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Mesenchymal Tumors (mesenchymal + tumor)
Kinds of Mesenchymal Tumors Selected AbstractsFrequency and characterization of HMGA2 and HMGA1 rearrangements in mesenchymal tumors of the lower genital tractGENES, CHROMOSOMES AND CANCER, Issue 11 2007Fabiola Medeiros Mesenchymal tumors of the lower genital tract predominantly occur in women of reproductive age and are mainly represented by aggressive angiomyxoma (AAM) and angiomyofibroblastoma (AMF). Whether these tumors are different phenotypic expressions of the same biological entity is still debatable. Genetic rearrangements of HMGA2 have been reported in a few cases of AAM but its frequency and clinicobiological implications have not been studied systematically. We evaluated 90 cases of mesenchymal tumors of the lower genital tract that comprised 42 AAMs, 18 AMFs, 6 cellular angiofibromas, 5 fibroepithelial stromal polyps, 15 genital leiomyomas, 3 superficial angiomyxomas, and 1 spindle cell lipoma. Fluorescence in situ hybridization was used to identify rearrangements of HMGA2 and its homologue HMGA1. HMGA2 rearrangements were identified in 14 AAMs (33%) and in 1 vaginal leiomyoma. All other tumors were negative for HMGA2 rearrangements. HMGA1 rearrangement was not found in any of the cases. RT-PCR confirmed transcriptional upregulation of HMGA2 only in tumors with HMGA2 rearrangements. Standard cytogenetic analyses were performed in two AAMs and one AMF. One AAM had a t(1;12)(p32;q15); the other tumors had normal karyotypes. Mapping and sequence analysis of the breakpoint showed fusion to the 3, untranslated region of HMGA2 to genomic sequences derived from the contig NT 032977.8 on chromosome 1p32. Our findings support the hypothesis that AAM and AMF are distinct biological entities. The diagnostic usefulness of HMGA2 rearrangements to differentiate between AAM and other tumors of the lower genital tract may be limited due to the their low frequency. © 2007 Wiley-Liss, Inc. [source] Detection of a t(1;22)(q23;q12) translocation leading to an EWSR1-PBX1 fusion gene in a myoepitheliomaGENES, CHROMOSOMES AND CANCER, Issue 7 2008Petter Brandal Chromosome banding as well as molecular cytogenetic methods are of great help in the diagnosis of mesenchymal tumors. Myoepithelial neoplasms of soft tissue including myoepitheliomas, mixed tumors, and parachordomas are diagnoses that have been increasingly recognized the last few years. It is still debated which neoplasms should be included in these morphologically heterogeneous entities, and the boundaries between them are not clear-cut. The pathogenetic mechanisms behind myoepithelial tumors are unknown. Only five parachordomas and one mixed tumor have previously been karyotyped, and nothing is known about their molecular genetic characteristics. We present a mesenchymal tumor classified as a myoepithelioma that had a balanced translocation t(1;22)(q23;q12) as the sole karyotypic change. A novel EWSR1-PBX1 fusion gene consisting of exons 1,8 of the 5,-end of EWSR1 and exons 5,9 of the 3,-end of PBX1 was shown to result from the translocation. Both genes are known to be targeted also by other neoplasia-specific translocations, PBX1 in acute lymphoblastic leukemia and EWSR1 in several solid tumors, most of which are malignant. Based on the structure of the novel fusion gene detected, its transforming mechanism is thought to be the same as for other fusion genes involving EWSR1 or PBX1. © 2008 Wiley-Liss, Inc. [source] Pleomorphic hyalinizing angiectactic tumor of the buccal mucosaJOURNAL OF ORAL PATHOLOGY & MEDICINE, Issue 8 2004Fumio Ide Pleomorphic hyalinizing angiectactic tumor (PHAT) of soft parts is a recently defined mesenchymal tumor of uncertain differentiation, with only a limited number of examples reported to date. We present a case of PHAT of the buccal mucosa in an 86-year-old woman. To our knowledge, there is no formal description of this tumor in the oral cavity. [source] PKC theta, a novel immunohistochemical marker for gastrointestinal stromal tumors (GIST), especially useful for identifying KIT-negative tumorsPATHOLOGY INTERNATIONAL, Issue 3 2005Atsushi Motegi Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor in the digestive tract and the majority of GIST has characteristic gain-of-function mutations of the c-kit gene, which encodes the KIT receptor for stem cell factor. The present study aimed to establish the usefulness of protein kinase C theta (PKC ,) as an immunohistochemical marker for GIST in comparison with KIT immunohistochemistry. PKC , immunohistochemistry was carried out not only on 48 cases of GIST and another 40 cases of gastrointestinal mesenchymal tumors, but also on 24 cases of various tumors known to be immunohistochemically positive for KIT. Immunohistochemically, 41 out of 48 cases (85%) of GIST were positive for PKC ,, and its expression was confirmed by Western blot analysis using six cases of surgically resected GIST. In the present study there were six GIST immunohistochemically negative for KIT, which histologically revealed a myxoid epithelioid appearance characteristic to that of GIST with platelet-derived growth factor receptor alpha mutation. All six GIST were immunohistochemically positive for PKC ,. No PKC , immunoreactivity was observed in other gastrointestinal mesenchymal tumors and various KIT-positive tumors except for three cases (14%) of gastrointestinal schwannomas. The present study revealed that PKC , is an immunohistochemically novel and useful marker for GIST, especially for GIST negative for KIT. [source] Sarcomatoid hepatocellular carcinoma with hepatoblastoma-like features in an adultPATHOLOGY INTERNATIONAL, Issue 6 2004Min-Sun Cho A mixed epithelial and mesenchymal tumor of the liver arising in an adult is rare and is mostly classified as sarcomatoid hepatocellular carcinoma (HCC). In this study, a case of sarcomatoid HCC in an adult with hepatoblastoma (HB)-like features, which produced difficulty in the differential diagnosis between sarcomatoid HCC and mixed HB, is presented. The epithelial component of the tumor composed of poorly differentiated HCC, Edmondson's grade III, and more primitive components, which were embryonal and small cell undifferentiated components of HB-like areas. The small undifferentiated cells surrounded HCC and the embryonal component of HB-like area, and revealed transition partly to areas of rhabdomyosarcoma. A small portion of chondrosarcoma was also noted. Immunohistochemical analysis showed that HCC and the embryonal component of HB-like areas expressed alpha-fetoprotein (AFP) and cytokeratin 8. The small undifferentiated cells were negative for AFP but stained with cytokeratin 8 as well as CD56, which is a marker of primitive cells in many sarcoma and HB. It is not certain whether small undifferentiated cells belong to hepatic progenitor cells or primitive mesenchymal cells. Polymerase chain reaction,single-strand conformation polymorphism analysis for beta-catenin mutation using microdissection revealed no mutation of any components. A review was undertaken of the cases previously reported as adult hepatoblastoma without detailed immunohistochemical study and consider many of them may be sarcomatoid HCC. These primitive and sarcomatoid components would be arising from the dedifferentiation process of HCC. [source] A malign mesenchymal tumor (sarcoma) of the pulmonary artery presenting as a form of acute thromboembolism: educational caseTHE CLINICAL RESPIRATORY JOURNAL, Issue 3 2010Yasin Abul No abstract is available for this article. [source] Synovial Cell Sarcoma: Diagnosis, Treatment, and OutcomesTHE LARYNGOSCOPE, Issue 11 2002Swapna S. Kartha Abstract Objectives/Hypothesis Synovial cell sarcoma is a mesenchymal tumor predominantly of the lower extremities. Three percent of cases arise in the head and neck region. It is thought that head and neck synovial sarcoma has a better prognosis than tumors of the extremities. Our experience has demonstrated aggressive behavior of this neoplasm in the head and neck. This compelled us to compare our experience with other studies. Study Design Retrospective chart review. Methods We obtained the records of patients diagnosed with head and neck synovial sarcoma from the Tumor Registry of the University of Louisville School of Medicine (Louisville, KY) and affiliated hospitals for data compiled between January 1990 and December 2000. Data on patient demographics, clinical findings and symptoms, histological findings, treatment, extent of disease, recurrence, and survival were recorded. The literature was reviewed identifying reports of synovial cell sarcoma. Results Five consecutive patients with synovial cell sarcoma were assessed at our facility. The median patient age was 28.2 years. All of the patients underwent an aggressive primary surgical excision followed by irradiation. All patients received chemotherapy after recurrence. Four of the five patients had local recurrence, and all five of the patients developed distant metastases. Three of the patients have died, and two are alive with evidence of disease. Novel sites are reported including the ethmoid sinus and the parotid gland. This group demonstrated a 40% 5-year overall survival, which was lower than the 60% 5-year survival reported in the literature for all sites. Conclusions Synovial cell sarcoma of the head and neck is a disease of young people and carries a poor prognosis. The aggressive nature of the disease may require modification of accepted treatment modalities and sequence. [source] Tyrosine kinase mutations in gastrointestinal stromal tumors in a nation-wide study in IcelandAPMIS, Issue 9 2010GEIR TRYGGVASON Tryggvason G, Hilmarsdottir B, Gunnarsson GH, Jónsson JJ, Jónasson JG, Magnússon MK. Tyrosine kinase mutations in gastrointestinal stromal tumors in a nation-wide study in Iceland. APMIS 2010; 118: 648,56. Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the gastrointestinal tract. It is characterized by activating mutations in the tyrosine kinase genes c-kit or PDGFRA. This study examined the mutation rate and type in a population-based material. All gastrointestinal mesenchymal tumors over the years 1990,2004 were evaluated and GIST tumors identified using immunohistochemistry (c-kit) and conventional pathologic parameters. Paraffin sections from all tumors were subjected to mutation analysis on exons 9, 11, 13 and 17 of the c-kit gene and exons 12 and 18 of the PDGFRA gene. To screen for mutations, we used a highly sensitive conformation-sensitive gel electrophoresis (CSGE) and to define the mutated alleles, we employed direct automated DNA sequencing. All c-kit-positive gastrointestinal mesenchymal tumors were entered into the study. Fifty-six tumors from 55 patients were analyzed. Mutations were found in 52 tumors representing a 92.9% mutational rate. Most of the mutations were found in c-kit exon 11 (76.8%), followed by c-kit exon 9 (10.7%). PDGFRA mutations were only found in three tumors. No correlation of mutation type with biologic behavior was found. This population-based study, using a sensitive CSGE method, identifies mutations in the great majority of patients with GIST. [source] Mutations in gastrointestinal stromal tumors , a population-based study from Northern Norway,APMIS, Issue 4 2007SONJA E. STEIGEN Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the gastrointestinal tract. This tumor typically expresses KIT, and has KIT or PDGFRA activating mutation. In this study we evaluated 89 GISTs diagnosed in Northern Norway during a 30-year period. KIT exons 8, 9, 11, 13, and 17 were analyzed by PCR amplification and direct sequencing. Subsequently PDGRA exons 12, 14, and 18 were evaluated in KIT wild-type cases. KIT mutations were found in 66 cases (75%), and PDGFRA mutations in 9 cases (10%). Most common were KIT exon 11 mutations, with 58 cases. Tumors with Kit exon 11 point mutations had a significantly better prognosis than those with deletions. There were five KIT exon 9 duplications, three exon 13 point mutations, and one point mutation in exon 17. There were nine PDGFGRA mutations: seven in exon 18 and two in exon 12. All but one PDGFRA mutant GISTs were gastric tumors with epithelioid morphology, and these tumors were on average smaller than those with KIT mutations. KIT and PDGFRA wild type was found in 15% of cases. Analysis of KIT and PDGFRA mutations is of significance for treatment with tyrosine kinase inhibitors, and may also have value when assessing the biological potential of GIST. [source] Gastrointestinal stromal tumors (GIST): A model for molecule-based diagnosis and treatment of solid tumorsCANCER SCIENCE, Issue 4 2003Yukihiko Kitamura Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the human gastrointestinal (GI) tract. The c-kit receptor tyrosine kinase (KIT) is expressed by practically all GISTs, and gain-of-function mutations of KIT are present in most GISTs. Interstitial cells of Cajal (ICC) are the pacemaker of the peristaltic movement of the GI tract. Since signals through KIT are essential for development of ICC and since multiple GISTs develop from the hyperplastic lesion of ICCs in familial GIST patients with germ-line mutations of KIT, GISTs are considered to originate from ICC. Imatinib mesylate, which was developed for treatment of chronic myeloid leukemia (CML), was found to be useful for treatment of GISTs. Imatinib mesylate inhibits BCR-ABL fused tyrosine kinase that causes CML. Imatinib mesylate also inhibits the mutated KIT observed in most GISTs, and this explains the effectiveness of Imatinib mesylate on GISTs. GISTs appear to serve as a model for molecule-based diagnosis and treatment of solid tumors. (Cancer Sci 2003; 94: 315,320) [source] Diagnosis of metastatic pancreatic mesenchymal tumors by endoscopic ultrasound-guided fine-needle aspiration,DIAGNOSTIC CYTOPATHOLOGY, Issue 11 2009Linda Varghese M.D. Abstract Involvement of the pancreas by metastatic sarcoma is rare, and can prove challenging to differentiate from sarcomatoid carcinomas which occur more commonly. The endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) technique has been successfully used for the diagnosis of pancreatic carcinomas whether primary or metastatic, and is now considered the most effective noninvasive method for the identification of pancreatic metastases. However, to date very few reports detail the diagnosis of mesenchymal neoplasms by EUS-FNA. Herein, we report a series of four patients who underwent EUS-FNA of the pancreas, where the diagnosis of metastatic sarcoma was made based on morphology and ancillary studies. The cases include metastases of leiomyosarcoma, liposarcoma, alveolar rhabdomyosarcoma, and solitary fibrous tumor. The history of a primary sarcoma of the chest wall, mediastinum, and respectively lower extremity was known for the first three of these patients while in the case of the solitary fibrous tumor a remote history of a paraspinal "hemangiopericytoma" was only elicited after the EUS-FNA diagnosis was made. We conclude that EUS-FNA is efficient and accurate in providing a diagnosis of sarcoma, even in patients without a known primary sarcoma, thus allowing institution of therapy without additional biopsies. Diagn. Cytopathol. 2009. © 2009 Wiley-Liss, Inc. [source] GASTRIC SCHWANNOMA WITH ADJACENT EXTERNAL PROGRESSION HARBORED ABERRANT NF2 GENEDIGESTIVE ENDOSCOPY, Issue 3 2009Naotaka Ogasawara Gastric schwannomas are rare benign mesenchymal tumors. We describe a schwannoma of gastric origin with adjacent external progression. Sections showed a spindle cell tumor arranged in interlaced bundles and fascicles that was S-100 and CD34 positive but c-KIT protein negative. Histology and immunohistochemistry revealed the typical appearance of a gastric schwannoma. Genetic evaluation revealed that the tumor harbored a point mutation in exon 6 of the tumor suppressor neurofibromatosis 2 (NF2) gene, which resulted in an amino acid substitution of NF2 protein, and no mutation in exon 4b of the NF1 gene. In conclusion, we identified a rare mutation of the NF2 gene in gastric schwannoma. A diagnosis can only be definitive when based on histological and immunohistochemical findings. Digestive tract schwannomas are rare mesenchymal tumors that are differentiated from gastrointestinal stromal tumors by the absence of KIT protein. Follow up suggested that complete resection is an effective long-term treatment strategy. [source] Detection of a t(1;22)(q23;q12) translocation leading to an EWSR1-PBX1 fusion gene in a myoepitheliomaGENES, CHROMOSOMES AND CANCER, Issue 7 2008Petter Brandal Chromosome banding as well as molecular cytogenetic methods are of great help in the diagnosis of mesenchymal tumors. Myoepithelial neoplasms of soft tissue including myoepitheliomas, mixed tumors, and parachordomas are diagnoses that have been increasingly recognized the last few years. It is still debated which neoplasms should be included in these morphologically heterogeneous entities, and the boundaries between them are not clear-cut. The pathogenetic mechanisms behind myoepithelial tumors are unknown. Only five parachordomas and one mixed tumor have previously been karyotyped, and nothing is known about their molecular genetic characteristics. We present a mesenchymal tumor classified as a myoepithelioma that had a balanced translocation t(1;22)(q23;q12) as the sole karyotypic change. A novel EWSR1-PBX1 fusion gene consisting of exons 1,8 of the 5,-end of EWSR1 and exons 5,9 of the 3,-end of PBX1 was shown to result from the translocation. Both genes are known to be targeted also by other neoplasia-specific translocations, PBX1 in acute lymphoblastic leukemia and EWSR1 in several solid tumors, most of which are malignant. Based on the structure of the novel fusion gene detected, its transforming mechanism is thought to be the same as for other fusion genes involving EWSR1 or PBX1. © 2008 Wiley-Liss, Inc. [source] Frequency and characterization of HMGA2 and HMGA1 rearrangements in mesenchymal tumors of the lower genital tractGENES, CHROMOSOMES AND CANCER, Issue 11 2007Fabiola Medeiros Mesenchymal tumors of the lower genital tract predominantly occur in women of reproductive age and are mainly represented by aggressive angiomyxoma (AAM) and angiomyofibroblastoma (AMF). Whether these tumors are different phenotypic expressions of the same biological entity is still debatable. Genetic rearrangements of HMGA2 have been reported in a few cases of AAM but its frequency and clinicobiological implications have not been studied systematically. We evaluated 90 cases of mesenchymal tumors of the lower genital tract that comprised 42 AAMs, 18 AMFs, 6 cellular angiofibromas, 5 fibroepithelial stromal polyps, 15 genital leiomyomas, 3 superficial angiomyxomas, and 1 spindle cell lipoma. Fluorescence in situ hybridization was used to identify rearrangements of HMGA2 and its homologue HMGA1. HMGA2 rearrangements were identified in 14 AAMs (33%) and in 1 vaginal leiomyoma. All other tumors were negative for HMGA2 rearrangements. HMGA1 rearrangement was not found in any of the cases. RT-PCR confirmed transcriptional upregulation of HMGA2 only in tumors with HMGA2 rearrangements. Standard cytogenetic analyses were performed in two AAMs and one AMF. One AAM had a t(1;12)(p32;q15); the other tumors had normal karyotypes. Mapping and sequence analysis of the breakpoint showed fusion to the 3, untranslated region of HMGA2 to genomic sequences derived from the contig NT 032977.8 on chromosome 1p32. Our findings support the hypothesis that AAM and AMF are distinct biological entities. The diagnostic usefulness of HMGA2 rearrangements to differentiate between AAM and other tumors of the lower genital tract may be limited due to the their low frequency. © 2007 Wiley-Liss, Inc. [source] ALK probe rearrangement in a t(2;11;2)(p23;p15;q31) translocation found in a prenatal myofibroblastic fibrous lesion: Toward a molecular definition of an inflammatory myofibroblastic tumor family?GENES, CHROMOSOMES AND CANCER, Issue 1 2001Nicolas Sirvent A prenatal tumor located in the lumbar paravertebral area was discovered during a routine ultrasound examination at 32 weeks of pregnancy and surgically removed at 4 months of life. The histopathological diagnosis was first suggested to be an infantile desmoid fibromatosis. The tumor karyotype showed a three-way translocation involving both chromosomes 2 and a chromosome 11, t(2;11;2)(p23;p15;q31). Fluorescence in situ hybridization with a probe flanking the ALK gene at 2p23 demonstrated a rearrangement, as previously described in inflammatory myofibroblastic tumors (IMTs). In light of the genetic analysis, the histopathological diagnosis was revised to IMT, although inflammatory cells were scarce. IMTs are pseudosarcomatous inflammatory lesions that primarily occur in the soft tissue and viscera of children and young adults. Our report describes for the first time the occurrence of IMT during prenatal life. The ALK rearrangement may represent the molecular definition of a subgroup of mesenchymal tumors, not always with complete morphological features of IMT, similar to the model of EWS rearrangement in the Ewing sarcoma family of tumors. © 2001 Wiley-Liss, Inc. [source] Tumors Associated With Oncogenic Osteomalacia Express Genes Important in Bone and Mineral MetabolismJOURNAL OF BONE AND MINERAL RESEARCH, Issue 6 2002Suzanne M. Jan De Beur Abstract Oncogenic osteomalacia (OOM) is associated with primitive mesenchymal tumors that secrete phosphaturic factors resulting in low serum concentrations of phosphate and calcitriol, phosphaturia, and defective bone mineralization. To identify overexpressed genes in these tumors, we compared gene expression profiles of tumors resected from patients with OOM and histologically similar control tumors using serial analysis of gene expression (SAGE). Three hundred and sixty-four genes were expressed at least twofold greater in OOM tumors compared with control tumors. A subset of 67 highly expressed genes underwent validation with an extended set of OOM and control tumors using array analysis or reverse-transcription polymerase chain reaction (RT-PCR). Ten of these validated genes were consistently overexpressed in all OOM tumors relative to control tumors. Strikingly, genes with roles in bone matrix formation, mineral ion transport, and bone mineralization were highly expressed in the OOM tumors. [source] Pathology of gastrointestinal stromal tumorsPATHOLOGY INTERNATIONAL, Issue 1 2006Seiichi Hirota Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumors in the gastrointestinal tract. It was found that most GIST expressed KIT, a receptor tyrosine kinase encoded by protooncogene c- kit. In normal gastrointestinal wall, KIT is expressed by interstitial cells of Cajal (ICC), which are a pacemaker for autonomous gastrointestinal movement. Because both GIST and ICC are double-positive for KIT and CD34, and because familial and multiple GIST appear to develop from diffuse hyperplasia of ICC, GIST are considered to originate from ICC or their precursor cells. It was also found that approximately 90% of the sporadic GIST have somatic gain-of-function mutations of the c- kit gene, and that the patients with familial and multiple GIST have germline gain-of-function mutations of the c- kit gene. These facts strongly suggest that the c- kit gene mutations are a cause of GIST. Approximately half of the sporadic GIST without c- kit gene mutations were demonstrated to have gain-of-function mutations in platelet-derived growth factor receptor-, (PDGFRA) gene that encodes another receptor tyrosine kinase. Because KIT is immunohistochemically negative in a minority of GIST, especially in PDGFRA gene mutation-harboring GIST, mutational analyses of c- kit and PDGFRA genes may be required to diagnose such GIST definitely. Imatinib mesylate was developed as a selective tyrosine kinase inhibitor. It inhibits constitutive activation of mutated KIT and PDGFRA, and is now being used for KIT-positive metastatic or unresectable GIST as a molecular target drug. Confirmation of KIT expression by immunohistochemistry is necessary for application of the drug. The effect of imatinib mesylate is different in various types of c- kit and PDGFRA gene mutations, and the secondary resistance against imatinib mesylate is often acquired by the second mutation of the identical genes. Mutational analyses of c- kit and PDGFRA genes are also significant for prediction of effectiveness of drugs including newly developed agents. [source] PKC theta, a novel immunohistochemical marker for gastrointestinal stromal tumors (GIST), especially useful for identifying KIT-negative tumorsPATHOLOGY INTERNATIONAL, Issue 3 2005Atsushi Motegi Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor in the digestive tract and the majority of GIST has characteristic gain-of-function mutations of the c-kit gene, which encodes the KIT receptor for stem cell factor. The present study aimed to establish the usefulness of protein kinase C theta (PKC ,) as an immunohistochemical marker for GIST in comparison with KIT immunohistochemistry. PKC , immunohistochemistry was carried out not only on 48 cases of GIST and another 40 cases of gastrointestinal mesenchymal tumors, but also on 24 cases of various tumors known to be immunohistochemically positive for KIT. Immunohistochemically, 41 out of 48 cases (85%) of GIST were positive for PKC ,, and its expression was confirmed by Western blot analysis using six cases of surgically resected GIST. In the present study there were six GIST immunohistochemically negative for KIT, which histologically revealed a myxoid epithelioid appearance characteristic to that of GIST with platelet-derived growth factor receptor alpha mutation. All six GIST were immunohistochemically positive for PKC ,. No PKC , immunoreactivity was observed in other gastrointestinal mesenchymal tumors and various KIT-positive tumors except for three cases (14%) of gastrointestinal schwannomas. The present study revealed that PKC , is an immunohistochemically novel and useful marker for GIST, especially for GIST negative for KIT. [source] Tyrosine kinase mutations in gastrointestinal stromal tumors in a nation-wide study in IcelandAPMIS, Issue 9 2010GEIR TRYGGVASON Tryggvason G, Hilmarsdottir B, Gunnarsson GH, Jónsson JJ, Jónasson JG, Magnússon MK. Tyrosine kinase mutations in gastrointestinal stromal tumors in a nation-wide study in Iceland. APMIS 2010; 118: 648,56. Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the gastrointestinal tract. It is characterized by activating mutations in the tyrosine kinase genes c-kit or PDGFRA. This study examined the mutation rate and type in a population-based material. All gastrointestinal mesenchymal tumors over the years 1990,2004 were evaluated and GIST tumors identified using immunohistochemistry (c-kit) and conventional pathologic parameters. Paraffin sections from all tumors were subjected to mutation analysis on exons 9, 11, 13 and 17 of the c-kit gene and exons 12 and 18 of the PDGFRA gene. To screen for mutations, we used a highly sensitive conformation-sensitive gel electrophoresis (CSGE) and to define the mutated alleles, we employed direct automated DNA sequencing. All c-kit-positive gastrointestinal mesenchymal tumors were entered into the study. Fifty-six tumors from 55 patients were analyzed. Mutations were found in 52 tumors representing a 92.9% mutational rate. Most of the mutations were found in c-kit exon 11 (76.8%), followed by c-kit exon 9 (10.7%). PDGFRA mutations were only found in three tumors. No correlation of mutation type with biologic behavior was found. This population-based study, using a sensitive CSGE method, identifies mutations in the great majority of patients with GIST. [source] Cyclooxygenase-2 expression and connection with tumor recurrence and histopathologic parameters in gastrointestinal stromal tumorsAPMIS, Issue 11 2009HÜSEYIN KEMAL TÜRKÖZ Tissue cyclooxygenase-2 (COX-2) is a rate-limiting enzyme in prostaglandin synthesis and has been shown to have roles in carcinogenesis and tumor progression. Evaluation of COX-2 overexpression in malignancies has been performed mostly on tumors of epithelial origin, and little is known about its presence in mesenchymal tumors, especially gastrointestinal stromal tumors (GIST). COX-2 has been reported to be widely expressed in GIST and has been suggested as a potential diagnostic marker. We evaluated the overexpression and roles of COX-2 in tumorigenesis in GIST with regard to its relation to prognostic parameters and tumor recurrence. We studied the presence of COX-2 expression immunohistochemically and its relation to clinicopathologic prognostic variables in 41 cases of GIST. COX-2 was overexpressed in 21 (51%) of 41 tumors. The extent of overexpression was greater in tumors that recurred after surgical resection. COX-2 overexpression was also higher in tumors with coagulative necrosis, high mitotic index and an infiltrative pattern of growth. The observation of greater COX-2 expression levels in GIST with unfavorable histopathologic variables is contrary to previous reports and consistent with the reported roles of COX-2 in carcinogenesis of epithelial malignancies. [source] Trends in incidence and survival of mesenchymal neoplasm of the digestive tract within a defined population of Northern Norway,APMIS, Issue 3 2006SONJA ERIKSSON STEIGEN Population-based incidence and survival data for gastrointestinal stromal tumor (GIST) are sparse due to the fact that GIST is a rather novel entity both clinically and pathologically, and has not been registered as a separate entity in population-based cancer registries. The aim of the present study was to reclassify all mesenchymal tumors within a defined population of northern Norway over a time-span of 30 years with the purpose of estimating trends of incidence and survival. One hundred and forty-one patients with mesenchymal neoplasms of the digestive tract were identified: 102 as GISTs, 32 as leiomyomatous tumors, 4 as schwannomas, and 3 as fibromas. Incidence rates of GIST showed a significant increase over the whole period, which was not observed for the non-GIST cases. Analysis of GIST cases showed that cases with more than 5 mitoses per 50 high power fields had an increased expected mortality 4 times that of those with fewer mitoses, and the combination of mitotic count and size of tumor can be recommended for categorizing the tumors into different risk levels. The study confirms that GIST is by far the most frequent mesenchymal neoplasm of the digestive tract and that the incidence has increased over the last 30 years. [source] Phase 1 pharmacokinetic and drug-interaction study of dasatinib in patients with advanced solid tumorsCANCER, Issue 6 2010Faye M. Johnson MD Abstract BACKGROUND: The recently developed the Src and Abelson (Abl) kinase inhibitor dasatinib has antitumor effects in epithelial and mesenchymal tumors. Preclinical data have indicated that dasatinib is metabolized primarily through cytochrome P450 3A4 (CYP3A4) and may cause QT prolongation. In light of its improved tolerability, the authors were interested in the safety of a once-daily dasatinib regimen. METHODS: The authors conducted a phase 1 trial of dasatinib in 29 patients with advanced solid tumors. Segment 1 of the trial was short term and sequential and was designed to determine whether the coadministration of the potent CYP3A4 inhibitor ketoconazole had an effect on the pharmacokinetics of dasatinib. Segment 2 was designed to evaluate the safety of dasatinib as dosing was increased. QT intervals were monitored closely in both segments. Efficacy was assessed in Segment 2 using both positron emission tomography and computed tomography. RESULTS: Hematologic toxicities were markedly less than those observed in patients with leukemia, whereas nonhematologic toxicities were similar. The authors determined that the maximum recommended dose was 180 mg once daily based on the incidence of pleural effusion. Coadministration of ketoconazole led to a marked increase in dasatinib exposure, which was correlated with an increase in corrected QT (QTc) values of approximately 6 msec. No adverse cardiac events were observed. CONCLUSIONS: The dose-limiting toxic effect for dasatinib was pleural effusion. The pharmacokinetic and cardiac studies indicated that coadministration of dasatinib with potent CYP3A4 inhibitors or agents that prolong the QTc interval should be avoided if possible. Close monitoring for toxicity and dose reduction should be considered if the coadministration of such agents cannot be avoided. Cancer 2010. © 2010 American Cancer Society. [source] A nonrandom association between gastrointestinal stromal tumors and myeloid leukemia,CANCER, Issue 3 2008Markku Miettinen MD Abstract BACKGROUND. Gastrointestinal stromal tumors (GISTs) are KIT-positive mesenchymal tumors of the gastrointestinal tract that are driven by activated KIT-signalling or platelet-derived growth factor receptor-, (PDFGRA) signaling. These tumors most commonly occur in the stomach and small intestine and encompass a clinical spectrum from benign to malignant. In the current study, the authors examined long-term follow-up data of 1892 GIST patients from the U.S. BACKGROUND. Nine patients (2 with gastric GISTs and 7 with GISTs of the small intestine) developed myeloid leukemia. There were 6 patients (4 women and 2 men) with acute myeloid leukemia (AML), including 1 case of promyelocytic and 1 case of myelomonocytic leukemia, and 3 patients (2 men and 1 woman) with chronic myeloid leukemia (CML). RESULTS. The leukemias developed 1.7 to 21 years after the GIST (median interval, 6 years). None of the GIST patients had received radiotherapy or chemotherapy prior to the leukemia diagnosis. Eight of 9 patients died of leukemia, and none died of GIST. All but 1 GIST case was found to have a low mitotic rate (0,1 per 50 high-power fields); however, tumor size varied from 3 to 18 cm (median, 4.5 cm). Standardized incidence ratios (SIRs) and their 95% confidence intervals (95% CIs) were calculated comparing the incidences of AML/CMLs in GIST patients with those in the 2000 through 2003 U.S. population. In GIST patients, the risk of AML was found to be significantly higher for women (SIR of 5.14; 95% CI, 1.34,11.4) and overall (SIR of 2.96; 95% CI, 1.07,5.8). There was a slightly increased risk for CML, but this was not statistically significant (SIR of 3.71; 95% CI, 0.7,9.1). CONCLUSIONS. Additional epidemiologic, clinical, and pathogenetic studies are needed to understand the apparent nonrandom association between GIST and myeloid leukemia. Cancer 2008. © 2007 American Cancer Society. [source] | ||||||||||||||||||||||