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1.
Nature ; 604(7906): 447-450, 2022 04.
Article in English | MEDLINE | ID: mdl-35444319

ABSTRACT

Nova explosions are caused by global thermonuclear runaways triggered in the surface layers of accreting white dwarfs1-3. It has been predicted4-6 that localized thermonuclear bursts on white dwarfs can also take place, similar to type-I X-ray bursts observed in accreting neutron stars. Unexplained rapid bursts from the binary system TV Columbae, in which mass is accreted onto a moderately strong magnetized white dwarf from a low-mass companion, have been observed on several occasions in the past 40 years7-11. During these bursts, the optical/ultraviolet luminosity increases by a factor of more than three in less than an hour and fades in around ten hours. Fast outflows have been observed in ultraviolet spectral lines7, with velocities of more than 3,500 kilometres per second, comparable to the escape velocity from the white dwarf surface. Here we report on optical bursts observed in TV Columbae and in two additional accreting systems, EI Ursae Majoris and ASASSN-19bh. The bursts have a total energy of approximately 10-6  times than those of classical nova explosions (micronovae) and bear a strong resemblance to type-I X-ray bursts12-14. We exclude accretion or stellar magnetic reconnection events as their origin and suggest thermonuclear runaway events in magnetically confined accretion columns as a viable explanation.

2.
Nature ; 554(7690): 69-72, 2018 02 01.
Article in English | MEDLINE | ID: mdl-29364880

ABSTRACT

Recurring outbursts associated with matter flowing onto compact stellar remnants (such as black holes, neutron stars and white dwarfs) in close binary systems provide a way of constraining the poorly understood accretion process. The light curves of these outbursts are shaped by the efficiency of angular-momentum (and thus mass) transport in the accretion disks, which has traditionally been encoded in a viscosity parameter, α. Numerical simulations of the magneto-rotational instability that is believed to be the physical mechanism behind this transport yield values of α of roughly 0.1-0.2, consistent with values determined from observations of accreting white dwarfs. Equivalent viscosity parameters have hitherto not been estimated for disks around neutron stars or black holes. Here we report the results of an analysis of archival X-ray light curves of 21 outbursts in black-hole X-ray binaries. By applying a Bayesian approach to a model of accretion, we determine corresponding values of α of around 0.2-1.0. These high values may be interpreted as an indication either of a very high intrinsic rate of angular-momentum transport in the disk, which could be sustained by the magneto-rotational instability only if a large-scale magnetic field threads the disk, or that mass is being lost from the disk through substantial outflows, which strongly shape the outburst in the black-hole X-ray binary. The lack of correlation between our estimates of α and the accretion state of the binaries implies that such outflows can remove a substantial fraction of the disk mass in all accretion states and therefore suggests that the outflows correspond to magnetically driven disk winds rather than thermally driven ones, which require specific radiative conditions.

3.
Spectrochim Acta A Mol Biomol Spectrosc ; 173: 356-360, 2017 Feb 15.
Article in English | MEDLINE | ID: mdl-27685004

ABSTRACT

Recently reported new phenomenon of Aggregation-Induced Raman Optical Activity is demonstrated here for the first time in the pre-resonance conditions for lutein diacetate and 3'-epi-lutein supramolecular self-assembles. We demonstrate that minor alterations in the lutein structure (e.g. acetylation of hydroxyl groups or different configuration at one of the chiral center) can lead to definitely different spectral profiles and optical properties due to formation of aggregates of different structure and type. Lutein forms only H-aggregates, lutein diacetate only J-aggregates, while 3'-epi-lutein can occur in both forms simultaneously. Variety of aggregates' structures is so large that not only the type of aggregation is different, but also their chirality. It is remarkable that even in the pre-resonance conditions, aggregation of lutein derivatives can lead to the intense ROA signal, and moreover, 3'-epi-lutein demonstrated the highest resonance ROA CID ratio that has ever been reported.

4.
Phys Rev Lett ; 112(9): 091301, 2014 Mar 07.
Article in English | MEDLINE | ID: mdl-24655237

ABSTRACT

Quantum entanglement of Hawking radiation has been supposed to give rise to a Planck density "firewall" near the event horizon of old black holes. We show that Planck density firewalls are excluded by Einstein's equations for black holes of mass exceeding the Planck mass. We find an upper limit of 1/(8πM) to the surface density of a firewall in a Schwarzschild black hole of mass M, translating for astrophysical black holes into a firewall density smaller than the Planck density by more than 30 orders of magnitude. A strict upper limit on the firewall density is given by the Planck density times the ratio M(Pl)/(8πM).

5.
Histopathology ; 53(3): 245-66, 2008 Sep.
Article in English | MEDLINE | ID: mdl-18312355

ABSTRACT

Gastrointestinal stromal tumours (GISTs) are the most common mesenchymal neoplasms of the gastrointestinal tract. Despite clinicopathological differences, GISTs share oncogenic KIT or platelet-derived growth factor-alpha (PDGFRA) mutations. Imatinib, KIT and PDGFRA inhibitor, has been successfully used in the treatment of metastatic GISTs. There are primary KIT or PDGFRA mutations diagnosed before imatinib treatment, linked to GIST pathogenesis, and secondary mutations detected during treatment, causing drug resistance. KIT exon 11 mutations are the most common. Gastric GISTs with exon 11 deletions are more aggressive than those with substitutions. KIT exon 11 mutants respond well to imatinib. Less common KIT exon 9 Ala502_Tyr503dup mutants occur predominantly in intestinal GISTs and are less sensitive to imatinib. An Asp842Val substitution in exon 18 is the most common PDGFRA mutation. GISTs with such mutation are resistant to imatinib. PDGFRA mutations are associated with gastric GISTs, epithelioid morphology and a less malignant course of disease. GISTs in neurofibromatosis 1, Carney triad and paediatric tumours generally lack KIT and PDGFRA mutations. Secondary KIT mutations affect exons 13-17. GISTs with secondary mutations in exon 13 and 14 are sensitive to sunitinib, another tyrosine kinase inhibitor. KIT and PDGFRA genotyping is important for GIST diagnosis and assessment of sensitivity to tyrosine kinase inhibitors.


Subject(s)
Gastrointestinal Stromal Tumors/diagnosis , Mutation , Proto-Oncogene Proteins c-kit/genetics , Receptor, Platelet-Derived Growth Factor alpha/genetics , Animals , Exons , Gastrointestinal Stromal Tumors/drug therapy , Gastrointestinal Stromal Tumors/genetics , Humans , Protein Kinase Inhibitors/therapeutic use , Receptor, Platelet-Derived Growth Factor alpha/antagonists & inhibitors
6.
Vet Pathol ; 42(3): 362-5, 2005 May.
Article in English | MEDLINE | ID: mdl-15872385

ABSTRACT

Gastrointestinal stromal tumors (GIST), KIT-positive and KIT signaling driven or platelet-derived growth factor receptor alpha (PDGFRA) signaling driven mesenchymal tumors, are poorly known in nonhuman primates. Availability of KIT- and PDGFRA-inhibitor drug imatinib mesylate has greatly raised the interest for these tumors. At necropsy of a 22-year-old male chimpanzee, a round, firm 2-cm intramural tumor was incidentally found in the midbody of the stomach and diagnosed as a GIST. Histologically, the mass was composed of spindle to polygonal epithelioid cells arranged in short to intermediate-length, interlacing streams, bundles, and nodular whorls often separated by hyalinized eosinophilic matrix. The mitotic rate was a maximum 1/50 high-power field. Immunohistochemically, the tumor cells were diffusely positive for KIT and CD34, focally positive for alpha-smooth muscle actin, and negative for muscle specific actin, desmin, S-100 protein, synaptophysin, and glial fibrillary acidic protein. Because the majority of human GISTs have gain-of-function KIT or PDGFRA mutations, genomic sequences of KIT exons 9, 11, 13, and 17 and PDGFRA exons 12 and 18 from this chimpanzee GIST were polymerase chain reaction amplified and sequenced. However, no mutation was identified in the analyzed "mutational hot spots." This study is the first extensive histomorphologic, immunohistochemical, and molecular genetic analysis of a chimpanzee GIST. More cases of nonhuman primate GISTs should be analyzed to discover the clinicopathologic spectrum of GISTs in these species.


Subject(s)
Ape Diseases/pathology , Gastrointestinal Stromal Tumors/veterinary , Pan troglodytes , Proto-Oncogene Proteins c-kit/metabolism , Animals , Antigens, CD34/metabolism , Ape Diseases/metabolism , Gastrointestinal Stromal Tumors/metabolism , Gastrointestinal Stromal Tumors/pathology , Immunohistochemistry/veterinary , Male , Proto-Oncogene Proteins c-kit/genetics , Receptor, Platelet-Derived Growth Factor alpha/genetics , Receptor, Platelet-Derived Growth Factor alpha/metabolism , Sequence Analysis, DNA/veterinary
7.
Gut ; 53(2): 235-40, 2004 Feb.
Article in English | MEDLINE | ID: mdl-14724156

ABSTRACT

BACKGROUND AND AIMS: The distinction between benign and malignant gastrointestinal stromal tumours (GISTs) is often unclear at the clinical and histopathology levels. GISTs are believed to arise from the stem cells of Cajal. In order to define genetic biomarkers and identify target genes related to GIST progression, we analysed and compared benign and malignant GISTs with verified follow up data using cDNA expression arrays. METHODS: Eight genes were frequently overexpressed in malignant GISTs and their overexpression was confirmed using quantitative real time reverse transcription-polymerase chain reaction. These genes included ezrin (villin 2 (VIL2)), collagen 8 alpha 1 subunit (COL8A1), G2/mitotic specific cyclin B1 (CCNB1), high mobility group protein (HMG2), TSG101 tumour susceptibility protein, CENP-F kinetochore protein, protein tyrosine kinase 2 (FAK), and protein kinase DYRK2. To test these genes in a clinical setting, we obtained diagnostic samples of 16 additional GISTs that were classified at diagnosis as benign, malignant, and uncertain malignant potential (UMP). RESULTS: There was remarkable gene overexpression in all malignant GISTs. Statistical analyses revealed significant correlations between overexpression of several gene pairs in malignant GISTs. We found the strongest correlations (rho>0.70) among the significant correlations (p<0.01) between CCNB1-CENP-F (rho = 0.87) and CCNB1-FAK (rho = 0.73). Gene expression of the UMP GISTs suggested two different groups. Three UMP GISTs had gene expression consistent with malignant tumours and their follow up data revealed that indeed these patients had recurrences later on. On the other hand, UMP GISTs that had low gene expression levels continued free of disease for several years. CONCLUSIONS: These results provide insight into the oncogenesis of GISTs and suggest that testing the expression profile of a number of genes may segregate GISTs into groups of different tumour behaviour.


Subject(s)
Gastrointestinal Neoplasms/genetics , Gastrointestinal Neoplasms/pathology , Neoplasm Proteins/genetics , Oligonucleotide Array Sequence Analysis , Chromosomal Proteins, Non-Histone/genetics , Collagen Type VIII/genetics , Cytoskeletal Proteins , DNA-Binding Proteins , Endosomal Sorting Complexes Required for Transport , Focal Adhesion Kinase 2 , Gene Expression , Genetic Markers , HMGB2 Protein/genetics , Humans , Microfilament Proteins , Phosphoproteins/genetics , Prognosis , Protein Serine-Threonine Kinases/genetics , Protein-Tyrosine Kinases/genetics , Reverse Transcriptase Polymerase Chain Reaction , Transcription Factors , Dyrk Kinases
8.
Vet Pathol ; 40(1): 42-54, 2003 Jan.
Article in English | MEDLINE | ID: mdl-12627712

ABSTRACT

Fifty canine gastrointestinal (GI) mesenchymal tumors were examined to determine the occurrence of leiomyomas (LM) and GI stromal tumors and to compare their clinicopathologic features. Twenty-one tumors (42%) were histologically reclassified as gastrointestinal stromal tumors (GISTs) and 29 tumors (58%) as LMs on the basis of their histologic similarity with homologous human tumors. The GISTs occurred equally in males and females, with a mean age of 11 years (range 5-14 years). Five GISTs (24%) were associated with clinical signs and six (29%) had metastasis in liver or abdominal cavity. The GISTs occurred in large intestine (10, 48%), small bowel (six, 29%), stomach (four, 19%), and mesentery of small intestine (one, 5%). Histologically, they were highly cellular spindle, or less commonly epithelioid tumors with mitotic rates ranging from 0 to 19 per 10 HPF. Eleven tumors (52%) were positive for CD117 (KIT); seven (33%) were positive for smooth muscle actin but none for desmin and S-100 protein. Sequences of KIT exon 11, often mutated in human GISTs, were evaluated from four GISTs. Deletion of Try556-Lys557 coexisting with duplication of Gln555 in one case of GIST and T to C transition resulting in substitution of Pro for Leu575 in another were identified. The LMs occurred predominantly in males (82%) with a mean age of 11 years (range 8-17 years). Nine tumors (31%) had associated clinical signs. They occurred in the stomach (22, 76%), esophagus (four, 14%), and intestines (three, 10%); all were paucicellular, had no mitoses, and were composed of mature smooth muscle cells. Twenty-eight (97%) were positive for smooth muscle actin and 18 (62%) for desmin but none for CD117 and S-100. Both GISTs and true LMs occur in the GI tract of dogs. Both tumors have distinctive pathologic features.


Subject(s)
Dog Diseases/pathology , Gastrointestinal Neoplasms/veterinary , Leiomyoma/veterinary , Amino Acid Sequence , Animals , Base Sequence , DNA, Neoplasm/chemistry , DNA, Neoplasm/genetics , Dog Diseases/genetics , Dog Diseases/metabolism , Dogs , Female , Gastrointestinal Neoplasms/genetics , Gastrointestinal Neoplasms/metabolism , Gastrointestinal Neoplasms/pathology , Immunohistochemistry/veterinary , Leiomyoma/genetics , Leiomyoma/metabolism , Leiomyoma/pathology , Male , Molecular Sequence Data , Mutation , Polymerase Chain Reaction/veterinary , Proto-Oncogene Proteins c-kit/genetics , Proto-Oncogene Proteins c-kit/metabolism , Sequence Alignment , Stromal Cells/pathology
9.
Am J Surg Pathol ; 25(9): 1121-33, 2001 Sep.
Article in English | MEDLINE | ID: mdl-11688571

ABSTRACT

Gastrointestinal stromal tumors (GISTs), the specific KIT-positive mesenchymal tumors of the gastrointestinal tract, have been sporadically reported in the rectum, but there are few clinicopathologic series. In this study we analyzed the clinicopathologic features of 133 anorectal GISTs, 3 intramural leiomyomas (LMs), and 8 leiomyosarcomas (LMSs) from the files of the Armed Forces Institute of Pathology and the Haartman Institute of the University of Helsinki. Ninety-six GISTs were documented as KIT-positive and three additional ones as CD34-positive. Thirty-four tumors were included by their histologic similarity to KIT- or CD34-positive cases. GIST-specific c-kit gene mutations, mostly in exon 11, were documented in 18 of 29 cases (62%). The GISTs occurred in adults with the age range of 17-90 years (median 60 years) with a significant male predominance (71%). The tumors ranged from small asymptomatic intramural nodules to large masses that bulged into pelvis causing pain, rectal bleeding, or obstruction. They were mostly highly cellular spindle cell tumors; four tumors had an epithelioid morphology. The tumors coexpressed CD34 and KIT and were rarely positive for smooth muscle actin or desmin and never for S-100 protein. Seventy percent of patients with tumors >5 cm with more than 5 mitoses/50 high power fields (HPF) (n = 31) died of disease, whereas only one tumor <2 cm with <5 mitoses/50 HPF (n = 21) recurred and none caused death. Long latency was common between primary operation and recurrences and metastases; either one occurred in 60 of 111 patients with follow-up (54%). Distant metastases were in the liver, bones, and lungs. Three benign actin- and desmin-positive and KIT-negative intramural LMs, similar to those seen in the esophagus, were identified. There were eight LMSs, six of which formed a polypoid intraluminal mass and were actin-positive and KIT-negative. Despite high mitotic counts, only one LMS patient died of disease. A great majority of rectal smooth muscle and stromal tumors are GISTs, which have a spectrum from minimal indolent tumors to overt sarcomas. Intramural LMs are exceptional, and true LMSs are rare, and similar to colonic ones, often present as intraluminal polypoid masses that appear to have a better prognosis than GISTs with similar mitotic rates.


Subject(s)
Anus Neoplasms/pathology , Gastrointestinal Neoplasms/pathology , Leiomyoma/pathology , Leiomyosarcoma/pathology , Stromal Cells/pathology , Adolescent , Adult , Aged , Aged, 80 and over , Anus Neoplasms/chemistry , Anus Neoplasms/genetics , Anus Neoplasms/surgery , Base Sequence , Biomarkers, Tumor/analysis , DNA Mutational Analysis , DNA, Neoplasm/analysis , Disease-Free Survival , Female , Follow-Up Studies , Gastrointestinal Neoplasms/chemistry , Gastrointestinal Neoplasms/genetics , Gastrointestinal Neoplasms/surgery , Humans , Immunohistochemistry , Leiomyoma/chemistry , Leiomyoma/genetics , Leiomyoma/surgery , Leiomyosarcoma/chemistry , Leiomyosarcoma/genetics , Leiomyosarcoma/surgery , Male , Middle Aged , Mitotic Index , Molecular Sequence Data , Mutation , Proto-Oncogene Proteins c-kit/analysis , Proto-Oncogene Proteins c-kit/genetics , Stromal Cells/chemistry
10.
Am J Surg Pathol ; 25(8): 979-87, 2001 Aug.
Article in English | MEDLINE | ID: mdl-11474281

ABSTRACT

Gastrointestinal autonomic nerve tumor (GANT) is a gastrointestinal neoplasm that ultrastructurally recapitulates the enteric neural plexus. This study identifies and defines the features of 10 cases of this rare mesenchymal tumor and compares its clinicopathologic and molecular genetic features with the data on gastrointestinal stromal tumor (GIST). The majority of patients in this series presented at an older age (mean 64 years). Tumors arose from the stomach (6), small intestine (2), and retroperitoneum (2). Mean tumor size was 14 cm; however, four neoplasms were <6 cm. Histologically, tumors were spindled or epithelioid; one epithelioid tumor demonstrated a previously undescribed rhabdoid histologic phenotype. All tumors were positive for CD117 (KIT), while eight of 10 were positive for CD34. In contrast, only two were positive for S-100, and all were negative for actin and desmin. Five GANTs demonstrated GIST-specific gain-of-function mutations in the juxtamembrane domain of the c-kit gene (50%). Three of 10 patients died of disease in 22-30 months, one patient died in the postoperative period, and one patient died of complications of CML. The clinicopathologic, histologic, immunohistologic, and molecular features of GANT are similar to GIST, indicating that GANT merely represents a phenotypic variant of GIST.


Subject(s)
Antigens, CD , Autonomic Nervous System Diseases/genetics , Autonomic Nervous System Diseases/metabolism , Gastrointestinal Neoplasms/genetics , Gastrointestinal Neoplasms/metabolism , Nervous System Neoplasms/genetics , Nervous System Neoplasms/metabolism , Adult , Aged , Aged, 80 and over , Amino Acid Sequence , Autonomic Nervous System Diseases/pathology , Base Sequence , Biomarkers, Tumor/metabolism , DNA, Neoplasm/analysis , Female , Gastrointestinal Neoplasms/pathology , Humans , Immunohistochemistry , Leukosialin , Male , Middle Aged , Nervous System Neoplasms/pathology , Organelles/ultrastructure , Proto-Oncogene Proteins c-kit/biosynthesis , Proto-Oncogene Proteins c-kit/genetics , Sialoglycoproteins/analysis , Stromal Cells/metabolism , Stromal Cells/pathology
11.
Cancer Genet Cytogenet ; 128(1): 24-30, 2001 Jul 01.
Article in English | MEDLINE | ID: mdl-11454425

ABSTRACT

Gastrointestinal stromal tumors (GISTs) are distinctive, KIT positive mesenchymal neoplasms. The genetic alterations leading to the malignant behavior of these tumors are not well known. In this study, we looked for recurrent numerical chromosomal changes, which may be associated with malignant GISTs, using interphase fluorescence in situ hybridization (FISH). Fourteen malignant primary tumors and two intra-abdominal recurrences were analyzed. Nine benign tumors were studied for comparison. In all cases, the presence of mutations in exons 9, 11 and 13 of the KIT gene were evaluated. Sixteen centromeric enumeration probes (CEP) for chromosomes 1, 2, 3, 4, 6, 7, 8, 9, 10, 11, 12, 15, 16, 17, 18, and X and three locus specific probes (LSI) for 22q11.2 (BCR-locus), 13q14 (RB1-locus) and 14q32 (IgH-locus) were used. The most common changes seen in malignant GISTs were losses of 14q32 and 22q11. However, these changes were commonly detected in benign tumors and represent early changes related to the pathogenesis of GISTs. Losses of chromosomes 1 and 9 were the only recurrent numerical changes seen exclusively in malignant GISTs. Other recurrent numerical changes seen predominantly in malignant tumors were gain of chromosome 8 and losses of chromosomes 7 and 15. The concurrent loss of chromosome 7 and gain of chromosome 8 (in 4 cases) was never seen together with loss of chromosomes 9 or 15 and only once with loss of chromosome 1. Mutations in KIT were found in the majority of malignant GISTs (64%) confirming a previously shown correlation between presence of such mutations and malignancy. KIT mutations were seen in four of five malignant GISTs with loss of chromosome 9, but only in one of four malignant tumors with loss of chromosome 1. These observations may reflect the different pathways leading to malignant transformation of GISTs.


Subject(s)
Chromosome Aberrations/genetics , Gastrointestinal Neoplasms/genetics , Mutation , Neoplasms, Muscle Tissue/genetics , Proto-Oncogene Proteins c-kit/genetics , Adult , Aged , Aged, 80 and over , Cytogenetic Analysis , DNA, Neoplasm/analysis , Female , Gastrointestinal Neoplasms/metabolism , Humans , Immunoenzyme Techniques , In Situ Hybridization, Fluorescence , Male , Middle Aged , Neoplasms, Muscle Tissue/metabolism , Ploidies , Proto-Oncogene Proteins c-kit/metabolism
12.
Am J Surg Pathol ; 25(5): 610-7, 2001 May.
Article in English | MEDLINE | ID: mdl-11342772

ABSTRACT

Synovial sarcoma (SS) is a mesenchymal neoplasm that typically shows epithelial differentiation. SS commonly metastasizes to lung and pleura, and has also been reported as the primary in these locations. The histologic distinction of SS from mesothelioma may be difficult because of the combination of epithelioid and spindle cells, potentially shared locations, and antigenic expression. In this study the authors examined 103 well-documented SSs including 41 biphasic, 44 monophasic, and 18 poorly differentiated SSs in comparison with 23 epithelioid and seven sarcomatous mesotheliomas. Most biphasic SSs (29 of 41, 71%) had fields or foci of calretinin-positive tumor cells. The spindle cell components were more often positive (55%), whereas 14% of tumors had positive epithelial cells. The monophasic and poorly differentiated SSs commonly had foci of calretinin-positive cells (in 52% and 56% of cases respectively). In comparison, all 23 epithelioid mesotheliomas (EM) were extensively calretinin positive and seven sarcomatoid mesotheliomas were variably calretinin positive. HBME-1 positivity was similarly detected in biphasic SS and EM (100% and 87% respectively). Among the other sarcomas, two of 15 malignant peripheral nerve sheath tumors were focally calretinin positive, whereas 16 epithelioid sarcomas, 20 leiomyosarcomas, 20 gastrointestinal stromal tumors, and 20 angiosarcomas were negative. Biphasic SSs differed from mesotheliomas by their more common BerEp4 positivity (90%) whereas EMs showed focal reactivity in 13% cases. Marked CD15 reactivity was rare in both. Wilms tumor protein-1 (WT1) was not detected in SS, but was present in 12 of 17 EMs. CD141 was rare in SS, limited to spindle cell components, whereas EMs typically showed prominent membrane staining in epithelial cells. Simple epithelial keratins were present in all epithelial cells of biphasic SS and mesothelioma (keratin 7[K7], K19), but were only focal in monophasic and poorly differentiated SS. Biphasic SSs were extensively K14 positive (89% of cases), whereas epithelial and sarcomatoid mesotheliomas typically showed only scattered positive cells. The potentially shared calretinin patterns in SS and mesothelioma require the use of other markers. The discriminating features include extensive BerEp4 positivity, rarity of CD141, and lack of WT1 in SS. Global expression of K7 and K19 in mesotheliomas versus focal expression in monophasic and poorly differentiated SSs, and differential patterns of K14 expression may also be helpful.


Subject(s)
Biomarkers, Tumor/analysis , Mesothelioma/chemistry , S100 Calcium Binding Protein G/analysis , Sarcoma, Synovial/chemistry , Soft Tissue Neoplasms/chemistry , Adolescent , Adult , Aged , Antibodies, Monoclonal/immunology , Antigens, Neoplasm/analysis , Antigens, Surface/analysis , Calbindin 2 , Child , DNA-Binding Proteins/analysis , Female , Humans , Immunoenzyme Techniques , Lewis X Antigen/analysis , Male , Mesothelioma/immunology , Mesothelioma/pathology , Middle Aged , Sarcoma, Synovial/immunology , Sarcoma, Synovial/pathology , Soft Tissue Neoplasms/immunology , Soft Tissue Neoplasms/pathology , Thrombomodulin/analysis , Transcription Factors/analysis , WT1 Proteins
13.
Am J Pathol ; 158(4): 1223-9, 2001 Apr.
Article in English | MEDLINE | ID: mdl-11290539

ABSTRACT

Perineurial cell tumors (PNTs) are rare neoplasms derived from or showing differentiation toward specialized lining cells of the nerve sheath, the perineurial cells. In this study, we have evaluated neurofibromatosis type 2 (NF2) gene alterations in eight PNTs using archival formaldehyde-fixed, paraffin-embedded tissue. Two conventional soft-tissue PNTs from the upper back and chest wall, one retiform soft tissue variant from the scapular region, and five sclerosing PNTs from the fingers and palm were studied. All cases showed histological features of PNTs, and the neoplastic cells were positive for epithelial membrane antigen and negative for S100 protein. The coding sequences (exons 1 to 15) of the NF2 gene were polymerase chain reaction (PCR) amplified and evaluated for mutations by direct sequencing of the PCR products. Five NF2 point mutations, two in the 5'-untranslated region (UTR) and three in exons 3, 6, and 8, were identified in four of eight cases (50%) studied. Exon mutations resulted in changes of predicted amino acids sequences: Asp-->Asn at codon 83, Glu-->Asp at codon 182, and Leu-->Val at codon 241. In two cases (one with a missense mutation in codon 241), the same point mutation in the 5'-UTR at the nucleotide position 8958 was identified. A loss of heterozygosity (LOH) study was performed in three cases. LOH at the NF2 locus was found in one case with a mutation in the 5'-UTR. However, in another case with exon 8 and 5'-UTR mutations, deletion of one allele of the NF2 gene was previously documented by fluorescence in situ hybridization. The coexistence of NF2 gene mutations and LOH at the NF2 locus indicates that the NF2 tumor suppressor gene is altered in PNTs by the two-hit mechanism.


Subject(s)
Mutation , Neurofibromatosis 2/genetics , Peripheral Nervous System Neoplasms/genetics , Adolescent , Adult , Base Sequence/genetics , Chromosomes, Human, Pair 22/genetics , Female , Hand , Humans , Immunohistochemistry , Loss of Heterozygosity , Male , Middle Aged , Molecular Biology , Mutation, Missense , Peripheral Nervous System Neoplasms/metabolism , Peripheral Nervous System Neoplasms/pathology , Point Mutation , Shoulder , Soft Tissue Neoplasms/genetics , Soft Tissue Neoplasms/metabolism , Soft Tissue Neoplasms/pathology , Thoracic Neoplasms/genetics , Thoracic Neoplasms/metabolism , Thoracic Neoplasms/pathology
14.
Am J Surg Pathol ; 25(2): 205-11, 2001 Feb.
Article in English | MEDLINE | ID: mdl-11176069

ABSTRACT

The diagnosis of metastatic malignant melanoma (MMM) may be difficult in surgical pathology, often complicated by the unpredictable spread of this tumor and its great variability on histologic evaluation. Traditionally used immunohistochemical markers on melanomas are insufficient because of either a relative lack of specificity (S100 protein) or variably reported sensitivity (HMB45). Information about some newer markers, such as tyrosinase (TYR) and Melan A, is more limited. Recently, based on the study of a small number of tumors, it was suggested that microphthalmia transcription factor (MITF) is 100% sensitive in the identification of metastatic melanoma. In the current study, we compared the diagnostic usefulness of MITF with that of four other markers in 266 cases of conventional metastatic melanomas from different sites, 33 cases of desmoplastic melanomas, and 1 case of melanoma with rhabdoid features. The specificity of MITF was evaluated by using a representative sample of control tumors. Microphthalmia transcription factor with nuclear positivity was seen in 235 of 266 cases of conventional MMM (88%), usually in more than 30% of tumor cells. However, some melanomas had only foci of MITF- and TYR-positive cells, whereas the majority of cells were generally S100 protein-positive. Only 1 of 30 desmoplastic melanomas (3%) had MITF-positive cells, representing epithelioid foci resembling conventional melanoma. Two cases had TYR in a similar pattern; all were HMB45-negative. One metastatic melanoma with rhabdoid features was negative for MITF and other markers except the S100 protein. Half of the S100 protein negative conventional melanomas (6 of 12) were MITF-positive, whereas 4 of 20 (20%) TYR-negative tumors had reactivity for MITF. The percentages of positive cases of MMM (10% or more tumor cells positive) diagnosed with the four other markers in descending order were 90% (S100 protein and TYR), 78% (melan-A), and 66% (HMB45). Microphthalmia transcription factor appeared to be specific, because significant reactivity was not found in 112 carcinomas, 20 lymphomas, 20 angiosarcomas, 20 fibrous histiocytomas, and 20 malignant peripheral nerve sheath tumors. However, positive nuclei were found focally among reactive histiocytes, especially in osteoclasts, epithelioid histiocytes, and sporadic other histiocytes. Microphthalmia transcription factor may be a valuable addition to the marker panel used in diagnosing melanoma, in combination with S100, TYR, and the other markers, but it is not present in cases of desmoplastic melanomas.


Subject(s)
DNA-Binding Proteins/analysis , Melanoma/chemistry , Skin Neoplasms/chemistry , Transcription Factors , Angiomyolipoma/chemistry , Angiomyolipoma/pathology , Antibodies, Monoclonal/immunology , Antigens, Neoplasm , Biomarkers, Tumor/analysis , Fluorescent Antibody Technique, Indirect , Histiocytes/chemistry , Histiocytes/cytology , Humans , Lymphangiomyoma/chemistry , Lymphangiomyoma/pathology , MART-1 Antigen , Melanoma/secondary , Melanoma-Specific Antigens , Microphthalmia-Associated Transcription Factor , Monophenol Monooxygenase/analysis , Neoplasm Proteins/analysis , S100 Proteins/analysis , Sensitivity and Specificity , Skin Neoplasms/pathology
15.
Virchows Arch ; 438(1): 1-12, 2001 Jan.
Article in English | MEDLINE | ID: mdl-11213830

ABSTRACT

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal (GI) tract. They are defined here as KIT (CD117, stem cell factor receptor)-positive mesenchymal spindle cell or epithelioid neoplasms primary in the GI tract, omentum, and mesentery. GISTs typically present in older individuals and are most common in the stomach (60-70%), followed by small intestine (20-25%), colon and rectum (5%), and esophagus (<5%). Benign tumors outnumber the malignant ones by a wide margin. Approximately 70% of GISTs are positive for CD34, 20-30% are positive for smooth muscle actin (SMA), 10% are positive for S100 protein and <5% are positive for desmin. The expression of CD34 and SMA is often reciprocal. GISTs commonly have activating mutations in exon 11 (or rarely exon 9 and exon 13) of the KIT gene that encodes a tyrosine kinase receptor for the growth factor named stem cell factor or mast cell growth factor. Ligand-independent activation of KIT appears to be a strong candidate for molecular pathogenesis of GISTs, and it may be a target for future treatment for such tumors. Other genetic changes in GISTs discovered using comparative genomic hybridization include losses in 14q and 22q in both benign and malignant GISTs and occurrence in various gains predominantly in malignant GISTs. GISTs have phenotypic similarities with the interstitial cells of Cajal and, therefore, a histogenetic origin from these cells has been suggested. An alternative possibility, origin of pluripotential stem cells, is also possible; this is supported by the same origin of Cajal cells and smooth muscle and by the common SMA expression in GISTs. GISTs differ clinically and pathogenetically from true leiomyosarcomas (very rare in the GI tract) and leiomyomas. The latter occur in the GI tract, predominantly in the esophagus (intramural tumors) and the colon and rectum (muscularis mucosae tumors). They also differ from schwannomas that are benign S100-positive spindle cell tumors usually presenting in the stomach. GI autonomic nerve tumors (GANTs) are probably a subset of GIST. Other mesenchymal tumors that have to be separated from GISTs include inflammatory myofibroblastic tumors in children, desmoid, and dedifferentiated liposarcoma. Angiosarcomas and metastatic melanomas, both of which are often KIT-positive, should not be confused with GISTs.


Subject(s)
Gastrointestinal Neoplasms/diagnosis , Amino Acid Sequence , Diagnosis, Differential , Gastrointestinal Neoplasms/chemistry , Gastrointestinal Neoplasms/genetics , Gastrointestinal Neoplasms/pathology , Humans , Immunohistochemistry , Leiomyoma/diagnosis , Leiomyoma/pathology , Molecular Sequence Data , Mutation , Neurilemmoma/diagnosis , Neurilemmoma/pathology , Oncogene Proteins/analysis , Oncogene Proteins/chemistry , Oncogene Proteins/genetics , Proto-Oncogene Proteins c-kit
16.
Virchows Arch ; 437(3): 275-83, 2000 Sep.
Article in English | MEDLINE | ID: mdl-11037348

ABSTRACT

Synovial sarcoma is a mesenchymal neoplasm of unknown histogenesis that shows various degrees of epithelial differentiation. It is known to contain simple epithelial keratins, and the possibility of complex epithelial keratin expression has been suggested. In this study, we immunohistochemically examined 110 well-documented synovial sarcomas including 44 biphasic, 48 monophasic, and 18 poorly differentiated (undifferentiated, highly mitotically active) tumors for 11 different keratin (K) polypeptides of the Moll catalogue. The epithelia of biphasic synovial sarcomas showed consistent, extensive reactivity for K7, K8, K14, K18, and K19. Other keratins seen in the epithelia of biphasic tumors included K17 (variable, in 77%), K13 (25%), K16 (23%), and K6 (24%) in the minority of biphasic tumors, predominantly in stratified-appearing epithelia. K10 was detected only focally in one case that showed keratinizing squamous differentiation. Focal expression of K20 was seen in 27% of cases. Monophasic synovial sarcomas had a more limited keratin repertory. Simple epithelial keratin positivity was detected, usually focally for K7 (79%), K19 (60%), K8 (45%), and K18 (46%). Two cases showed more extensive keratin positivity in the spindle cells. The monophasic tumors showed limited positivity for complex epithelial keratins: K14 (28%) and K17 (10%). K20 was detected focally in 6% of the monophasic tumors; other keratins were not detected. The poorly differentiated synovial sarcomas showed limited simple epithelial keratin reactivity, usually limited to scattered cells: K19 (61%), K7 (50%), K18 (47%), K8 (33%), but five cases showed more extensive positivity. Complex epithelial keratins were scant: K14 in one case and K17 in two cases. The immunoreactivity of capillary endothelia seen for K7 and K18 (but not for K8 and K19 with the antibodies used) is a potential diagnostic pitfall, and may cause overdiagnosis of synovial sarcoma if not properly recognized. In summary, we show complex patterns of keratins in synovial sarcoma, especially in the biphasic tumors. Such patterns establish a baseline in differential diagnostic considerations, and give an insight into the complex epithelial differentiation of this enigmatic mesenchymal tumor.


Subject(s)
Keratins/analysis , Sarcoma/chemistry , Synovial Membrane , Adolescent , Adult , Aged , Child , Female , Humans , Immunohistochemistry , Male , Mesothelioma/chemistry , Middle Aged , Sarcoma/pathology
17.
Am J Pathol ; 157(4): 1091-5, 2000 Oct.
Article in English | MEDLINE | ID: mdl-11021812

ABSTRACT

Gastrointestinal stromal tumors (GISTs), the most common mesenchymal tumors of the gastrointestinal tract, typically express the KIT protein. Activating mutations in the juxtamembrane domain (exon 11) of the c-kit gene have been shown in a subset of GISTs. These mutations lead into ligand-independent activation of the tyrosine kinase of c-kit, and have a transforming effect in vitro. Several groups have studied the clinical implication of the c-kit mutation status of exon 11 in GISTs and a possible relationship between c-kit mutations and malignant behavior has been established. Recently, a 1530ins6 mutation in exon 9 and missense mutations, 1945A>G in exon 13 of the c-kit gene were reported. The frequency and clinical importance of these findings are unknown. In this study we evaluated 200 GISTs for the presence of mutations in exons 9 and 13 of c-kit. Six cases revealed 1530ins6 mutation in exon 9 and two cases 1945A>G mutation in exon 13. All tumors with mutations in exon 9 and 13 lacked mutations in exon 11 of c-kit. None of the analyzed tumors had more than one type of c-kit mutation. All but one of the eight tumors with mutations in exon 9 or 13 of the c-kit gene were histologically and clinically malignant. All four of six cases with exon 9 mutation of which location of primary tumor was known, were small intestinal, suggesting that this type of mutation could preferentially occur in small intestinal tumors. Exon 9 and 13 mutations seem to be rare, and they cover only a small portion (8%) of the balance of GISTs that do not have mutations in exon 11 of c-kit. This finding indicates that other genetic alterations may activate c-kit in GISTs, or that KIT is not activated by mutations in all cases.


Subject(s)
Exons , Gastrointestinal Neoplasms/genetics , Gastrointestinal Neoplasms/pathology , Mutation/genetics , Proto-Oncogene Proteins c-kit/genetics , Stromal Cells/pathology , Adult , Aged , Base Sequence/genetics , Female , Gene Frequency , Humans , Male , Middle Aged , Reference Values
18.
Am J Surg Pathol ; 24(10): 1339-52, 2000 Oct.
Article in English | MEDLINE | ID: mdl-11023095

ABSTRACT

Gastrointestinal stromal tumors (GISTs), mesenchymal tumors largely specific for the gastrointestinal tract, have been well defined in the stomach and small intestine, but have not been extensively documented or contrasted with true smooth muscle tumors in the colon. This study was undertaken to determine the clinicopathologic features of GISTs of the colon, excluding the rectum, and to compare them with leiomyosarcomas (LMSs) of the same location. A total of 37 colonic GISTs and seven LMSs from the files of the Armed Forces Institute of Pathology and the Haartman Institute of the University of Helsinki were analyzed. The GISTs occurred predominantly in adults older than 50 years of age (median, 67 yrs), and most were histologically malignant; four small benign tumors (< or = 1 cm) were incidentally detected, and 10 others had minimal mitotic activity (five or fewer mitoses per 50 high-power fields). The colonic GISTs were typically transmural tumors with frequent intraluminal and outward bulging components. Histologically, they usually showed a spindle cell pattern (92%), whereas 8% were epithelioid. Most tumors (19 of 25) were positive for CD117 (KIT) and for CD34 (16 of 27); six tumors coexpressed alpha-smooth muscle actin and CD117; none showed desmin or S-100 protein. C-kit mutations in exon 11 were seen in 5 (36%) of 14 colonic GISTs. None of the patients with incidental small tumors had a recurrence, whereas 2 of 10 patients with tumors larger than 1 cm but minimal mitotic activity died of the disease with liver metastasis. Nearly all patients whose tumor was larger than 1 cm and showed more than five mitoses per 50 high-power fields died of disease; half had evidence of metastasis. LMSs were typically intraluminally bulging, polypoid masses that showed a histologic likeness to differentiated smooth muscle cells. They occurred in five men and two women with a median age of 61 years. Most LMSs were high-grade histologically and showed smooth muscle actin, desmin, or both. All were negative for CD34 and CD117 and lacked c-kit mutations. Five of the seven patients died of disease, and two had a long-term survival, despite high mitotic activity. These results show that KIT-positive GISTs are more common than LMSs of the colon, and these tumor groups have clinicopathologic differences that warrant their separation.


Subject(s)
Colonic Neoplasms/pathology , Leiomyoma/pathology , Leiomyosarcoma/pathology , Stromal Cells/pathology , Adult , Aged , Aged, 80 and over , Amino Acid Sequence , Base Sequence , Biomarkers, Tumor/analysis , Colonic Neoplasms/chemistry , Colonic Neoplasms/genetics , Colonic Neoplasms/surgery , DNA Primers/chemistry , DNA, Neoplasm/analysis , Female , Humans , Immunoenzyme Techniques , Leiomyoma/chemistry , Leiomyoma/genetics , Leiomyoma/surgery , Leiomyosarcoma/chemistry , Leiomyosarcoma/genetics , Leiomyosarcoma/surgery , Male , Middle Aged , Molecular Sequence Data , Mutation , Neoplasm Proteins/analysis , Polymerase Chain Reaction , Proto-Oncogene Proteins c-kit/analysis , Proto-Oncogene Proteins c-kit/genetics , Treatment Outcome
19.
Arch Pathol Lab Med ; 124(6): 894-7, 2000 Jun.
Article in English | MEDLINE | ID: mdl-10835530

ABSTRACT

Most mesenchymal tumors of the gastrointestinal tract are now referred to as gastrointestinal stromal tumors (GISTs). The tumors differ from ordinary leiomyomas and schwannomas in several respects: the GISTs typically express c-kit protein (CD117) and CD34, 30% to 50% of them are (often focally) positive for alpha-smooth muscle actin, and all are negative for desmin and S100 protein. Recently, mutations in the exon 11 of the c-kit gene have been identified and confirmed as a molecular genetic marker for the subset of GISTs. In this report, we describe a mesenchymal tumor removed from the pelvic cavity of a 52-year-old woman, who is alive without disease 36 months after the surgery. The 5-cm tumor was densely attached to the external aspect of the urinary bladder but was attached to small intestine by only filmy adhesions. The tumor grossly resembled a leiomyoma and was histologically composed of sheets of spindle cells with a dense collagenous background. The mitotic activity was low, less then 1 per 50 high-power fields. Immunohistochemically, the tumor cells were negative for alpha-smooth muscle actin and desmin and positive for CD117 and CD34. Molecular genetic analysis of the exon 11 of the c-kit gene revealed a point mutation in the region commonly mutated in GISTs. This mutation substituted T for A in the codon 557, leading to the change of amino acid sequence (tryptophan for arginine) of the KIT protein. This case illustrates that tumors phenotypically and genotypically similar to GISTs may present in sites other than the tubular gastrointestinal tract.


Subject(s)
Point Mutation , Proto-Oncogene Proteins c-kit/genetics , Urinary Bladder Neoplasms/genetics , Urinary Bladder Neoplasms/pathology , Amino Acid Sequence , Amino Acid Substitution , Antigens, CD34/analysis , Female , Gastrointestinal Neoplasms/genetics , Genotype , Humans , Middle Aged , Molecular Sequence Data , Phenotype , Proto-Oncogene Proteins c-kit/analysis , Proto-Oncogene Proteins c-kit/chemistry , Sequence Alignment , Treatment Outcome , Urinary Bladder Neoplasms/immunology , Urinary Bladder Neoplasms/surgery
20.
Mod Pathol ; 13(5): 536-41, 2000 May.
Article in English | MEDLINE | ID: mdl-10824925

ABSTRACT

C-kit proto-oncogene product (KIT, CD117) is a tyrosine kinase growth factor receptor for stem cell factor. This receptor is important for the development and maintenance of hematopoietic stem cells, mast cells, germ cells, melanocytes, and interstitial cells of Cajal and is constitutively expressed in them. Among mesenchymal tumors, KIT seems to be specific for the gastrointestinal stromal tumors, which consistently express this protein. Activating mutations in the tyrosine kinase or juxtamembrane domains of c-kit gene have been found in mastocytoma, seminoma, and gastrointestinal stromal tumors. Following up our initial observation of KIT expression in one angiosarcoma, we examined 50 angiosarcomas, 13 Kaposi sarcomas, 10 epithelioid hemangioendotheliomas, and 31 hemangiomas of different types for KIT expression using a polyclonal antiserum specific to KIT. Adult and fetal tissues and neovascular endothelia in 20 carcinomas were studied for comparison. More than half (56%) of the angiosarcomas representing different clinicopathologic and histologic subtypes and 2 of 13 Kaposi sarcoma were KIT positive. All epithelioid hemangioendotheliomas and hemangiomas were negative, with the exception of two infantile hemangiomas that showed KIT reactivity. The fetal capillary endothelia of lungs, placenta, and soft tissues were also KIT positive, although in soft tissues and placenta, KIT positivity was more prominent in the first trimester. However, endothelia of adult vessels and neovascular capillaries of carcinomas were negative. None of the four KIT-positive angiosarcomas and one KIT-positive Kaposi sarcomas that were studied showed mutations in the juxtamembrane or tyrosine kinase domains of the c-kit gene. These results indicate that KIT expression occurs in a subset of angiosarcomas, and the expression probably represents oncofetal expression (i.e., reversion of the tumor cell phenotype to that of fetal endothelial cells that may show KIT expression).


Subject(s)
Endothelium, Vascular/chemistry , Hemangiosarcoma/metabolism , Proto-Oncogene Proteins c-kit/biosynthesis , Adult , DNA Mutational Analysis , DNA, Neoplasm/chemistry , DNA, Neoplasm/genetics , Endothelium, Vascular/cytology , Endothelium, Vascular/embryology , Exons , Fetus , Hemangioendothelioma, Epithelioid/metabolism , Hemangioendothelioma, Epithelioid/pathology , Hemangioma, Capillary/metabolism , Hemangioma, Capillary/pathology , Hemangiosarcoma/genetics , Hemangiosarcoma/pathology , Humans , Immunohistochemistry , Infant , Mutation , Proto-Oncogene Mas , Proto-Oncogene Proteins c-kit/genetics , Sarcoma, Kaposi/genetics , Sarcoma, Kaposi/metabolism , Sarcoma, Kaposi/pathology
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