Hepatocyte growth factor and c-MET in benign and malignant peripheral nerve sheath tumors

Hepatocyte growth factor (HGF), secreted by mesenchymal cells, has pleiotropic biological activities on several cell types. HGF and its receptor, the c-met proto-oncogene product (c-MET) have been implicated in the genesis and progression of several carcinomas and sarcomas. It has been suggested that MET/HGF autocrine signaling may contribute to tumorigenesis in sarcomas. HGF has been recently found to be a mitogen for rat Schwann cells and to be present in neurofibromas in NF1 patients. In this investigation, we assessed the immunoreactive patterns of HGF and MET in benign and malignant peripheral nerve sheath tumors (PNST) using archival formalin-fixed tissue. The standard avidin-biotin-peroxidase method was used. All benign tumors were negative with HGF. Eight cases of MPNST were positive with both HGF and MET. In some malignant PNST, positivity with both ligand and the receptor may be indicative of an autocrine mediated signal transduction and may implicate HGF/MET in tumor progression. Immunoreactivity with MET was strikingly greater in MPNST in contrast to benign PNST; this finding may prove to be helpful in distinguishing some histologically low-grade MPNST from cellular and atypical benign PNST.     

MR imaging of edema accompanying benign and malignant bone tumors

To evaluate the incidence, quantity, and presentation of intra- and extraosseous edema accompanying benign and malignant primary bone lesions, the magnetic resonance (MR) studies of 63 consecutive patients with histologically proven primary bone tumors were reviewed. MR scans were assessed for the presence and quantity of marrow and soft tissue edema and correlated with peroperative findings, resected specimens and follow-up data. The signal intensity and enhancement of tumor and edema prior to and after intravenous administration (if any) of gadolinium-labeled diethylene triamine pentaacetate (Gd-DTPA) was analyzed. Marrow edema was encountered adjacent to 8 of 39 malignant tumors and 14 of 24 benign lesions. Soft tissue edema was found accompanying 28 of 39 malignancies and 10 of 24 benign disorders. On unenhanced T1-weighted MR images tumor and edema were difficult to differentiate. Tumor inhomogeneity made this differentiation easier on T2-weighted sequences. In 36 patients the contrast medium Gd-DTPA was used. Edema was present in 27 of these patients and the respective enhancement of tumor and edema could be compared. Edema always enhanced homogeneously, and in most cases it enhanced to a similar degree as or more than tumor. Marrow and, more specifically, soft tissue edema is a frequent finding adjacent to primary bone tumors. The mere presence and quantity of marrow and soft tissue edema are unreliable indicators of the biologic potential of a lesion. Unenhanced MR scans cannot always differentiate between tumor and edema, but the administration of Gd-DTPA is of assistance in differentiating tumor from edema.(ABSTRACT TRUNCATED AT 250 WORDS)     

Tumor endoprosthesis in malignant bone tumors

In the Department of Orthopedics at the University of Vienna, tumor endoprostheses have been implanted after resections of tumors of the upper extremities since 1974 and of the knee joint since 1976. For replacement of the humerus after tumor resection, a system of modular tumor endoprostheses was developed very early. Initially, it was ceramic and later on made of titanium alloys, which were also implanted in combination with custom-made prostheses with cementless stem-plate fixation in 57 patients until February 1990. In 43 of these patients (75.4%) adequate resection (2 radical and 41 wide) had been performed. Of 49 patients with a follow-up period of at least 24 months, 36 patients had a mean disease-free survival time of 106.1 months. Between 1976 and 1981, 16 custom-made endoprostheses were used after tumor resection of the knee joint. Since 1982 we have used a modular system of tumor endoprostheses suitable for replacement of the proximal and distal femur, proximal tibia, total femur and total knee joint. Of 75 patients who had been operated on up to February 1990, 67 patients (89.3%) had undergone adequate resection (2 radical and 65 wide). Out of 32 of these patients, 24 (75%) exhibited a disease-free survival time of at least 24 months (mean 48.2 months). Out of 213 patients with resection/reconstruction (160 endoprostheses), 77.8% had a survival time of at least 24 months, a results which is considerably better than in 146 patients with amputation in which case the respective value was 69.4%.(ABSTRACT TRUNCATED AT 250 WORDS)     

Telomerase activity in the differentiation of benign and malignant adrenal tumors

BACKGROUND: Telomerase is an RNA-dependent DNA polymerase that extends the ends of chromosomes by synthesizing the 6 oligonucleotide repeat TTAGGG and thus serves as a marker for cellular immortality. Although absent in most adult somatic tissues, telomerase activity is present in stem cells and is reactivated in nearly all primary human malignancies. In this study we sought to determine whether tumors of the adrenal glands contain telomerase activity and whether telomerase activity can be used to differentiate benign and malignant tumors of the adrenal glands. METHODS: Tissue was obtained from 23 specimens at adrenalectomy. Adjacent normal adrenal tissue was obtained for control. All specimens were rapidly frozen and stored at -80 degrees C until assay. Telomerase activity was determined by the telomeric repeat amplification protocol (TRAP). RESULTS: Telomerase activity was present in 5 of 23 (22%) of the adrenal tumors. All 3 malignant tumors were strongly TRAP positive. There was a single cortical adenoma that had very weak telomerase activity. The single TRAP-positive tumor of the adrenal medulla was a ganglioneuroma. CONCLUSIONS: Benign adrenal tumors infrequently contain telomerase activity, whereas telomerase reactivation appears to be common in malignant tumors of the adrenal glands. These data suggest that determination of telomerase activity may offer a novel way to facilitate the differentiation of benign and malignant adrenal tumors.     

The neuronal marker protein gene product 9.5 (PGP 9.5) is phenotypically expressed in human breast epithelium, in milk, and in benign and malignant breast tumors

The aim of this study was to examine the expression of the well-established neuronal marker protein gene product 9.5 (PGP 9.5) in nonneuroendocrine tissues of the human breast. Using antibodies directed against PGP 9.5 in an immunohistological technique, a positive staining of nerves and, surprisingly, a positive cytoplasmic reaction were obtained in normal breast epithelium, in all cases of fibroadenomata (n = 7) and in carcinoma cells in 5 out of 16 cases of breast cancers. In screening several human breast cancer cell lines, a positive immunoreaction was observed in 4 out of 6 of the cell lines. To exclude the possibility that this immunoreactivity was false, positive lysates from the same cell lines and preparations from human breast milk were subjected to NaDodSO4-polyacrylamide gel electrophoresis and Western blotting. This study confirmed the presence of PGP 9.5 in both milk and breast cancer cell lines. Because any contamination with nerve fibers can be excluded having used cell culture material or milk, it can be concluded that the presence of PGP 9.5 in the normal epithelium and in breast cancer cells is genuine. PGP 9.5 expression is, therefore, a feature of normal breast epithelia and breast cancer cells and cannot be regarded as 'neuron' specific.     

Special diagnostic problems in primary malignant bone tumors

The diagnosis of primary malignant bone tumors, which only account for 1% of malignancies in humans, represents quite a challenge for the pathologist. Apart from the often overlapping morphology between different entities, heterogeneity within one and the same tumor has to be kept in mind. Furthermore, in most cases the diagnosis must be established based on small biopsy specimens and occasionally even on frozen sections. In this context detailed clinical information including the patient's age and exact localization of the tumor, as depicted by X-ray or MRI, are essential requirements for a correct diagnosis. In addition, multiple biopsies from different tumor sites may be of help. For example, 25% of osteogenic sarcomas (OSA) are chondroplastic. Others may contain areas similar to fibrosarcoma (FSA) or malignant fibrous histiocytoma (MFH). Since 90% of OSA occur in the second decade of life whereas chondrosarcomas, FSA and MFH usually manifest after the age of 40 years, a biopsy solely composed of malignant chondromatous tissue obtained from a tibial lesion of a 10-year-old child should most likely be considered as part of an OSA. In the differential diagnosis of the so-called small, round cell tumors, which include Ewing sarcoma, malignant lymphoma and small-cell OSA, immunohistochemical staining of the paraffin-embedded material and a molecular biological/genetic work-up of frozen material are most helpful. In this paper the histomorphological characteristics and criteria for differential diagnosis of the most common primary malignant bone tumors are discussed.     

Surgical approaches to benign and malignant tumors of the ampulla of vater

Ampullary tumors include a diverse group of benign and malignant neoplasms. A surgical approach to their management was initiated in 1899 by Halsted and continues to evolve. Surgical options include a spectrum of operative procedures designed to relieve symptoms and to remove malignant or potentially malignant tumors. This article discusses the issues relevant to ampullary tumor management with emphasis on the currently accepted and controversial aspects of the surgical approach.     

Organization of type III collagen in benign and malignant ovarian tumors. An immunohistochemical study

BACKGROUND: Abnormal interaction with the extracellular matrix is a basic property of malignant cells. Type III collagen is a major constituent of the extracellular matrix of soft tissues. METHODS: Deposition of the aminoterminal propeptide of type III procollagen (PIIINP) was studied in benign (n = 41), borderline (n = 4), and malignant (n = 32) human ovarian tumors using the avidin-biotin-immunoperoxidase technique and affinity-purified antibodies to human PIIINP: It was then compared with the serum PIIINP concentrations of the patients at the time of operation. RESULTS: In malignant tumors, the distribution of PIIINP was irregular both close to the epithelial cancer cells and further away, in the stroma. Another feature typical of malignant tumors was the varying staining intensity of the PIIINP-positive fibers. The benign tumors were characterized by a regular organization and an intensive staining of PIIINP: Borderline tumors showed a slightly decreased staining intensity and altered PIIINP distribution. A significant positive correlation was found between the PIIINP concentration in serum and the degree of irregularity in the distribution of PIIINP: CONCLUSIONS: These preliminary results indicate that malignant transformation in ovarian tumors is associated with disintegration of adjacent collagenous structures and with alterations in type III procollagen metabolism, which also leads to increased serum PIIINP levels. They suggest that biochemical or immunohistochemical detection of the PIIINP antigen could be clinically useful in ovarian tumors.     

OraTest. A new method for differentiating between benign and malignant oral tumors

Recent cloning and expression studies have revealed that the opioid mu-, delta-, kappa- and orphan receptors are seven-transmembrane domain receptors whose actions are mediated through activation of guanine nucleotide binding protein (G-protein). The activation of G-proteins by the opioid receptor can be measured by assessing agonist stimulation of membrane binding of the non-hydrolyzable analog of guanosine triphosphate (GTP), guanosine-5'-O-(3-[35S] thio) triphosphate ([35S] GTP gamma S). Our recent data suggest that 1) the level of spinal mu-, delta-, kappa- and orphan-receptor agonist-stimulated [35S] GTP gamma S binding closely parallels that of receptor binding densities, 2) the neuroanatomical distribution of opioid agonist-stimulated [35S] GTP gamma S binding relates to receptor binding distribution, 3) newly isolated opioid peptides, endomorphin-1 and -2, can activate G-proteins by specific stimulation of mu-receptors and act as partial agonists with moderate catalytic efficacies, 4) mu-receptor densities could be rate-limiting steps in the G-protein activation by mu-agonists in the spinal cord region. In conclusion, opioid agonist-stimulated [35S] GTP gamma S binding can provide a functional method to localize receptors not only by their ability to bind ligands, but also according to their ability to activate an intracellular signal transducer.     

Expression of sialosyl-Tn antigen (monoclonal antibody MLS102 reactive) in normal tissues and malignant tumors of the digestive tract

Oncogenic transformation is often associated with changes in the glycosylation state of malignant cells. We investigated the immunohistochemical localization of sialosyl-Tn antigen [O-linked NeuAc(alpha 2-->6)GAINAc] using a novel monoclonal antibody MLS102 in normal and malignant digestive-tract tissues. In normal tissues, weak MLS102 immunoreactivity was observed in the epithelium of the esophagus, stomach and colon. However, MLS102 immunoreactivity was strong in the goblet cells of the duodenum, but not in the Brunner glands. In carcinomas of the esophagus, stomach, colon, pancreas and biliary tract, positive staining was detected with a high frequency (80%-100%). In mucinous carcinomas and signet-ring cell carcinomas, malignant cells themselves and the mucins they secreted were strongly positive for sialosyl-Tn antigen. There was no significant correlation between the frequency of expression of sialosyl-Tn antigen and the degree of differentiation (grade). However, in the case of well-differentiated adenocarcinomas, sialosyl-Tn antigen was found mainly in the supranuclear areas (Golgi area), on the apical surface and in the adjacent cytoplasm. In poorly differentiated adenocarcinomas, the antigen was often detected in the whole plasma membrane and cytoplasm. Therefore, monoclonal antibody MLS102 may be useful in further elucidating the characteristics of digestive-tract cancers, and possibly in their treatment.     

Functional analysis of trk proto-oncogene product in medulloblastoma cells

MED-L cells with the 75 kd low-affinity nerve growth factor receptor (p75NGFR) and MED-H cells with the proto-oncogene tropomyosin receptor kinase product (p140trk) were isolated selectively from a parent MED-3 cell line derived from cerebellar medulloblastoma by panning, and the interaction of nerve growth factor (NGF) with these cell lines was analyzed. NGF treatment induced neuronal differentiation, growth inhibition, and tyrosine phosphorylation of p140trk in MED-H cells, but not in MED-L cells. Medulloblastoma cells express the functional NGFR, p140trk, which regulates their differentiation and growth.     

Type IV collagenase (M(r) 72,000) expression in human prostate: benign and malignant tissue

The expression of type IV collagenase (M(r) 72,000) has been examined in tissues from patients with benign prostatic hyperplasia (6 patients) and varying Gleason grades of malignant prostate cancer (18 patients). Immunoperoxidase labeling indicated that expression of the type IV collagenase was weak or nonexistent in benign tissue but consistently strong in the glandular and ductal epithelial cells of prostate tumors diagnosed at Gleason grades 1-8. In moderate to advanced cancer (i.e., Gleason grades 2 to 8), invasive tumor foci in the stromal tissue produced relatively modest amounts of type IV collagenase. The normal stromal tissue (i.e., fibroblasts) uniformly failed to produce detectable levels of type IV collagenase in the 24 patients examined. Northern and quantitative slot blot hybridization assays demonstrated that collagenase type IV mRNA levels were low in benign tissue and high in malignant tumors. In contrast, the stromal cells did not express significant amounts of type IV collagenase mRNA. Enzyme-linked immunosorbent assays demonstrated that the amounts of type IV collagenase protein correlated directly with the mRNA levels in the tumor tissue. The studies suggest that type IV collagenase may be selectively overexpressed by malignant, preinvasive prostatic epithelial cells.     

Use of extendable total femoral replacements in children with malignant bone tumors

Although rarely required, extendable reconstruction devices for replacing the entire femur offer children with malignant bone tumors the opportunity of a nearly normal development by overcoming an expected leg length discrepancy. Femoral integrity can be restored, allowing most patients to walk without the use of aids. There are no data available to provide evidence regarding long term results and morbidity in such patients. Six patients (range 2-12 years of age), three with osteogenic osteosarcoma and three with Ewing's sarcoma, were treated between 1988 and 1996 with custom made Stanmore extendable prosthetic total femoral replacements. One patient died 12 months after surgery because of complications relating to pulmonary metastasis. The remaining five patients were observed between 2.7 and 8.9 years (average, 5 years). No tumor recurrence has been recorded and no amputation has been performed. All surviving patients underwent an average of 9.4 operative procedures (range, 4-16 procedures) including 6.4 extension procedures (range, 3-10 procedures), and one prosthetic revision (range, 0-3 procedures). Five revisions in two patients were necessary because of infection, loosening of the prosthesis, mismatch between femoral head and acetabulum, or full extension of the extending mechanism. The functional results were measured in accordance with the Musculoskeletal Tumor Society rating score, with an average result of 77.3%. Total femoral replacement in a growing individual achieves good functional results yet has various risks for an uncertain outcome. Careful selection of the patient and realistic appraisal of the long term prospects are essential for successful treatment.     

Expression of two morphologic parameters concerning tumor-stroma interaction in benign and malignant melanocytic skin lesions

BACKGROUND: The 13C-urea breath (13C-UBT) test value is (semi-)quantitatively related to Helicobacter pylori density in the gastric antrum, and the value correlates with the grade of gastritis. The aim of this study was to assess variation of the 13C-urea breath test value by sociodemographic factors in H. pylori-positive children. METHODS: The analysis was performed on 127 asymptomatic children (aged 5-7 years) who were identified as H. pylori-positive with the 13C-UBT test in a large population-based epidemiologic study in the city of Ulm (southern Germany). The parents of the children were asked to fill out a standardized questionnaire about sociodemographic data. RESULTS: Forty-two infected children (33.1%) were of German nationality, 47 children (37.0%) were of Turkish and 38 children (29.9%) were of another nationality. Turkish children had a significantly higher 13C-UBT value (geometric mean = 27.2%) than German children (16.7%) or children with another nationality (19.3%) (P < 0.001). Girls had a trend towards higher values than boys (P = 0.058 after adjustment for nationality). Body mass index, education of the parents, and prior use of antibiotics were unrelated to the extent of the 13C-UBT. CONCLUSIONS: This study identified significant variation in the extent of the 13C value by nationality among H. pylori-infected children. Further studies are needed to elucidate the causes and potential consequences of these variations.