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Biomedical subjects

A O Vortmeyer

Publications and source records attributed to A O Vortmeyer.

At least 55 records · Page 3Linked to original sources
PubMed1999

Multiple endocrine neoplasia type 1: atypical presentation, clinical course, and genetic analysis of multiple tumors.

Multiple endocrine neoplasia type 1 (MEN1) is characterized by the development of endocrine tumors of the parathyroid and pituitary glands, pancreas, and duodenum. Less frequently occurring tumors associated with MEN1 include non-endocrine tumors such as lipomas and angiofibromas. An increased incidence of thyroid neoplasms, leiomyomas, adrenal cortical hyperplasia, hepatic focal nodular hyperplasia, and renal angiomyolipoma has been noted in the MEN1 population. The pathogenesis of non-neuroendocrine tumors in MEN1 is unknown. We report a complex clinical course and a detailed morphologic and genetic analysis of a series of tumors that developed in a patient with MEN1. All tumors were microdissected and analyzed for loss of heterozygosity of the MEN1 gene. A germline mutation of the MEN1 gene was detected, and deletions of the MEN1 gene were consistently detected in multiple neuroendocrine tumors involving the parathyroid glands and the pancreas and a hepatic neuroendocrine tumor metastasis, as predicted by Knudson's "two hit" hypothesis. Two hits of the MEN1 gene were also detected in esophageal leiomyoma tissue, suggesting that tumorigenesis was directly related to the patient's underlying MEN1. In contrast, follicular thyroid adenoma, papillary thyroid carcinoma, hepatic focal nodular hyperplasia, and adrenal cortical hyperplasia consistently showed retained heterozygosity of the MEN1 gene with flanking markers and an intragenic marker. Therefore, these tumors appear to develop along pathogenetic pathways that are different from classical MEN1-associated tumors.

Adult↗
PubMed1999

Telomerase activity in microdissected human gliomas.

Future improvements in the diagnosis and treatment of human gliomas might rely on obtaining more specific information concerning the biologic characteristics of individual tumor cells. Telomerase, a ribonucleoprotein that synthesizes telomeres, has been reported to be expressed in a majority of human tumors, including several subtypes of brain tumor. We hypothesized that a quantitative assay for telomerase activity, combined with selective microdissection of tumor or normal brain cells, might reveal telomerase gain-of-function to be important in the pathogenesis of gliomas and that telomerase levels might have prognostic significance. We used tissue microdissection for selective analysis of tumor cells obtained from eight patients with glioma, one with a meningioma, and one with a primary B-cell lymphoma of the central nervous system. Normal brain tissue microdissected from another patient was used as a control. Telomerase activity was screened by an electrophoretic method and then assayed by a quantitative ELISA method. All of the eight gliomas had positive telomerase activity, as did the lymphoma. The meningioma and normal brain were negative. Quantitative analysis of telomerase activity did not correlate with tumor grade nor predict outcome. Selective tissue microdissection, combined with qualitative and quantitative telomerase assays, permits rapid and reliable detection of telomerase activity in diverse brain tumor tissues. These preliminary findings suggest that telomerase reactivation is a frequent event in glioma tumorigenesis that can be sensitively and specifically detected in gliomas of all histologic grades. Furthermore, specific detection of telomerase reactivation represents another mechanism by which tumor formation and progression might become the target of novel therapeutics.

Adult↗
PubMed1998

Mutation of the uracil DNA glycosylase gene detected in glioblastoma.

Despite extensive characterization of genetic changes in gliomas, the underlying etiology of these tumors remains largely unknown. Spontaneous DNA damage due to hydrolysis, methylation, and oxidation is a frequent event in the brain. Failure of DNA repair following this damage may contribute to tumorigenesis of gliomas. Uracil DNA glycosylase (UDG), an enzyme which excises uracil from DNA, is an important component of the base excision repair pathway. The sequence of a human homologue of uracil DNA glycosylase gene (UNG) has been recently identified. We performed PCR-based SSCP mutational analysis of UNG in 11 sporadic gliomas (six glioblastomas, two anaplastic astrocytomas, and three oligodendrogliomas) and eight glioblastoma cell lines. One out of six sporadic glioblastomas had a point mutation in exon 3, which resulted in a missense mutation in codon 143. None of the eight glioblastoma cell lines or the five non-glioblastoma sporadic gliomas showed a mutation. Genetic alterations of UNG may play a role in the development of a subset of primary glioblastomas.

Adult↗
PubMed1998

Pluripotent tumor cells in benign pituitary adenomas associated with multiple endocrine neoplasia type 1.

Analysis of human tumor cells in vitro enhances the study of numerous neoplastic conditions. However, it has been difficult to establish long-term cultures of adenoma cells, especially those of neuroendocrine origin, because the endocrine cells survive only briefly in culture, and fibroblasts overgrow the culture dish in 1 or 2 weeks. We describe cells isolated from pituitary adenomas in two patients with multiple endocrine neoplasia type 1 in which cells with a mesenchymal phenotype evolved from pituitary tumor cells. It appears that these poorly differentiated cells arose from multipotent adenoma cells. This represents a path of cell differentiation not observed previously in humans and may help explain the diverse nature of the benign tumors in multiple endocrine neoplasia type 1.

Adenoma↗
PubMed1998

Loss of heterozygosity and somatic mutations of the VHL tumor suppressor gene in sporadic cerebellar hemangioblastomas.

Cerebellar hemangioblastoma is a benign central nervous system neoplasm with characteristic proliferation of vascular and stromal cells. There is increasing evidence that the stromal cell population may represent the neoplastic component of hemangioblastoma, whereas the vascular component may be composed of reactive, nonneoplastic cells. Therefore, successful genetic testing for loss of heterozygosity requires selective analysis of target cell populations. Here, tissue microdissection was used to selectively analyze the stromal cell component of 20 archival sporadic cerebellar hemangioblastomas for loss of heterozygosity at the Von-Hippel Lindau (VHL) gene and somatic VHL gene mutations. Allelic deletions at the VHL gene locus were detected in the stromal cell component with one or more markers (D3S1038, D3S1110, and/or 104/105) in 10 of 19 (52.6%) informative cases. In all cases, heterozygosity at the VHL gene locus was retained in the vascular component. In two cases, aberrant bands in exon 2 of the VHL gene were demonstrated in the stromal cells by PCR-based single-strand conformation polymorphism analysis, and somatic missense mutations were successfully characterized in two of the sporadic hemangioblastomas by direct sequencing. The results suggest that allelic losses and mutations of the VHL tumor suppressor gene play a role in sporadic cerebellar hemangioblastoma tumorigenesis. Furthermore, because the genetic changes were detected in selectively procured stromal cell areas, the data provide strong evidence that the stromal cell represents a neoplastic component of hemangioblastoma.

Adolescent↗
PubMed1998

Multiple neuroendocrine tumors of the pancreas in von Hippel-Lindau disease patients: histopathological and molecular genetic analysis.

Although pancreatic neuroendocrine tumors (NETs) in von Hippel-Lindau (VHL) disease have been reported, their pathological features have not been characterized. In addition, it is unknown whether alterations of the VHL gene are responsible for pancreatic NET development. To evaluate NETs in VHL patients, we performed histopathological analysis of 30 pancreatic tumors in 14 patients. In addition, DNA from NETs and normal pancreatic tissue from 6 patients with documented germ-line VHL gene mutations was studied for allelic deletions of the second copy of the VHL gene by fluorescence in situ hybridization and polymerase chain reaction-based single-strand conformational polymorphism analysis. Morphologically, the tumors were characterized by solid, trabecular, and/or glandular architecture and prominent stromal collagen bands. Sixty percent of the tumors revealed at least focally clear-cell cytology. All tumors were positive for panendocrine immunohistochemistry markers (chromogranin A and/or synaptophysin); 35% of NETs demonstrated focal positivity for pancreatic polypeptide, somatostatin, insulin, and/or glucagon; and no immunostaining for pancreatic and gastrointestinal hormones was observed in 65% of tumors. Dense core neurosecretory granules were evident by electron microscopic examination, and the clear cells additionally revealed abundant intracytoplasmic lipid. All NETs that were subjected to genetic analysis showed allelic loss of the second copy of the VHL gene. We conclude that multiple, nonfunctional pancreatic NETs occur in VHL patients. Stromal collagen bands and clear-cell morphology are important histological features of VHL-associated NETs. The presence of allelic deletions of the VHL gene in pancreatic NETs provides direct molecular evidence for a role of the gene in their tumorigenesis and establishes NET as an independent tumor type of VHL disease.

Adolescent↗
PubMed1998

Loss of heterozygosity of the von Hippel Lindau gene locus in polypoid dysplasia but not flat dysplasia in ulcerative colitis or sporadic adenomas.

Carcinoma in ulcerative colitis (UC) develops from dysplastic precursor lesions, which include flat dysplasia (FD) and polypoid dysplasias (PD). PD may present as single or multiple polypoid structures or as plaque-like lesions that, independent of histological grade, are an indication for colectomy. PDs are histologically similar to adenomas and may not be readily distinguished by light microscopy. It is not known whether FD and PD are different entities, or whether they represent etiologically similar lesions with different morphological expression. We microdissected 25 cases of UC with PD and 19 samples of FD with surrounding chronic colitis (CC) in UC. Loss of heterozygosity (LOH) at the von Hippel Lindau (vHL) gene locus and the putative tumor suppressor genes APC, INK4A (9p16), and p53 was studied. LOH of the vHL gene, INK4A (9p16), and APC was also studied in 11 sporadic adenomas of the colon. LOH at the vHL locus was present in 50% of the samples of PD and in 12% of the samples of FD. LOH was seen in CC close to PD and FD in 26% and 12% of cases, respectively. No adenoma showed LOH of the vHL gene markers studied. LOH in p53 was seen in PD in 16% cases and in FD in 42% cases and in CC close to PD and FD in 0% and 14% cases, respectively. LOH patterns between PD and FD of the markers for APC and 9p16 were not different. LOH in APC was seen in two of five cases of adenoma. We conclude that PD and FD share genetic alterations in APC and 9p16 genes. More frequent involvement of the VHL gene in PD and surrounding CC and involvement of p53 in HGD and CC in FD may represent genetic differences between the development of PD and FD and may be the cause of the different morphology. The infrequency of LOH at the vHL locus in adenomas versus PD may serve as a discriminator between adenomas and PD in diagnostically problematic cases.

Adenoma↗
PubMed1998

Allelic deletion at chromosome 9p21(p16) and 17p13(p53) in microdissected sporadic dysplastic nevus.

A critical area of chromosomal loss at region p16(9p21-22) and p53(17p13) has been implicated in the genesis of malignant melanoma. It is still unclear whether the genetic alterations can be detected in dysplastic nevus, a premalignant lesion of malignant melanoma. We have searched the frequency of p16 and p53 deletion in nine dysplastic nevi and 13 benign intradermal nevi with five microsatellite markers. Hemizygous deletion was detected in seven of nine (78%) dysplastic nevi at one or more loci for p16 and three of seven (43%) for p53, respectively. No loss of heterozygosity (LOH) was detected in any of the benign intradermal nevi. All three dysplastic nevi with LOH for p53 also showed LOH at p16. However, not all dysplastic nevi showing p16 deletion showed p53 gene deletion. Therefore, these data suggest that deletion of p16 may play an important role in the development of dysplastic nevus as an early event and that the changes may represent an early event in the development of malignant melanoma.

Adolescent↗
PubMed1998

Comparison of genetic alterations in colonic adenoma and ulcerative colitis-associated dysplasia and carcinoma.

Carcinoma is an important complication of ulcerative colitis (UC) and develops from dysplastic precursor lesions. Genetic changes involved in the malignant transformation have not been fully characterized. We studied 19 cases of UC with high-grade dysplasia (HGD) and eight samples of associated carcinoma (CA). Microdissection of normal epithelium, epithelium at the site of chronic inflammation, HGD, and CA was performed. Polymerase chain reaction (PCR) amplification for loss of heterozygosity (LOH) of the following polymorphic microsatellites of putative tumor suppressor gene loci was done: APC (5q), DCC (18q), p16 (9p), p53 (17p), and 8p12. To compare genetic alterations, 22 typical adenomas of the colon were studied with the markers for APC and pl6 gene loci. The results indicated that LOH of p16 and p53 were present in nondysplastic epithelium, HGD, and CA. However, the LOH in nondysplastic epithelium was detected in some associated HGD, but not all. Whereas LOH of p16 was present in 7 of 14 cases of HGD (50%), it was noted in only 1 of 22 adenomas (5.0%). LOH in the APC and DCC gene loci in UC was noted in HGD with associated CA, but LOH of APC was not present either in cases of nondysplastic epithelium or in HGD alone. Conversely, LOH in APC was present in 4 of 19 colonic adenomas. We conclude that LOH of p53 and p16 in nondysplastic epithelium may be associated with chronic reparative processes. These changes may lead to susceptibility to further genetic damage involving the APC and DCC gene loci in the development of dysplasia and progression of CA in UC. The low frequency of LOH in the p16 gene (9p) in adenomas compared with dysplasia in UC combined with infrequent LOH in APC gene loci in cases of pure dysplasia in UC may support this combination of markers as a clinical test for the differentiation of polypoid dysplasia from adenomas in UC.

Adenoma↗
PubMed1998

Trisomy 7-harbouring non-random duplication of the mutant MET allele in hereditary papillary renal carcinomas.

The gene defect for hereditary papillary renal carcinoma (HPRC) has recently been mapped to chromosome 7q, and germline mutations of MET (also known as c-met) at 7q31 have been detected in patients with HPRC (ref. 2). Tumours from these patients commonly show trisomy of chromosome 7 when analysed by cytogenetic studies and comparative genomic hybridization (CGH). However, the relationship between trisomy 7 and MET germline mutations is not clear. We studied 16 renal tumours from two patients with documented germline mutations in exon 16 of MET. Fluorescent in situ hybridization (FISH) analysis showed trisomy 7 in all tumours. To determine whether the chromosome bearing the mutant or wild-type MET gene was duplicated, we performed duplex PCR and phosphoimage densitometry using polymorphic microsatellite markers D7S1801 and D7S1822, which were linked to the disease gene locus, and D1S1646 as an internal control. We determined the parental origin of chromosome alleles by genotyping parental DNA. In all 16 tumours there was an increased signal intensity (2:1 ratio) of the microsatellite allele from the chromosome bearing the mutant MET compared with the allele from the chromosome bearing the wild-type MET. Our study demonstrates a non-random duplication of the chromosome bearing the mutated MET in HPRC and implicates this event in tumorigenesis.

Adult↗
PubMed1998

Cutaneous tumors in patients with multiple endocrine neoplasia type 1 show allelic deletion of the MEN1 gene.

Multiple endocrine neoplasia type 1 (MEN1), the heritable tendency to develop tumors of the parathyroid, pituitary, and entero-pancreatic endocrine tissues, is the consequence of a germline mutation in the MEN1 gene. Endocrine tumors in these patients result when the mutant MEN1 allele is accompanied by loss of the normal MEN1 allele. Recently it was reported that MEN1 patients also exhibit several cutaneous tumors, including multiple angiofibromas, collagenomas, and lipomas. The purpose of this study was to examine skin lesions from patients with MEN1 for allelic loss of the MEN1 gene. Skin lesions from five patients with MEN1 were examined using fluorescence in situ hybridization. Six angiofibromas, three collagenomas, and one lipoma showed allelic deletion of the MEN1 gene. Allelic deletion was not observed in a melanocytic nevus or acrochordon from patients with MEN1. It was also not observed in an angiofibroma from a patient with tuberous sclerosis. These results suggest that loss of function of the wild-type MEN1 gene product plays a role in the development of angiofibromas, collagenomas, and lipomas in patients with MEN1.

Adolescent↗
PubMed1998

Hepatobiliary lymphoepithelioma-like carcinoma associated with Epstein-Barr virus.

We describe the clinical and pathologic features of a lymphoepithelioma-like carcinoma (LELC) that originated in the hepatobiliary system. A woman, aged 71 years, was first seen with a noncholangiolar adenocarcinoma with lymphoid stroma, which was discovered by open liver biopsy in 1993. In 1995, retroperitoneal and peripancreatic lymph nodes were involved by LELC. There currently is no evidence of distant metastasis outside the hepatobiliary peripancreatic region. Review of the biopsy material revealed a well-differentiated adenocarcinoma with transition into LELC. Epstein-Barr virus (EBV) transcripts were expressed in all histologic phases of the tumor by in situ hybridization using immunoalkaline phosphatase-labeled oligonucleotide probes for EBV-encoded RNA 1 on formalin-fixed, paraffin-embedded sections. Polymerase chain reaction analysis for EBV nuclear antigen 2 was consistent with EBV strain type A. The LMP-1 gene was found to be wild type by polymerase chain reaction analysis. To our knowledge, this is the first report of a primary hepatobiliary adenocarcinoma associated with EBV infection that transformed into an undifferentiated LELC.

Adenocarcinoma↗
PubMed1998

Genetic changes associated with primary Merkel cell carcinoma.

Merkel cell carcinoma (MCC) is a malignant tumor of the skin with a well-established neuroendocrine phenotype but an unknown histogenetic origin. Cytogenetic and molecular studies have shown evidence for genetic changes on the distal portion of chromosome 1p in different tumors with well-established neuroendocrine origins, specifically neuroblastomas, malignant melanomas, and pheochromocytomas. Involvement of chromosome 1 in MCC recently has been demonstrated by cytogenetic analysis and analysis of loss of heterozygosity (LOH) in metastatic tumor tissue. We performed analysis of LOH of the distal portion of chromosome 1p in paraffin material of 10 primary MCCs after tissue microdissection, using the polymorphic markers D1S160, D1S243, D1S468, D1S1646, and D1S1598. Seven of 10 analyzed MCCs shared a distal deletion involving 1p35-36. None of the cases showed 1p involvement proximal to 1p35. The findings are similar to those described for malignant melanoma, pheochromocytoma, and neuroblastoma, tumors known to originate from neural crest cells. In conjunction with previous cytogenetic data, we conclude that Merkel cell carcinogenesis shares pathogenetic mechanisms with other neoplasms of neural crest derivation.

Aged↗