a lesser extent K19 were seen in occasional cases of ESMC with chordoid features. HBME-1 reacted strongly with chordoma and skeletal chondrosarcoma but was almost never positive in renal or colorectal carcinoma. These carcinomas lacked K5-reactivity, in contrast to chordoma. Chordomas were also consistently positive for neuron-specific enolase and occasionally focally for synaptophysin, but never for chromogranin. In contrast, pituitary adenomas regularly expressed the full spectrum of neuroendocrine markers and differed from chordoma by having a narrower repertoire of keratins, often showing negative or focal keratin 8- or AE1/AE3 reactivity and being almost always K19-negative. These findings indicate that chordoma can be immunohistochemically separated from tumors that can resemble it. Immunohistochemistry is especially useful in the diagnosis of small biopsy specimens that offer limited material for morphological observation.

Topics: Adenocarcinoma, Mucinous; Adenoma; Antibodies, Monoclonal; Antigens, Neoplasm; Biomarkers, Tumor; Bone Neoplasms; Carcinoma; Chondrosarcoma; Chordoma; Colonic Neoplasms; Diagnosis, Differential; Humans; Immunohistochemistry; Keratins; Kidney Neoplasms; Pituitary Neoplasms

This report describes five cases of osteofibrous dysplasia-like adamantinoma of the tibia in young patients ranging from ages 4 1/2 to 14 years. Radiologically and histologically, these cases were indistinguishable from osteofibrous dysplasia of bone, and no epithelial cells were recognized on routine staining. However, epithelial differentiation was seen in the form of scattered keratin-positive cells in all five cases, and tonofilaments in four cases. The patients were treated by curettage, and three had recurrences. Follow-up showed no progression to classic adamantinoma. Osteofibrous dysplasia-like adamantinoma is a special histological type of adamantinoma that affects children and adolescents. It differs from classic adamantinoma in that it lacks conspicuous nests and masses of epithelial cells, and the prognosis after conservative treatment is generally good. Recent publications suggest that osteofibrous dysplasia-like adamantinoma is a precursor of classic adamantinoma. In a comparative study of three cases of classic adamantinoma, we found, in the fibroblastic stroma of the tumors, spindle epithelial cells that were indistinguishable from the epithelial cells of osteofibrous dysplasia-like adamantinoma. This finding suggests that there is an overlap between these conditions. Four additional cases of osteofibrous dysplasia of the tibia from our files lacked epithelial differentiation. It is most likely that osteofibrous dysplasia is part of the morphologic spectrum of adamantinoma.

Topics: Adolescent; Adult; Bone Neoplasms; Child; Child, Preschool; Female; Fibrous Dysplasia of Bone; Humans; Immunoenzyme Techniques; Intermediate Filaments; Keratins; Male; Neoplasms, Glandular and Epithelial; Tibia

We describe a 60-year-old woman with leg pain. Although metastatic bone tumor and atypical cells mimicking signet-ring cells in the bone marrow picture were observed, systemic survey revealed no primary lesion. The patient died two months after admission from systemic progress of the disease. Autopsy revealed a small focus of adenocarcinoma within the right upper lobe of the lung and systemic metastases without any particular changes in the gastrointestinal tract. The tumor cells of the lung were diffusely positive for cytokeratin 7, whereas cytokeratin 20 immunoreactivity was weak and focal, and that supported the lung origin of the present tumor. Moreover, the tumor cells in the bone marrow showed a similar pattern in immunoreactivity. These findings suggest that cytokeratin 7 and cytokeratin 20 immunoreactivity is helpful for the premortem diagnosis of the metastatic tumor of unknown origin.

Topics: Biomarkers, Tumor; Bone Marrow; Bone Neoplasms; Carcinoma, Signet Ring Cell; Digestive System; Female; Fibula; Humans; Keratins; Lung; Lung Neoplasms; Middle Aged; Neoplasm Proteins; Neoplasms, Unknown Primary; Organ Specificity; Protein Isoforms; Radionuclide Imaging

Occult dissemination of tumor cells mainly determines the prognosis of patients with primary prostate cancer. The effect of androgen deprivation on micrometastatic tumor cells in these patients is currently unknown. We therefore used an immunocytochemical assay with monoclonal antibodies (MAbs) directed against epithelial cytoskeleton proteins (i.e., cytokeratins) to monitor the concentration of isolated tumor cells in the bone marrow of 36 prostate cancer patients (stage C), who underwent hormonal androgen deprivation with Flutamide and Leuprorelin acetate. Tumor cells in cytologic bone marrow preparations were detected using an assay that employed the MAb CK2 directed against cytokeratin (CK) 18 and the alkaline anti-alkaline phosphatase staining method. Prior to therapy, we detected between 1 and 38 CK-positive cells per sample of 2 x 10(6) nucleated cells in 21 patients, while the remaining 15 patients displayed tumor-free marrow samples. There was no significant correlation between the concentration of CK-positive cells and the volume of hypo-echogenic lesions as an indicator of the primary tumor volume or the serum level of prostate-specific antigen (PSA). After androgen deprivation, 20 of the 21 initially positive patients either became negative (n = 16) or showed at least a reduction in the concentration of CK-positive cells (n = 4). Moreover, only 2 of the 15 patients with negative pre-treatment findings became positive. All of the 7 patients with remaining tumor cells in the bone marrow after therapy showed no detectable amounts of PSA in their serum. Our findings suggest that serum PSA concentration is no indicator of micrometastatic disease in bone marrow. Neoadjuvant androgen deprivation appears to eliminate disseminated CK-positive tumor cells present in bone marrow, a preferred site of overt metastasis in prostate cancer patients.

Topics: Adenocarcinoma; Androgen Antagonists; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Bone Neoplasms; Chemotherapy, Adjuvant; Combined Modality Therapy; Disease-Free Survival; Flutamide; Follow-Up Studies; Humans; Keratins; Leuprolide; Male; Neoplasm Proteins; Prognosis; Prostatectomy; Prostatic Neoplasms; Treatment Outcome; Ultrasonography

Chordoma is a well-known bone tumor that shows epithelioid features and in which the expression of cytokeratins (CKs) has been reported to appear very frequently. Numerous immunohistochemical analyses of CK expression have been conducted using such monoclonal antibodies as CAM5.2, which react with CK8, CK18, and CK19, and AE1/AE3, which react with CKs 1-8, 10, 14-16 and 19 in chordoma. No detailed analysis, however, of the expression of each component of CK has yet been conducted in chordoma; thus, the subsets of CK expressed there have yet to be clarified. With the use of immunohistochemical techniques with a panel of monoclonal antibodies against each subset of CK, the authors studied the expression of CKs in 16 specimens of classic chordoma and 14 specimens of the fetal notochord to clarify the subsets of CK expressed in chordoma and to evaluate the similarities and differences of CK expression between chordoma and the fetal notochord. All of the chordoma specimens showed a strong positive immunoreactivity for CK8 and CK19, whereas nine (56.3%) chordoma specimens showed a positive immunoreaction for CK18. In addition, four chordoma specimens were focally positive for keratin-903, which reacts with high molecular weight CKs such as CK1, CK5, CK10, and CK14; one specimen also showed a strong CK7 expression. All of the notochord specimens were also positive for CK8 and CK19, but none showed a positive immunoreaction for keratin-903, CK7, or CK18. In addition, none of the chordoma or notochord specimens showed immunoreactivity for CK20. The expression of CK8 and CK19, observed in all of the chordoma and notochord specimens, was thus considered to be maintained throughout the neoplastic transformation, although some aberrant CK expressions (CK7, CK18, and keratin-903) also occurred in the chordoma specimens examined in this study.

Topics: Adult; Aged; Bone Neoplasms; Child, Preschool; Chordoma; Female; Fetal Proteins; Humans; Immunohistochemistry; Keratins; Male; Middle Aged; Neoplasm Proteins; Notochord

Angiosarcoma of bone is a rare, high-grade sarcoma of vascular origin. This article describes an epithelioid angiosarcoma in the humerus of a 48-year-old man. A multilocular osteolytic lesion with undefined margins and destroyed cortical and medullary bone, associated with a large soft tissue mass was demonstrated radiologically in the proximal metaphysis of the right humerus. The tumor, resected by amputation, was composed mostly of proliferating malignant cells with an epithelioid morphology. It had a predominantly sheet-like growth pattern, and an occasional pseudoglandular or alveolar arrangement, mimicking an adenocarcinoma. The dilated anastomotic vascular spaces lined by epithelioid endothelial cells and the intracytoplasmic lumina/vacuoles that sometimes contained erythrocytes suggested focal endothelial differentiation. On immunohistochemical investigation, many neoplastic cells expressed cytokeratin and endothelial markers: factor-VIII related antigen, CD31, and UEA-I. The ultrastructure of the tumor was consistent with that of an angiosarcoma. Our patient died of disease shortly after the diagnosis, implying an aggressive clinical course. Awareness of the existence of skeletal epithelioid angiosarcoma, combined with the identification of intracytoplasmic lumina, or at least small vasoformative foci, and immunohistochemical positivity for endothelial markers provide the best guide for distinguishing this tumor from metastatic carcinomas.

Topics: Biomarkers, Tumor; Bone Neoplasms; Epithelioid Cells; Fatal Outcome; Hemangiosarcoma; Humans; Humerus; Immunohistochemistry; Keratins; Lectins; Male; Middle Aged; Plant Lectins; Platelet Endothelial Cell Adhesion Molecule-1; von Willebrand Factor

This article describes 11 cases of myxoid chondrosarcoma (MCS), with 10 arising in soft tissues and one developing in bone. Most of the tumors (six) were located in the lower extremities. Two lesions developed in the fingers, a previously unreported location for MCS. Four cases showed secondary bone destruction, which is a rare feature of this tumor. S100 protein was expressed by tumor cells in all the specimens. Four out of eight tumors studied by electron microscopy contained intracisternal microtubular structures. Two tumors showed areas of spindle cell proliferation that merged with the areas of typical myxoid pattern. The cells in these areas had fibroblastic/myofibroblastic features by electron microscopy and were found to express cytokeratin by immunohistochemistry. The concomitant expression of cytokeratin and S100 protein in the spindle cells suggests that they represent a less differentiated cartilaginous component with unusual features. The clinical significance of the presence of such spindle cell areas presently remains unknown. Although myxoid chondrosarcoma is a slow-growing tumor, it has a high potential for metastases. Four of 11 patients in this series developed metastases.

Topics: Adolescent; Adult; Aged; Bone Neoplasms; Chondrosarcoma; Endoplasmic Reticulum, Rough; Female; Fingers; Foot; Humans; Immunohistochemistry; Keratins; Male; Microscopy, Electron; Microtubules; Middle Aged; Radiography; Retrospective Studies; S100 Proteins; Soft Tissue Neoplasms

The correlative effects of taxol on the reduction of circulating PC-3 ML human prostatic tumor cells and bone metastasis have been examined in SCID mice. Normally, following injection of 2 x 10(5) cells i.v., the circulating levels in peripheral blood drop by about 50 and 100%, after 8 and 24 h, respectively. In contrast, in taxol-treated mice (40-60 mg/m2/injection given 0, 3, 7 and 23 h following injection of the cells) the numbers of circulating human prostatic PC-3 ML tumor cells were reduced by 100% at 8 h. In similar experiments were mice were injected with taxol 2 h prior to injecting the cells, dosages of 40 and 60 mg/m2/injection reduced circulating tumor cells about 91 and 100%, respectively, by 8 h. Alternatively, if PC-3 Ml cells were pretreated with taxol (0.5 and 1.0 microM for 8 and 24 h) prior to injection, tumor cell clearance by 7 h was also significantly increased (80-100%). Correlative studies showed that the incidence of bone metastases (observed after 40 days) was reduced significantly (a) in mice treated with 40 and 60 mg/m2/injection (i.e. from 73-80% in controls to 15-0% in treated mice) and (b) in mice injected with PC-3 ML cells pre-exposed to 0.5-1.0 microM taxol for 7 h. Immunofluorescence studies with tubulin antibodies showed that the microtubules were disrupted in cells exposed to taxol in vivo and in vitro under conditions that significantly increased cellular clearance from the blood. Taken together, the data suggests that taxol at nontoxic dosages (to mice) can prevent metastases by directly reducing the circulating levels of tumor cells.

Topics: Animals; Bone Neoplasms; Cell Survival; Humans; Idoxuridine; Keratins; Male; Mice; Mice, SCID; Neoplasm Metastasis; Paclitaxel; Prostatic Neoplasms; Transplantation, Heterologous; Tubulin; Tumor Cells, Cultured

Occult micrometastases detected by immunohistochemistry have prognostic significance in patients with localized breast cancer. To determine the usefulness of this technique and of polymerase chain reaction in detecting occult prostate cancer, we evaluated the sensitivity and specificity of immunohistochemistry and polymerase chain reaction amplification of mRNA to detect prostate cancer cells in bone marrow samples. We used cells from an established prostate cancer cell line (LNCAP) mixed with lymphocytes at various dilutions from 10(5) cancer cells in 10(6) lymphocytes to 1:10(6). Both techniques had a 100% specificity and identified cancer cells at all dilutions. Polymerase chain reaction was more sensitive than immunohistochemistry at the lowest dilutions (10(-5) and 10(-6), p = 0.033). We have evaluated seven patients with prostate cancer for micrometastases. Both of the patients with known metastatic prostate cancer and one of the five patients with clinically localized tumors had micrometastases. Detection of micrometastases may be useful in the staging of prostate cancer.

Topics: Base Sequence; Bone Marrow; Bone Neoplasms; Humans; Immunohistochemistry; Keratins; Male; Molecular Sequence Data; Poisson Distribution; Polymerase Chain Reaction; Prostate-Specific Antigen; Prostatic Neoplasms; RNA, Messenger; Sensitivity and Specificity; Tumor Cells, Cultured

Individual disseminated epithelial tumour cells were detected in bone marrow aspirates in 41 of 108 patients (37%) with squamous cell cancer of the head and neck region by an immunocytochemical technique based on monoclonal antibodies raised against the cytokeratin No. 19. In the clinical stage I (T1N0M0) tumour cells were detected only in 26.3% of the patients, whereas in stage IV (T4N0M0, T(all)N2-3M0, T(all)N(all)M1) almost twice as many patients (47.7%) presented with tumour cells in the bone marrow. Apparently, grade of differentiation of the tumour (grading) had no influence on the spread of single tumour cells. An influence of the different localisations of the primary tumour on tumour cell spread or the rate of tumour recurrence cannot as yet be discovered. Cytokeratin No. 19 expressing cells were not detectable in the bone marrow of 18 patients with non-malignant disease. Seventy-three patients were included in a follow-up study with a mean observation time of 25 months (range: 4-52 months). The presence of epithelial cells at the time of primary treatment appears to indicate a significantly higher risk of development of local or distant tumour recurrences (p = 0.01). Of 46 patients initially exhibiting no tumour cells in the bone marrow, only 14 had a clinical recurrence. Whereas 17 of 27 patients who presented with tumour cells in the bone marrow developed either a local tumour recurrence or distant metastases in different organs. Patients presenting with bone marrow tumour cells showed a significantly shorter disease-free survival than those without (p = 0.002).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Biomarkers, Tumor; Biopsy, Needle; Bone Marrow; Bone Neoplasms; Carcinoma, Squamous Cell; Head and Neck Neoplasms; Humans; Immunoenzyme Techniques; Keratins; Leukocyte Common Antigens; Neoplasm Recurrence, Local; Prognosis

A breast tumour in a 47-year-old female with axillary lymph node metastasis was interpreted as the rare malignant adenomyoepithelioma based on morphological and immunohistochemical studies. Multiple bone metastases developed and the patient died after 7 months. The malignant neoplasm consisted of cords and interlacing bundles of spindle cells with indistinct cell borders and clear cytoplasm. The cells stained positively for cytokeratin, S-100 protein, GFAP, and muscle-specific actin, and possessed basal lamina, pinocytic vesicles, tonofilaments, desmosomes, and intermediate filaments with dense bodies. In some areas, cells with microvillous projections enclosed small spaces. In the breast, foci of myoepithelioma with various morphological subtypes and infiltration coexisted, demonstrating the origin of the malignant tumour. The histogenesis of the myoepithelial tumours is discussed.

Topics: Biopsy; Bone Neoplasms; Breast Neoplasms; Female; Humans; Immunohistochemistry; Keratins; Lymphatic Metastasis; Microscopy, Electron; Middle Aged; Myoepithelioma

Monoclonal antibodies (mAbs) specific for cytokeratins are potent probes for the identification of disseminated individual epithelial tumour cells in mesenchymal organs such as bone marrow. We have used a monoclonal antibody (mAB) against cytokeratin 18 (CK18) for the detection of individual metastatic tumour cells in bone marrow aspirates from 84 patients with carcinoma of the prostate. CK18+ cells were detected in a sensitivity of 1 per 8 x 10(5) marrow cells using the alkaline phosphatase anti-alkaline phosphatase (APAAP) system for staining. We were able to detect CK18+ tumour cells in the marrow of 33% of patients with stage N0M0 prostate cancers. The incidence of CK18+ cells showed a significant correlation with established risk factors, such as local tumour extent, distant metastases and tumour differentiation. For further characterization of such cells in patients with prostate cancer, we developed an immunocytochemical procedure for simultaneous labelling of cytokeratin component no. 18 (CK18) and prostate-specific antigen (PSA). In a first step, cells were incubated with a murine mAb against PSA, followed by gold-conjugated goat anti-mouse antibodies. In a second step, a biotinylated mAb to CK18 was applied as primary antibody and subsequently incubated with complexes of streptavidin-conjugated alkaline phosphatase, which were developed with Newfuchsin substrate. The binding of gold-labelled antibodies was visualized by silver enhancement. CK18+ cells co-expressing PSA were found in bone marrow aspirates from 5 out of 14 patients with carcinomas of the prostate. The specificity of CK18 for epithelial tumour cells in bone marrow was supported by negative staining of 12 control aspirates from patients with benign prostatic hyperplasia (BPH).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Bone Marrow Diseases; Bone Neoplasms; Carcinoma; Cells, Cultured; Humans; Immunohistochemistry; Keratins; Male; Phenotype; Prostate-Specific Antigen; Prostatic Neoplasms; Staining and Labeling

Twenty-four cases of adamantinoma and 24 cases of osteofibrous dysplasia of the long bones were studied to evaluate the expression and distribution of cytokeratin (CK) subtypes in relation to histogenesis and differentiation. The immunohistochemical study was performed on tissue fixed in buffered formalin and embedded in paraffin wax utilizing antibodies to vimentin, factor VIII, epithelial membrane antigen and cytokeratins of different molecular weights. In all cases the vimentin antibody marked positively in stroma, endothelium and osteoblasts, while factor VIII expression was confined to endothelial cells. In 71% of adamantinomas, vimentin showed strong immunoreactivity in the tumour cells of nests and tubules. CKAE1/AE3 and CK19 were strongly expressed in all morphological patterns of adamantinoma emphasizing their epithelial origin, while the antibodies to CK8 and CK18 showed a high percentage of negative responses. In osteofibrous dysplasia the epithelial-like component was much smaller than in adamantinoma and was present in scattered islands composed of a few cell positive for CKAE1/AE3 and CK19 and negative for other keratins. These results suggest that these two lesions are of a similar histogenesis.

Topics: Ameloblastoma; Antibodies, Monoclonal; Bone Neoplasms; Female; Fibrous Dysplasia of Bone; Fibula; Humans; Immunohistochemistry; Keratins; Male; Tibia; Vimentin

Seventy-nine cases of small round cell tumors involving bone were studied in an attempt to learn whether the immunohistochemical features of the lesions might allow distinction of small cell osteosarcoma from other potential differential diagnostic considerations, including Ewing's sarcoma, atypical Ewing's sarcoma, primitive neuroectodermal tumor, mesenchymal chondrosarcoma, lymphoma, and the Askin tumor. The tissues studied were all formalin-fixed, decalcified, paraffin sections from patients between the ages of 16 and 48 years. With one exception (a small cell osteosarcoma), none of the lesions was cytokeratin positive. Moreover, none of the lesions was epithelial membrane antigen, desmin, factor VIII-related antigen, synaptophysin, or Leu-M1 positive. Accordingly, strong positivity for these antibodies in a majority of tumor cells should prompt inclusion of tumor types other than those listed above in the differential diagnosis. Vimentin positivity was seen in a majority of the tumors studied irrespective of histologic type. Scattered tumor cells (< 25%) showed positivity with antibodies to muscle-specific actin and smooth muscle actin in several of the different tumor types studied. No lesions other than lymphoma were leukocyte-common antigen (LCA) positive; all but two lymphomas were LCA positive, while all but one lymphoma were L26 positive. One (lymphoblastic) lymphoma was LCA and L26 negative. S-100, neuron-specific enolase, and Leu-7 did not prove to be specific for "neural-associated" tumors, but rather appeared in some small cell osteosarcomas, Ewing's sarcomas, atypical Ewing's sarcomas, primitive neuroectodermal tumors, mesenchymal chondrosarcomas, lymphomas, and Askin tumors. Antibody to cell surface antigen HBA71 was positive in three Ewing's sarcomas (two typical and one atypical) and negative in small cell osteosarcoma (three cases), mesenchymal chondrosarcoma (two cases), and lymphoma (one case). While some guidance may be derived from analysis of immunohistochemical staining patterns in a given lesion, the results reported in the present study do not suggest that routine immunohistochemistry alone will permit distinction of these small cell tumors of bone from one another. The value of immunohistochemical studies appears to lie particularly in the use of antibodies to LCA and S-100 protein to distinguish lymphoma and mesenchymal chondrosarcoma, and perhaps antibody to HBA71 to distinguish neural family lesions (such as Ewing's sarcoma)

Topics: Adolescent; Adult; Antigens, Differentiation; Bone Neoplasms; Chondrosarcoma, Mesenchymal; Desmin; Diagnosis, Differential; Humans; Immunohistochemistry; Keratins; Leukocyte Common Antigens; Lymphoma; Membrane Glycoproteins; Middle Aged; Mucin-1; Osteosarcoma; S100 Proteins; Sarcoma, Ewing; Sarcoma, Small Cell; Synaptophysin; von Willebrand Factor

Whether the peripheral ameloblastoma (PA) and intraoral basal cell carcinoma (BCC) are two different clinical entities or essentially the same lesion still remains unresolved. The immunophenotypes of neoplastic cells of peripheral and intraosseous ameloblastomas, ameloblastic carcinomas, and BCCs were studied using a panel of monoclonal/polyclonal antibodies and lectins. The major cytokeratins (CKs) of neoplastic cells of ameloblastomas were CKs 5 and 14, whereas co-expression of CKs 8, 18, and 19 was observed in the cells of the stellate reticulum-like areas. Metaplastic squamous and keratinizing cells found in follicular and acanthomatous variants of ameloblastomas expressed CKs 1 and 10, involucrin, and binding sites for the lectins Ulex europeaus agglutinin I and Helix pomatia agglutinin. beta 2-Microglobulin was uniformly negative in all cases of ameloblastomas and ameloblastic carcinomas studied. Cutaneous BCCs also demonstrated similar reactive patterns with the above-mentioned antigens. The most striking feature is the presence of a peritumorous band-like peanut agglutinin staining found in both BCCs and PAs but not in intraosseous ameloblastomas. This unique peanut agglutinin staining pattern of PA may be diagnostically useful for its histopathologic distinction from an intraosseous ameloblastoma that has infiltrated the soft tissue. The neoplastic cells of ameloblastomas express markers of less-differentiated epithelial cells. Despite differences in epithelial origins, PAs are tumors analogous to cutaneous BCCs.

Topics: Adolescent; Adult; Aged; Ameloblastoma; Antigens, Differentiation; beta 2-Microglobulin; Bone Neoplasms; Carcinoma, Basal Cell; Female; Humans; Immunoenzyme Techniques; Keratins; Lectins; Male; Middle Aged; Protein Precursors; Receptors, Mitogen; Skin Neoplasms; Soft Tissue Neoplasms

The combination of a primary osteosarcoma of bone with a second carcinomatous cell type has been recognized, although immunohistochemical studies currently have not been performed in an attempt to understand the histogenesis of such a tumor.. In this report, the authors performed immunohistochemical studies on a primary osseous carcinosarcoma. Using a biotin-streptavidin peroxidase conjugate technique, the expression of keratin, epithelial membrane antigen, and vimentin was analyzed.. The epithelial cells expressed cytokeratin and epithelial membrane antigen but did not express vimentin. The mesenchymal cells strongly expressed vimentin, and only rare cells expressed cytokeratin.. The clinical, morphologic, and immunophenotypic data in this instance strongly suggest divergent differentiation of a primitive multipotential uncommitted stem cell in a primary osseous tumor.

Topics: Adolescent; Bone Neoplasms; Epithelium; Humans; Keratins; Male; Membrane Glycoproteins; Mucin-1; Osteosarcoma; Vimentin

To gain more insight into the differentiation characteristics of the epithelial cells of the adamantinoma of the long bones, we studied the specific keratin immunoreactivity pattern using monoclonal antibodies on 34 primary, recurrent, or metastatic specimens of 22 patients. The results revealed the widespread presence of keratins 14 and 19 in all specimens studied; 74% showed immunoreactivity of keratin 5, and focal staining of keratin 17 was detected in 50%. Keratins 7 and 13 were found in three adamantinoma specimens. This keratin immunoreactivity pattern was independent of histologic subtype, despite marked variety in differentiation pattern, suggesting a common histogenesis for all subtypes of adamantinoma. Furthermore, the pattern was conserved both in local recurrences and in metastasis. The major pattern found in our study differs significantly from other bone and soft tissue tumors with known epithelial characteristics, e.g., synovial sarcomas, chordomas, and epithelioid sarcomas, in that it lacks immunoreactivity of keratins 8 and 18. Our results suggest a basal epithelial cell-like differentiation of adamantinomas.

Topics: Adolescent; Adult; Aged; Ameloblastoma; Antibodies, Monoclonal; Bone Neoplasms; Cell Transformation, Neoplastic; Child; Child, Preschool; Female; Humans; Immunohistochemistry; Keratins; Male; Middle Aged; Neoplasm Recurrence, Local

An immunocytochemical investigation has been carried out on five cases of chordoma (2 of the sacrum, 2 in the spheno-occipital bone and 1 in the parapharyngeal area) to study the expression of the 5 classes of intermediate filaments (IF): cytokeratin (CK), desmin (DES), GFAP, neurofilaments (NF) and vimentin (VIM). Our results show that constant coexpression of CK, NF and VIM does occur in chordomas, whereas DES and GFAP are not demonstrable in tumor cells. The three detected IF are invariably present in all cell types but not in intracellular vacuoles or in the extracellular mucoid substance. The pattern of immunoreactivity of chordomas appears very unique as very few other neoplasms demonstrate the simultaneous occurrence of 3 distinct IF. Only choroid plexus tumors have been shown to manifest CK-NF-VIM immunoreactivity. The complex immunophenotype of chordomas may be related to their supposed origin from the notochord which normally undergoes conspicuous changes in location and morphology during embryonal development. Such changes might require the contemporary presence of multiple IF; IF expression, in fact, is known to be related to cell function and morphology. Notochordal cells and their neoplastic counterpart may consequently express an IF pattern which reflects unique architectural and morphological variations occurring during embryonal and tumor growth. Together with the speculative value of the detection of CK, NF and VIM in chordomas, the unusual immunocytochemical pattern of these tumors might provide useful diagnostic tool in differential diagnosis.

Topics: Adult; Aged; Bone Neoplasms; Chordoma; Female; Humans; Immunoenzyme Techniques; Intermediate Filaments; Keratins; Male; Middle Aged; Retrospective Studies; Vimentin

A clinicopathological and immunohistochemical study of 12 cases of osteofibrous dysplasia (OFD), two cases of differentiated adamantinoma, and five cases of adamantinoma of long bones is presented. Although OFD and differentiated adamantinoma showed similar radiologic findings, differentiated adamantinoma was more likely to be a recurrent lesion than osteofibrous dysplasia and seemed to require a more extensive surgical procedure. Immunohistochemically, cytokeratin- and vimentin-positive cells were seen in both OFD and differentiated adamantinoma. The positive cells were scattered in the former, and were both scattered and nest-like in the latter. Both these lesions, however, were negative for epithelial membrane antigen. Excluding two cases of Ewing-like adamantinoma, the other three cases of adamantinoma were also positive for cytokeratin and vimentin. These results suggest that these three lesions share the same histogenetic origin. The two cases of Ewing-like adamantinoma differ from tibial adamantinoma in their radiological, histological and immunohistochemical aspects, and seem to constitute a distinct variant of adamantinoma with a different histogenesis.

Topics: Adolescent; Adult; Ameloblastoma; Bone Neoplasms; Cell Nucleus; Child; Cytoplasm; Epithelium; Female; Fibrous Dysplasia of Bone; Humans; Immunohistochemistry; Keratins; Male; Middle Aged; Osteoblasts; Osteoclasts; Radiography; Tibia; Vimentin

The most controversial aspect of osteofibrous dysplasia (OFD) is its possible histogenetic relationship to adamantinoma of long bone. Evidence is recently beginning to accumulate that OFD may be a reactive process to regressive adamantinoma. To verify the concept, 13 lesions of OFD were studied again by immunohistochemistry for cytokeratins of different molecular masses, as well as by conventional stainings. In addition, 2 adamantinomas and 6 fibrous dysplasias of the tibia were studied for reference. A small number of spindle- or ovoid-shaped cells scattered individually in the fibro-osseous stroma showed positive reactions for cytokeratins of 55-57 kDa in 2 lesions, and for those of 45-56.5 kDa in 8 lesions of 13 OFDs, although no definite epithelial island could be detected even by immunohistochemistry. Adamantinomas also showed single cytokeratin-positive cells dispersed in fibroblastic stroma, in addition to epithelial islands positive for cytokeratins of both 55-57 kDa and 45-56.5 kDa. All cases of fibrous dysplasia were negative for cytokeratins. During the observation, no case of OFDs progressed to classic adamantinoma. The present study, demonstrating the existence of an intermediate stage between "differentiated adamantinoma" and total elimination of adamantinomatous components, gives further support for the concept that OFD is a secondary reactive process to adamantinomatous tissue. In practice, the existence of single scattered cytokeratin-immunoreactive cells in otherwise typical OFDs may not indicate the truly malignant behaviour of classic adamantinoma, unless discrete epithelioid cell nests are also found.

Topics: Adolescent; Adult; Bone Neoplasms; Child; Child, Preschool; Female; Fibroma; Humans; Immunohistochemistry; Infant; Keratins; Male; Osteoma; Tibia

Five cases of a previously undescribed variant of epithelioid sarcoma are presented. This variant differs from the usual lesion in its absence of the typical necrobiotic nodular epithelioid pattern. It is instead composed of deceptively bland fibrohistiocytic and myoid cells arranged in a fibroma-like or dermatofibroma-like pattern with an affinity for osseous involvement. The clinical presentation, ultrastructural features, and presence of vimentin and low molecular weight keratin within the tumor cells justifies their designation as an epithelioid sarcoma variant.

Topics: Adolescent; Adult; Bone Neoplasms; Calcaneus; Diagnosis, Differential; Female; Femoral Neoplasms; Fibroma; Fingers; Histiocytoma, Benign Fibrous; Humans; Humerus; Keratins; Male; Neoplasm Recurrence, Local; Neoplasms, Multiple Primary; Sarcoma; Skin Neoplasms; Soft Tissue Neoplasms; Thigh; Tibia; Toes; Ulna; Vimentin

The clinical and morphological findings of 53 chondroblastomas in the files of the Bone Tumour Registry of Westphalia are presented. The mean age of all patients was 19.2 years. The male-to-female ratio was 1.5:1. Forty-two of the tumours (79.8%) were located in the long tubular bones and short tubular bones of the hands and were closely related to the growth plate. Six cases (11.3%) were found in the flat bones, 4 cases (7.5%) in the tarsal bones and 1 case (1.9%) in the craniofacial bones. The characteristic radiological feature of 44 investigated lesions was a mostly eccentric radiolucency with a geographic pattern of bone destruction and matrix calcifications. Periosteal reaction was evident in 9% of the cases. Most tumours demonstrate the typical morphological features of chondroblastoma, but 3 cases resembled a giant cell tumour. In 2 cases a haemangiopericytoma-like growth pattern was observed. Nine of the tumours had an aneurysmal bone cyst-like component. Vascular invasion was seen in 1 case. Immunohistochemically most cells in 30 of the cases and fetal chondroblasts in 3 cases were strongly positive with vimentin and S-100 protein. Collagen type II was positive in the chondroid matrix of the tumours and in fetal cartilage tissue; collagen type VI was present focally around individual tumour cells and was always seen in the chondroid matrix of the lesions and in fetal cartilage. These findings support the cartilaginous nature of these tumours. In paraffin sections, 46.6% of the cases revealed a distinct positive reaction of some tumour cells with the monoclonal cytokeratin antibody KL1 (molecular weight 55-57 kDa). Only 4 of them demonstrated a coexpression with the other monoclonal cytokeratin antibody CK (clone MNF 116, molecular weight 45-56.5 kDa). In paraffin sections all fetal chondroblasts were negative with both cytokeratin antibodies. Frozen sections of 3 tumours showed a strong positive reaction with both cytokeratin antibodies in many chondroblasts, indicating an "aberrant" cytokeratin expression. Osteoclast-like giant cells stained positive with leucocyte-common antigen (LCA) and with the macrophage-associated antibody KP1, but were negative with the other macrophage-associated antibody MAC 387. Recurrence rate was 10.7%. The clinical course of all tumours was benign.

Topics: Adolescent; Adult; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Biomarkers, Tumor; Bone Neoplasms; Child; Child, Preschool; Chondroblastoma; Collagen; Female; Humans; Immunohistochemistry; Keratins; Leukocyte Common Antigens; Male; Middle Aged; Radiography; S100 Proteins; Vimentin

The authors identified five leiomyosarcomas (LMS) in a review of 13 nonmatrix-producing spindle cell sarcomas of bone. Only two were initially recognized as LMS; the others had been diagnosed as malignant fibrous histiocytoma (two) and fibrosarcoma (one). The patients, four of whom were women, ranged in age from 32 to 70 years. Sites included proximal humerus (two), distal femur (two), and rib (one). All tumors presented with clinical and radiographic features consistent with a diagnosis of primary bone neoplasms, although one probably represented a solitary metastasis from a primary uterine LMS. Radiographs showed lytic bone destruction with a moth-eaten appearance, and three cases had soft tissue extension. Histologically, all tumors showed broad, interlacing fascicles of spindle cells with pleomorphic nuclei, frequent mitoses, and necrosis. Two cases had a focal storiform pattern and bizarre multinucleated cells, and two other cases had focally prominent osteoclast-like giant cells. Extensive immunoreactivity for muscle actin was seen in all cases and for desmin in three. In each case, electron microscopy showed definite smooth muscle differentiation including cytoplasmic filaments with densities. At this writing, two patients are free of disease (including the patient with a presumed metastasis), one is alive with locally recurrent disease, and two are dead of disease. Experience suggests that LMS of bone is a distinct clinicopathologic entity that may be more common than previously recognized. Application of immunohistochemistry and electron microscopy to nonmatrix-producing bone sarcomas should facilitate diagnosis of additional cases.

Topics: Actins; Adult; Aged; Bone Neoplasms; Combined Modality Therapy; Cytoplasm; Desmin; Female; Femur; Humans; Humerus; Immunohistochemistry; Keratins; Leiomyosarcoma; Male; Middle Aged; Neoplasm Recurrence, Local; Radiography; Ribs; Vimentin

Monoclonal antibodies (Mab) are potent probes to identify individual tumour cells or small tumour cell clusters in bone marrow. In the present study, various antibodies directed against either cell surface or intracytoplasmic antigens of epithelial cells were assessed for their ability to detect such cells in bone marrow of patients with breast, colorectal and gastric cancer. According to the presented data, monoclonal antibodies against intracellular cytokeratin (CK) components are superior in terms of specificity and sensitivity to antibodies reacting with epitopes of the cell membrane. Using a monoclonal antibody against the cytokeratin polypeptide 18 in connection with the alkaline phosphatase anti-alkaline phosphatase detection system (APAAP), we could detect tumour cells in bone marrow of 34 out of 97 patients with gastric cancer examined at the time of primary surgery. The incidence of positive findings was correlated to established risk factors, such as histological classification and locoregional lymph node involvement. Clinical follow-up studies on 38 patients demonstrated a significantly increased relapse rate in patients presenting with CK-positive cells in their bone marrow at the time of primary surgery. Thus the described technique may help to identify patients with gastric cancer carrying a high risk of early relapse.

Topics: Antibodies, Monoclonal; Antigens, Surface; Bone Neoplasms; Breast Neoplasms; Colorectal Neoplasms; Female; Humans; Keratins; Stomach Neoplasms

Chondroid chordomas are cartilage-rich neoplasms, most often located in the spheno-occipital region, that have a better prognosis than classic chordomas. The immunohistochemical features of 19 classic and chondroid chordomas were studied retrospectively using avidin-biotin-complex (ABC) immunoperoxidase histochemistry on formalin-fixed, paraffin-embedded tissue. Of the 19 tumors, all located in the spheno-occipital region, 5 exhibited predominantly chondroid morphologic features. The 14 classic chordomas showed the following pattern of antigen expression (percent of tumors positive): epithelial membrane antigen (EMA) 100%, AE 1/3 (a "cocktail" of monoclonal antibodies directed against low and high molecular weight epidermal cytokeratins) 100%, DP keratin (DPK) 100%, vimentin 100%, S100 86%, neuron specific enolase (NSE) 100%, carcinoembryonic antigen (CEA) 57%, and HMB-45 (an anti-melanoma-associated antibody) 57%. The five chondroid chordomas exhibited the following pattern: EMA 0%, AE 1/3 0%, DPK 0%, vimentin 100%, S100 100%, NSE 100%, CEA 0%, and HMB-45 0%. The focal, weak HMB-45 positivity (performed on the index case because of a clinical concern of metastatic melanoma) seen in 57% of the classic chordomas is a previously unreported finding. This finding suggests either that classic chordomas are capable of HMB-45 expression or that this antibody has broader reactivity than previously recognized. The lack of cytokeratin, EMA, and CEA expression by the chondroid chordomas is similar to chondrosarcomas as reported in the literature and dissimilar to the classic chordoma group. These immunohistochemical findings suggest that chondroid chordomas may more validly be classified as low grade chondrosarcomas.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Bone Neoplasms; Carcinoembryonic Antigen; Child; Chordoma; Female; Humans; Immunohistochemistry; Keratins; Male; Middle Aged; Phosphopyruvate Hydratase; Prognosis; Retrospective Studies; Vimentin

The present study is based on the histopathological and immunohistochemical examination of seven chondroblastomas, including one lung metastasis occurring 9 years after treatment. Chondroblastomas were shown to co-express vimentin, S-100 protein, neuron-specific enolase, and the epithelial markers recognized by CAM 5.2, EMA and a polyclonal cytokeratin antibody. The cytokeratins present in the tumour cells of the lung metastasis were characterized as cytokeratins 8, 18, 19 and, to a lesser extent, cytokeratin 7. The results suggest aberrant cytokeratin expression in chrondroblastomas.

Topics: Adolescent; Adult; Bone Neoplasms; Chondroblastoma; Female; Humans; Immunohistochemistry; Keratins; Male

A case of neuroendocrine lung tumor located beneath the pleura in a 71-year-old woman is reported. At autopsy, the tumor was found to have metastasized to the bones and liver without involving the hilar lymph nodes. Histologically, the tumor cells at the primary site and in the liver metastasis exhibited a carcinoid-like organoid structure, whereas pleomorphic giant cells were noted in the bone metastasis. The argyrophilic tumor cells were immunoreactive for neuron-specific enolase, chromogranin A, serotonin, calcitonin, calcitonin gene-related peptide, gastrin-releasing peptide, neuropeptide Y, gastrin, pancreatic polypeptide, glicentin, the alpha-subunit of human chorionic gonadotropin, keratin, epithelial membrane antigen, Leu M1 and carcinoembryonic antigen. Electron microscopy revealed abundant neurosecretory granules in the cytoplasm. This was considered to be a rare case of neuroendocrine lung tumor showing carcinoid-like histology at the primary site and large-cell transformation in bone metastasis.

Topics: Aged; Autopsy; Bone Neoplasms; Calcitonin; Calcitonin Gene-Related Peptide; Carcinoembryonic Antigen; Carcinoid Tumor; Cell Transformation, Neoplastic; Chorionic Gonadotropin; Chromogranin A; Chromogranins; Female; Giant Cell Tumors; Humans; Immunohistochemistry; Keratins; Lung Neoplasms; Membrane Glycoproteins; Microscopy, Electron; Mucin-1; Phosphopyruvate Hydratase; S100 Proteins; Serotonin

We report two cases of osteoclast-like giant cell tumour of urinary bladder associated with papillary transitional cell tumours. Both cases were morphologically identical to giant cell tumour of bone. The giant cells stained strongly for acid phosphatase which was resistant to tartrate digestion, a staining reaction typical of osteoclasts. In view of the ability of urinary bladder to induce metaplastic and neoplastic bone, we believe that these tumours may represent extraosseous giant cell tumours of bone.

Topics: Acid Phosphatase; Aged; Bone Neoplasms; Carcinoma; Carcinoma, Transitional Cell; Diagnosis, Differential; Giant Cell Tumors; Humans; Immunohistochemistry; Keratins; Male; Membrane Glycoproteins; Mucin-1; Muramidase; Osteoclasts; S100 Proteins; Urinary Bladder Neoplasms; Vimentin

In 95% of patients with primary breast cancer, the extent of metastases cannot be proven by conventional methods. Nevertheless, more than 50% of these patients have a relapse within five years. To improve the predictive value for recurrency, we examined bone marrow aspirates of 128 patients with primary breast cancer. Bone marrow aspirates from 2-6 sites of the skeleton (iliac crest and sternum) were taken as well as biopsies for histological examination. The immunohistochemical studies were carried out on interphase smears and stained with cytoceratin antibodies (PKK 1) and antibodies against tumor-specific antigen TAG 12 (12 H 12). All patients were screened for distant metastases (X-ray, ultrasound, bone scan). Tumor cells and micrometastases in bone marrow were detected in 41 patients (32%). Their presence was correlated to other prognostic factors (tumor size, lymph node status, oestrogen/progesterone receptors). The median duration of follow-up was 39.5 months. 14 patients (45%) in the tumor cell positive group relapsed, compared to only 4 out of 36 patients in the tumor cell negative group. In 29% we found bone metastases. The relapse free interval was shorter for patients with micrometastases (8 vs. 15.8 months). The presence of tumor cells in bone marrow aspirates detected at the time of primary surgery, is a useful prognostic factor and a good predictor of metastases and may help in selecting patients for systemic adjuvant treatment.

Topics: Antibodies, Monoclonal; Antigens, Neoplasm; Biomarkers, Tumor; Biopsy, Needle; Bone Marrow; Bone Neoplasms; Breast Neoplasms; Female; Follow-Up Studies; Glycoproteins; Humans; Keratins; Neoplasm Staging

Twenty chordomas from 20 patients, including 17 nonchondroid and three chondroid types, were studied with a variety of antibodies directed against cytokeratin (AE-1/3), epithelial membrane antigen, carcinoembryonic antigen, S100 protein, vimentin, alpha 1-antichymotrypsin, and lysozyme. All 17 nonchondroid chordomas stained for cytokeratin, and most (16) stained for epithelial membrane antigen. In contrast, two chondroid chordomas failed to stain for either cytokeratin or epithelial membrane antigen, while one of them did stain for both antigens. Sixteen of the 20 chordomas (80%) stained for S100 protein, including all three chondroid chordomas. Vimentin was found in six (30%), and alpha 1-antichymotrypsin in 16 chordomas (80%). Carcinoembryonic antigen and lysozyme were each found in two specimens (10%). While these findings basically agree with the immunohistochemical studies of other investigators, there are a few discrepancies. Most significant is the lack of epithelial markers in two of three chondroid chordomas located at the base of the skull. Possible reasons for the discrepancies are discussed.

Topics: Bone Neoplasms; Chordoma; Humans; Immunoenzyme Techniques; Keratins; Membrane Glycoproteins; Mucin-1; S100 Proteins

A malignant fibrous histiocytoma of the sacrum complicating the course of radiation therapy for endometrial carcinoma is presented. Although the tumor fulfilled the clinical, radiologic, and histologic criteria for a postirradiation malignant fibrous histiocytoma of bone, it also expressed cytokeratin. That this immunoreactivity reflected keratin synthesis by the tumor and not an unusual pattern of cross-reactivity with another intermediate filament such as vimentin is strongly suggested by the reproducibility of the immunoreactivity utilizing both polyclonal and monoclonal antibodies and extinction of the immunoreactivity following absorption of the primary antiserum with keratin proteins. This is the first reported instance of keratin expression by a malignant fibrous histiocytoma; it indicates that sarcomas apart from synovial sarcoma and epithelioid sarcoma may sometimes express this protein.

Topics: Aged; Bone Neoplasms; Female; Histiocytoma, Benign Fibrous; Humans; Immunohistochemistry; Keratins; Neoplasms, Radiation-Induced; Uterine Neoplasms; Vimentin

Dedifferentiated chondrosarcoma is a biphasic tumour, comprising well-differentiated chondrosarcoma and an anaplastic non-cartilaginous sarcoma juxtaposed but distinct from each other. Two cases of dedifferentiated chondrosarcoma, one primary and one recurrent, demonstrated muscle differentiation when studied with monoclonal antibodies to muscle specific actin, desmin and myoglobin. One of the tumours was also positive for cytokeratin, identified by AE1/AE3 and CAM 5.2 antibodies. Our findings are consistent with the concept that these tumours are capable of diverse patterns of morphological and immunophenotypic differentiation.

Topics: Adult; Anaplasia; Bone Neoplasms; Cell Transformation, Neoplastic; Chondrosarcoma; Female; Humans; Immunohistochemistry; Keratins; Middle Aged; Muscles; Pelvic Bones; Ribs

The relationship of "chordoid sarcoma" (CS) to chordoma and myxoid chondrosarcoma has been debated for several years. In order to reassess this issue, we studied 5 CS, 5 chordomas, and 3 skeletal myxoid chondrosarcomas ultrastructurally and immunohistochemically. By electron microscopy, CS demonstrated smooth cellular outlines, macular intercellular junctions, and cytoplasmic inclusions of matrix-like material. Chordomas displayed a closely similar fine structural appearance, but in addition contained small, membrane-bound, glycogen-containing inclusions. Skeletal myxoid chondrosarcomas resembled CS, except that the former lesions had spiculated cell membranes and lacked intercellular junctions. Immunohistochemically, all CS cases expressed vimentin and lacked cytokeratin (CK). Leu 7 and S100 protein were seen in four cases each of CS, and three of these tumors demonstrated diffuse or focal reactivity for epithelial membrane antigen (EMA). Similar phenotypic features were seen in chordomas, except that all of them stained diffusely for CK, as well as EMA. Skeletal myxoid chondrosarcomas expressed vimentin, S100, and Leu 7 uniformly, but were devoid of epithelial markers. In aggregate, these data support the classification of "chordoid sarcoma" as a form of chondrosarcoma, but reveal that it may exhibit an "epithelial" antigen in some cases.

Topics: Adult; Aged; Aged, 80 and over; Antigens, Neoplasm; Bone Neoplasms; Child, Preschool; Chondrosarcoma; Chordoma; Female; Humans; Immunoenzyme Techniques; Infant; Keratins; Male; Membrane Glycoproteins; Middle Aged; Mucin-1; S100 Proteins; Soft Tissue Neoplasms; Vimentin

Two cases of malignant rhabdoid tumor of the kidney (MRT) and two cases of bone metastasizing renal tumor (BMRT) were studied using electron microscopy and immunohistochemistry, in an attempt to evaluate the histogenetic relation to classical Wilms' tumor (2 cases). The two cases of MRT showed ultrastructural features of intermediate filament clusters in the cytoplasm. Vimentin, keratin, laminin, and peanut (PNA) lectin were immunohistochemically demonstrated in two cases of MRT. Tissue polypeptide antigen (TPA) was detected in one case. As for BMRT, the metastatic lesion exhibited numerous rosette-like structures of tumor cells. Vimentin was immunohistochemically demonstrated in one case, but no other antibodies were stained in two cases. Two cases of classical Wilms' tumor immunohistochemically demonstrated vimentin, keratin, PNA lectin, and TPA. MRT and BMRT fall within the broad spectrum of Wilms' tumors from the histogenetic aspect, but their clinical behavior is distinct.

Topics: Bone Neoplasms; Child; Creatine Kinase; Humans; Immunoenzyme Techniques; Isoenzymes; Keratins; Kidney; Kidney Neoplasms; Laminin; Lectins; Microscopy, Electron; Myoglobin; Peanut Agglutinin; Rhabdomyosarcoma; Sarcoma; Vimentin; Wilms Tumor

Ten cases of dedifferentiated chondrosarcoma (DCS) were immunohistochemically and histochemically compared with 12 de novo malignant fibrous histiocytomas, 10 osteoblastic osteosarcomas, 9 conventional chondrosarcomas, and 4 fibrosarcomas (all of bone or soft tissues), in order to discern similarities and differences in the immunophenotypes of these neoplasms. All cases of DCS and malignant fibrous histiocytoma were reactive for alpha-1-antichymotrypsin, and several examples of both tumor types bound peanut agglutinin, and expressed positivity for alpha-1-antitrypsin and lysozyme. None of these four cellular markers was observed in de novo osteosarcoma and fibrosarcoma; in addition, conventional chondrosarcoma lacked all of them except for peanut agglutinin receptors. S100 protein reactivity and binding of wheat germ agglutinin were detectable in conventional chondrosarcomas and in rare cells of the anaplastic components of primary DCS, but not in malignant fibrous histiocytoma arising ab initio and the other sarcomas. These results suggest the evolution of a second neoplastic cellular clone in DCS, with primitive morphological and phenotypic characteristics.

Topics: Adult; Aged; Aged, 80 and over; alpha 1-Antichymotrypsin; alpha 1-Antitrypsin; Bone Neoplasms; Chondrosarcoma; Female; Histiocytoma, Benign Fibrous; Histocytochemistry; Humans; Immunoenzyme Techniques; Keratins; Lectins; Male; Middle Aged; S100 Proteins; Vimentin

Topics: Adult; Aged; Antibodies, Monoclonal; Antigens, Neoplasm; Bone and Bones; Bone Neoplasms; Chordoma; Female; Humans; Immunoenzyme Techniques; Intermediate Filament Proteins; Keratins; Male; Middle Aged; Vimentin

This is a unique case of chondroid chordoma arising in the sacrococcygeal area of an asymptomatic man. S100 protein was detected in both chondroid and chordoid tissues; epithelial membrane antigen (EMA) and cytokeratin were present in abundant amounts in the cytoplasm of chordoma cells but not in chondroid cells. The presence of cytokeratin and EMA in chordoma implies the epithelial nature of the tumor and is extremely helpful as a differential marker for chordoma. I suggest that EMA, cytokeratin, and S100 protein should be used conjunctively to provide a resolution for difficult diagnostic problems when dealing with chordomas, especially with their variants, such as chondroid chordomas, which often cause further confusion.

Topics: Bone Neoplasms; Chordoma; Humans; Immunoenzyme Techniques; Keratins; Male; Middle Aged; S100 Proteins; Sacrococcygeal Region

A primary neoplasm of the proximal humerus in a 68-year-old woman was unique histologically in that it contained both malignant cartilaginous and squamous cell components. The epithelial differentiation was confirmed by the demonstration of keratin by immunohistochemical techniques and of basement membrane, tonofilaments, and well-formed desmosomes by electron microscopy. The patient died 3 1/2 years after the onset of symptoms, without clinical evidence of either a primary tumor elsewhere or metastasis. The differential diagnosis from other bone tumors with epithelial differentiation, such as adamantinoma and "primitive multipotential primary sarcoma," is discussed. This is a rare primary neoplasm of bone of unknown histogenesis. Intermutability or metaplasia between mesenchymal and epithelial tissues is a possibility. The tumor probably originated from multipotential stem cells with the ability to undergo biphasic or dual differentiation toward mesenchymal and epithelial elements.

Topics: Aged; Bone Neoplasms; Carcinoma, Squamous Cell; Chondrosarcoma; Female; Histocytochemistry; Humans; Humerus; Immunoenzyme Techniques; Keratins; Microscopy, Electron; Neoplasms, Multiple Primary; Radionuclide Imaging

Chordomas are rare slow-growing but locally invasive tumors. They are thought to develop from residues of the notochord. Three chordomas and ten chondroid tumors were investigated by an indirect immunoperoxidase method for expression of the epithelial markers: MAM-6, keratin, tissue polypeptide antigen (TPA) and for carcinoembryonic antigen (CEA). In all the chordomas investigated the antigens MAM-6, keratin and TPA were detected using monoclonal antibodies and conventional antisera, respectively. These data provide further evidence of the epithelial nature and the ectodermal origin of chordomas. Moreover, the findings suggest that immunohistochemical methods may be useful for the differential diagnosis between chordomas and morphologically similar chondroid tumors.

Topics: Antibodies, Monoclonal; Bone Neoplasms; Carcinoembryonic Antigen; Chondrosarcoma; Chordoma; Coccyx; Diagnosis, Differential; Humans; Immune Sera; Immunoenzyme Techniques; Keratins; Lumbar Vertebrae; Membrane Proteins; Mucin-1; Osteosarcoma; Peptides; Sphenoid Bone; Spinal Neoplasms; Tissue Polypeptide Antigen

Five cases of chordoma, diagnosed by fine-needle aspiration (FNA) biopsy, are presented. Four cases were histologically confirmed, and in one, immunocytochemical and ultrastructural studies were performed on both the aspirate and tissue specimen. Four cases presented as sacral masses, while in the fifth case, a destructive lesion of the clivus extended into the soft tissues of the lateral neck. A spectrum of cytomorphologic features was encountered including the presence of abundant microtissue fragments and cells in a dissociate pattern, often with abundant metachromatic extracellular matrix. Stellate and cuboidal cells often contained intracytoplasmic vacuoles of varying sizes. Intranuclear inclusions, mitotic figures, and anisonucleosis were prominent features of several cases. Immunoperoxidase studies on a single case demonstrated cytoplasmic staining for low- and high-molecular-weight cytokeratins, vimentin, and epithelial membrane antigen, while glial fibrillary acidic protein and carcinoembryonic antigen were negative. Ultrastructural features included the presence of mitochondrial endoplasmic reticulum complexes, occasional desmosome-like junctions, and abundant extracellular matrix adherent to the tumor cells. We believe the cytomorphologic findings are characteristic and, when taken in concert with immunocytochemical and ultrastructural studies, allow differentiation of chordoma from other primary or metastatic neoplasms occurring in bone. As demonstrated in our series, chordoma is often an unsuspected diagnosis. We believe that FNA biopsy of these lesions can lead to a correct preoperative diagnosis and may also be utilized to document recurrence and thus facilitate the evaluation and management of patients with these lesions.

Topics: Aged; Biopsy, Needle; Bone Neoplasms; Cervical Vertebrae; Chordoma; Female; Histocytochemistry; Humans; Immunoenzyme Techniques; Keratins; Male; Microscopy, Electron; Middle Aged; Sacrum; Spinal Neoplasms

The light microscopic, ultrastructural, and immunohistochemical characteristics of two tibial adamantinomas are presented. The immunohistochemical studies utilized specific antibodies against Factor VIII-related antigen and keratin protein, considered as markers for endothelial and epithelial cells, respectively. These revealed positive staining for keratin in the tumor cells of both cases, whereas Factor VIII was not found in either. Ultrastructurally, both tumors had tonofilaments, desmosomes, gap junctions, microvillous-like projections, and basement membranes. Patient 1 had disease that was histologically of the classic spindle cell type; the disease of Patient 2 was atypical and closely resembled an epithelioid angiosarcoma. Immunohistochemical and ultrastructural findings in each case indicate an epithelial component in tibial adamantinoma.

Topics: Adolescent; Ameloblastoma; Antigens; Bone Neoplasms; Factor VIII; Female; Histocytochemistry; Humans; Immunoenzyme Techniques; Keratins; Male; Microscopy, Electron; Tibia; von Willebrand Factor

Adamantinoma of the tibia was studied by electron microscopy and immunohistochemistry. The palisading tumor cell nests were invested with a continuous basal lamina. The peripheral tumor cells of the nests were bound to each other by desmosomes. Intermediate densities in the form of incomplete hemidesmosomes were seen in the outermost cells of the nests. There were two types of cytoplasmic filaments--tonofilaments and actinlike microfilaments. The latter occurred predominantly in the cytoplasm beneath the plasma membrane of the outermost cells of the nests. This could be implicated in the motile and invasive properties of the tumor cells. Immunohistochemic stains localized keratin in most tumor cells. Coagulation factor VIII-related antigen was localized in the endothelial cells of the stroma but not in the tumor cells. These findings indicate the appendicular adamantinoma to be of ectodermal epithelial origin, most likely a variant of basal cell carcinoma.

Topics: Aged; Ameloblastoma; Antigens; Bone Neoplasms; Cytoskeleton; Factor VIII; Histocytochemistry; Humans; Keratins; Male; Microscopy, Electron; Tibia; von Willebrand Factor

The nature of the neoplastic cells in a case of adamantinoma of the tibia was studied with an immunocytochemical method. The antigens investigated were factor VIII-related antigen and keratin, as markers for endothelial cells and epithelial cells, respectively. The tumor cells of adamantinoma stained strongly for keratin but were completely negative for factor VIII-related antigen. These results strongly suggest that cells of tibial adamantinomas are of epithelial rather than endothelial nature, thus confirming previous light-microscopic observations and electron-microscopic studies performed on this tumor. Although the negativity for factor VIII-related antigen does not rule out by itself the presence of an endothelial component, the fact that the tumor cells are positive for keratin makes this possibility highly unlikely. Additional cases of this entity should be studied with these cytoplasmic markers in order to confirm the findings here presented.

Topics: Adult; Antigens; Bone Neoplasms; Bone Transplantation; Cell Differentiation; Epithelial Cells; Factor VIII; Humans; Immunoenzyme Techniques; Keratins; Male; Tibia