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PubMed2006

p53 plays a central role in UVA and UVB induced cell damage and apoptosis in melanoma cells.

We investigated whether p53 plays a role in UV induced apoptosis in melanoma. UVA and UVB induced apoptosis in dose dependent and wild type p53 melanoma cells were much more vulnerable than the mutant cells, indicating that p53 played a role in UV-induced apoptosis in melanoma. No difference in p53 expression pattern between the primary and matched metastatic melanomas was noticed in tumour tissue or cell lines from the same patients. Our findings indicate that expression of p53 plays a role in UV-induced apoptosis in melanoma cells, but not important in melanoma progression from primary to metastasis.

Apoptosis↗
PubMed2005

Cathepsin D expression in renal cell cancer-clinical implications.

BACKGROUND: Whereas the expression of Cathepsin D (Cath D) is suggested to enhance the biological aggressiveness of human malignancies, its role in renal cell carcinoma (RCC), however, has not been investigated. METHODS: By tissue microarray analysis, tumor and benign tissue samples from 176 RCC patients were investigated for Cath D expression by immunohistochemistry and Western blots. Expression levels were correlated to clinical variables and to the postoperative outcome. RESULTS: High Cath D expression levels were detected in 29%/9% of tumor and benign tissue samples, respectively (p < 0.0001). In case of a high vs. low Cath D expression level, development of distant metastases was observed in 12% vs. 88% of cases (p < 0.05). With a median follow-up of 50 (2-146) months, high level Cath D expression was correlated with an improved long-term survival when compared with patients presenting with decreased expression [median long-term survival: 82 vs. 53 months in case of a high vs. low expression level] (p < 0.05). CONCLUSIONS: The Cath D staining pattern predicted a reduced risk for metastatic spread and tumor dependent death, hereby indicating its role as a biological variable revealing additional prognostic information for renal cell cancer patients. Increased expression of Cath D in tumor vs. benign tissue samples might indicate a role for the development and progression of RCC.

Biomarkers, Tumor↗
PubMed2004

Mucinous borderline ovarian tumors: points of general agreement and persistent controversies regarding nomenclature, diagnostic criteria, and behavior.

This report focuses on the borderline category of ovarian mucinous tumors and summarizes the points of general agreement and persistent controversies identified by experts in the field who participated in the Borderline Ovarian Tumor Workshop held in Bethesda, MD, in August 2003. Points of agreement and persistent controversies regarding nomenclature, diagnostic criteria, and behavior are addressed for the following ovarian mucinous tumor categories: mucinous borderline ovarian tumor (M-BOT; synonymously referred to as atypical proliferative mucinous tumor of ovary or mucinous ovarian tumor of low malignant potential), M-BOT with intraepithelial carcinoma, and M-BOT with microinvasion. The morphologic spectrum of M-BOTs with regard to distinction from mucinous cystadenoma and the confluent glandular/expansile type of invasive mucinous carcinoma is also addressed. Non-ovarian mucinous tumors, including the secondary ovarian mucinous tumors associated with pseudomyxoma peritonei and metastatic mucinous carcinomas with a deceptive pattern of invasion, are recognized as tumors that can simulate primary M-BOTs. Improved classification of these mucinous tumors has clarifed the behavior of true M-BOTs by excluding these simulators from the M-BOT category.

Cystadenocarcinoma, Mucinous↗
PubMed2006

Ovarian serous carcinoma presenting with mediastinal lymphadenopathy 20 months before the intraabdominal mass: role of immunohistochemistry.

INTRODUCTION: Metastatic involvement of the mediastinal lymph nodes is an extremely uncommon finding in epithelial ovarian cancers. CASE REPORT: A 63-year-old woman was admitted to hospital for dyspnoea due to an anterior mediastinal mass. The surgical biopsy showed a 6-cm metastatic lymph node with a papillary pattern, scattered psammomas and immunoreactivity for WT1, Cytokeratin 7, EMA and negative for E-cadherin, GCFDP-15, Thyroglobulin, Cytokeratin 20, Cytokeratin 5/6, CEA, Vimentin, Calretinin, TTF1. After 20 months a follow-up CT identified an ovarian mass with the same histological pattern and immunoreactivity of the mediastinal nodule. RESULTS: Immunohistochemistry, especially WT1, is useful in assessing the ovarian origin of an unusual metastasis particularly if it is the first presentation of the disease.

Diagnosis, Differential↗
PubMed1988

Interactions between bladder tumor cells as tumor spheroids from the cell line J82 and human endothelial cells in vitro.

Multicellular tumor spheroids (MCTS) are a reliable model of nonvascularized tumor cell aggregates showing a well defined three-dimensional growth pattern and are comparable with small metastatic cancer cell complexes in blood circulation. In the present study we have established a co-culture system of multicellular bladder tumor spheroids with human endothelial cells on extracellular matrix (ECM) in order to investigate morphological and proliferative changes of endothelial and tumor cells within a defined time of cell-cell interaction. The MCTS--endothelial cell--extracellular matrix complex was observed within coculture periods from 1/2 to seven days. Morphological changes (light microscopy, scanning and electron microscopy) indicated that MCTS are not influenced by cocultured endothelial cells. The tumor cells invaded into the ECM after degradation of endothelial cells in the center of the contact zone. Endothelial cells, however, showed degenerative changes as well as a complex reaction in their proliferation activities. We could recognize an initial increase of proliferation of endothelial cells next to the MCTS. Later on, endothelial cells next to invading tumor cells showed changes in morphological polarity. The model system used has the advantage of using human tumor tissue. It distinguishes between basic cellular mechanisms like adherence, migration, DNA synthesis and proliferation in the study of the contact of tumor cells and vascular endothelial cells as an important event in hematogenous tumor spread.

Cell Communication↗
PubMed1986

Vascular changes associated with growth of primary and transplantable pancreatic adenocarcinomas induced in Syrian golden hamsters by N-nitrosobis(2-oxopropyl)amine (BOP) and N-nitrosobis(2-hydroxypropyl)amine (BHP).

Microangiographic and histological methods were used to characterize vascular structure of primary and transplantable pancreatic adenocarcinomas induced by propylnitrosamines in Syrian golden hamsters. Originally of well-differentiated tubular morphology, serial transplantation subcutaneously to the back region was not associated with change in histopathological pattern or increase in invasive or metastatic potential. In contrast, pancreatic subserosal grafts displayed prominent invasion of surrounding tissues. Whereas primary tumors induced by N-nitrosobis(2-oxopropyl)amine (BOP) and those transplanted subserosally were characterized by hypovascularity, subcutaneous transplantation resulted in hypervascular tumors. Encasement, which is defined as invasion of normal arteries by the tumor, showing uneven caliber, irregular outline, appeared on earlier microangiographic findings rather than luminal irregularity, which is change of tumor vessels in neovascularization and occurs in tumor blood vessels subsequent to transplantation. The vascular component of subcutaneously transplanted tumors had a total vessel length ranging from 9.2 +/- 0.7 mm to 18.1 +/- 1.1 mm, a total vessel surface from 2.5 +/- 0.4 mm2 to 9.3 +/- 0.6 mm2 and a total vessel volume from 0.07 +/- 0.02 mm3 to 0.49 +/- 0.04 mm3, indicating that the vessels were of relatively large diameter and short length.

Adenocarcinoma↗
PubMed1997

Expression of MAGE genes in ocular melanoma during progression from primary to metastatic disease.

Primary melanomas that form within the eye have a unique pattern of disease progression as compared with melanomas that form within the skin. A high percentage of patients (approximately 50%) develop metastatic tumors that occur predominately in the liver. An unusual characteristic of ocular melanomas is the prolonged disease-free interval that extends for many years between the development of primary and metastatic tumors. It is estimated that the shortest interval between dissemination of tumor cells from the eye and the appearance of clinically detectable metastases is 6 years. A recent report indicated that fresh uveal melanoma tissue and metastatic tumor biopsies failed to express melanoma antigen gene (MAGE)-1, MAGE-2, or MAGE-3. In the present study, we examined the expression of MAGE genes on fresh and cultured tumor cells obtained from an ocular melanoma patient during different stages of progressive disease. MAGE gene expression was determined by reverse transcription-polymerase chain reaction using MAGE-1, MAGE-2 and MAGE-3 specific primers. Our results demonstrate that primary ocular tumor tissue and cultured tumor cells both express significant levels of MAGE-1, 2, and 3 at the time of enucleation. A high percentage of tumor cells within the primary tumor appear to express MAGE as demonstrated by consistent MAGE expression in 16 tumor cell clones. Metastatic liver tumors that developed 3 years after enucleation and 18 years after the initial formation of the primary tumor also expressed high levels of MAGE-1, -2, and -3. MAGE was expressed on fresh tumor tissue from a single biopsy and cultured tumor cells obtained from three of four different metastatic tumor nodules. When the MAGE-negative metastatic tumor cells were treated with the demethylating agent 5-Aza-2-Deoxycytidine (5-Aza-dC), transcription of MAGE-1 was restored, indicating the MAGE genes were not deleted. Our results demonstrate that in some patients, MAGE genes are expressed on primary and metastatic ocular melanomas.

Antigens, Neoplasm↗
PubMed2005

Lack of clinical efficacy of imatinib in metastatic melanoma.

This two-centre phase-II trial aimed at investigating the efficacy of imatinib in metastasised melanoma patients in correlation to the tumour expression profile of the imatinib targets c-kit and platelet-derived growth factor receptor (PDGF-R). The primary study end point was objective response according to RECIST, secondary end points were safety, overall and progression-free survival. In all, 18 patients with treatment-refractory advanced melanoma received imatinib 800 mg day(-1). In 16 evaluable patients no objective responses could be observed. The median overall survival was 3.9 months, the median time to progression was 1.9 months. Tumour biopsy specimens were obtained from 12 patients prior to imatinib therapy and analysed for c-kit, PDGF-Ralpha and -Rbeta expression by immunohistochemistry. In four cases, cell lines established from these tumour specimens were tested for the antiproliferative effects of imatinib and for functional mutations of genes encoding the imatinib target molecules. The tumour specimens stained positive for CD117/c-kit in nine out of 12 cases (75%), for PDGF-Ralpha in seven out of 12 cases (58%) and for PDGF-Rbeta in eight out of 12 cases (67%). The melanoma cell lines showed a heterogenous expression of the imatinib target molecules without functional mutations in the corresponding amino-acid sequences. In vitro imatinib treatment of the cell lines showed no antiproliferative effect. In conclusion, this study did not reveal an efficacy of imatinib in advanced metastatic melanoma, regardless of the expression pattern of the imatinib target molecules c-kit and PDGF-R.

Adult↗
PubMed1997

Application of fuzzy reasoning in an expert system for ultrasonography.

OBJECTIVES: To apply fuzzy reasoning in a computer-assisted diagnostic system for ultrasonography and to evaluate its clinical utility as a diagnostic aid for the unskilled clinician. METHODS: A computer-assisted diagnostic system for ultrasonography was constructed to differentiate metastatic from inflammatory lymph nodes. The pattern of a skilled clinician's considerations was simulated with the fuzzy expert system. Three fuzzy production rules were set up according to the diagnostic criteria for lymphadenopathy. Each rule was transformed into a membership function. The max-min composition method was used for inference and the centroid method for defuzzification. The system was tested with 20 clinicians who were one to three years after graduation and inexperienced in ultrasonography. Accuracy, sensitivity and specificity were evaluated. RESULTS: The average increase in accuracy was 8.5%, and the sensitivity and specificity 10.7% and 6.4% respectively. These scores were significant for accuracy (P = 0.005), sensitivity (P = 0.02) and specificity (P = 0.036). CONCLUSIONS: Application of fuzzy reasoning in an expert system for ultrasonography improves the diagnostic performance of inexperienced clinicians.

Clinical Competence↗
PubMed2002

Identification of a mutated fibronectin as a tumor antigen recognized by CD4+ T cells: its role in extracellular matrix formation and tumor metastasis.

CD4+ T cells play an important role in orchestrating host immune responses against cancer, particularly by providing critical help for priming and extending the survival of CD8+ T cells. However, relatively little is known about major histocompatibility complex class II-restricted human tumor antigens capable of activating CD4+ T cells. Here, we describe the identification of a mutated fibronectin (FN) as a tumor antigen recognized by human histocompatibility leukocyte antigen-DR2-restricted CD4+ T cells. Deoxyribonucleic acid (DNA) sequencing analysis indicated that this gene contains a mutation that results in the substitution of lysine for glutamic acid and gives rise to a new T cell epitope recognized by CD4+ T cells. Tumor cells harboring the mutant FN resulted in the loss of FN matrix formation and the gain of metastatic potential based on the migration pattern compared with that of tumor cells that express wild-type FN. Additional experiments using cell lines stably expressing the mutated FN cDNA demonstrated that the point mutation in FN was responsible for the loss of FN staining in extracellular matrices and the enhancement of tumor cell migration. These findings represent the first demonstration that a mutated gene product recognized by CD4+ T cells is directly involved in tumor metastasis, which indicates the importance of CD4+ T cells in controlling the spread of tumor cells to distant anatomic sites.

Antigens, Neoplasm↗
PubMed1983

Immunopathologic characterization of a monoclonal antibody that recognizes common surface antigens of human ovarian tumors of serous, endometrioid, and clear cell types.

A murine monoclonal antibody, OC125, reacts with a surface component of ovarian tumor cells from humans, but fails to react with normal adult ovarian cells. The spectrum of reactivity of OC125 in ovarian tumors from humans was defined by testing cryostat tissue sections from 60 selected ovarian tumors by indirect immunofluorescence. OC125 stained 7/7 benign, and borderline serous ovarian tumors, 19/23 (83%) serous adenocarcinomas, 2/2 mixed serous and endometrioid carcinomas, 2/3 endometrioid carcinomas, 1/4 clear cell carcinomas, and 2/2 undifferentiated carcinomas. No reactivity was found in eight mucinous ovarian tumors or any of the other 11 epithelial sex cord, germ cell, on hematopoietic tumors tested. In neoplastic cysts, papillae, and glands, the staining was most intense on the luminal surface or in subjacent cytoplasm. Cells in solid sheets also showed peripheral staining. Within a reactive tumor, both negative and positive cells could be found, intimately intermixed. There were no differences in these staining patterns between tissues from primary and metastatic sites. The expression of the OC125 antigen was not related to the degree of malignancy as judged by pathologic criteria. Although mucinous tumors lacked reactivity with OC125, seven of eight mucinous adenomas and adenocarcinomas bound a monoclonal antibody against carcinoembryonic antigen (CEA). Thus, OC125 recognizes a common antigen in some but not all ovarian tumors of serous, clear cell, endometrioid, or undifferentiated type. OC125 may prove useful in the pathologic and cytologic identification of certain types of ovarian tumor cells. Its lack of reactivity with mucinous tumors suggests these belong in a distinct subgroup of ovarian epithelial tumors.

Adenocarcinoma↗
PubMed1984

Factor VIII related antigen and glial fibrillary acidic protein immunoreactivity in the differential diagnosis of central nervous system hemangioblastomas.

Nineteen hemangioblastomas, nine angioblastic meningiomas, ten metastases to the brain (including five renal cell carcinomas), and five primary renal cell carcinomas were studied using the immunoperoxidase method for Factor VIII related antigen and glial fibrillary acidic protein (GFAP). All tumor types showed Factor VIII immunoreactivity confined to endothelial cells. Factor VIII immunostaining revealed a distinct, though probably nondiagnostic, vascular pattern for hemangioblastomas as compared with metastatic carcinomas and angioblastic meningiomas. Most of the hemangioblastomas and metastases showed numerous GFAP-reactive cells with unequivocal astrocytic morphology primarily at the interface with brain parenchyma but also occasionally deep within the tumor. Within metastases these cells often were associated with penetrating fibrovascular septa. In a minority of hemangioblastomas and metastatic carcinomas there were rare GFAP immunoreactive cells that were indistinguishable from stromal or metastatic tumor cells, respectively. Angioblastic meningiomas showed no GFAP reactivity. It is concluded that the presence of GFAP-reactive cells alone is not helpful in differentiating between hemangioblastomas and intra-axial lesions. The lack of stromal cell immunoreactivity in angioblastic meningiomas and the rare staining of stromal cells in hemangioblastomas, seen also in central nervous system (CNS) metastases, suggest that except for the endothelial cells lining vessels, these primary CNS lesions are not antigenically closely related to either endothelial cells or astroglia. Furthermore, in the evaluation of tumors within the CNS, the significance of rare GFAP-positive tumor cells must be interpreted with caution.

Cerebellar Neoplasms↗
PubMed1992

Pattern of 2-deoxy-2-[18F]-fluro-D-glucose accumulation in liver tumours: primary, metastatic and after chemotherapy.

Eight patients with liver metastases from adenocarcinoma of the colon or rectum, two with suspected hepatic metastases and one with primary hepatoma were studied with 2-deoxy-2-[18F]-fluro-D-glucose (18F-FDG) using positron emission tomography (PET). In five of the patients with metastatic tumour a second examination was performed four weeks after treatment with recombinant interleukin-2 (rIL2) and fluorouracil (5FU). In all tumours (one primary and eight metastatic) the radioactivity was seen to accumulate in a rim around each tumour with a large central area showing no uptake. In the five cases imaged after treatment with rIL2, the appearance of the tumour uptake was the same as before treatment. In the two cases of suspected but not proven metastases, no abnormal accumulation of 18F-FDG was seen.

Adenocarcinoma↗
PubMed1986

Cutaneous metastases from chondrosarcoma.

This report describes a patient with histologically confirmed multiple cutaneous metastases from a skeletal chondrosarcoma and reviews the two previously published cases of this very unusual pattern of metastasis. We conclude that metastatic chondrosarcoma should be considered in the differential diagnosis of multiple cartilaginous tumors of the skin, and that radiotherapy may play a role in the management of metastatic chondrosarcoma.

Bone Neoplasms↗
PubMed1981

Schwann cell features in neurotropic melanoma.

Schwann cell features were found on ultrastructural examination of a neurotropic melanoma (de novo type) of the lip. A neurotropic pattern of growth was retained in metastatic tumors in lymph nodes and lung. Melanin was not demonstrable in extra-epidermal tumor cells.

Adult↗
PubMed1989

Metastatic breast carcinoma mimicking granular cell tumor.

Metastatic breast carcinoma may assume many patterns. We describe a case in which cutaneous, pulmonary and lymph node metastases of an adenocarcinoma of the breast all resembled granular cell tumor. In all sites, the lesion stained positive with antibodies against EMA and cytokeratins, but failed to stain with anti-S100.

Adenocarcinoma↗
PubMed2005

Tenascin-C in primary Merkel cell carcinoma.

BACKGROUND/AIMS: Merkel cell carcinoma (MCC) is a rare malignant cutaneous neuroendocrine tumour that mostly affects the elderly. It shows rapid progression of the primary tumour, together with a vertical growth pattern into the underlying subcutaneous tissue. Metastatic dissemination to regional lymph nodes is early and frequent. Tenascin-C (Tn-C) is a large extracellular matrix glycoprotein that is expressed in various benign and malignant processes. Expression of Tn-C is also associated with invasion and cellular proliferation, and is often downregulated in fully evolved advanced carcinomas. In previous studies, Tn-C expression correlated with prognosis in tumours of different origin. METHODS: Immunohistochemistry was used to investigate the expression of Tn-C in 25 MCC specimens and to evaluate the prognostic importance of this glycoprotein. RESULTS: Seventeen samples expressed Tn-C. Staining was mainly seen in the invasion borders and within the connective tissue septae inside the tumours. The expression of Tn-C correlated significantly with large tumour size. There was also frequent expression of Tn-C in primary tumours with metastatic dissemination. Most of the Tn-C negative samples were of small size. CONCLUSIONS: Tn-C expression seems to increase with tumour size and malignant behaviour. Expression was slightly enhanced in tumours with high proliferative indices. Expression is seen mainly in areas of invasive growth and, in this respect, resembles that of other invasive tumours.

Aged↗