Percutaneous fine-needle aspiration (FNA) cytology is an important diagnostic test for the evalua... more Percutaneous fine-needle aspiration (FNA) cytology is an important diagnostic test for the evaluation and management of selected renal masses. Cytogenetic analysis of cytology specimens can serve as an adjunct for precise classification because certain tumors are associated with specific chromosomal aberrations. This study summarizes our experience with the application of conventional cytogenetics and fluorescence in situ hybridization (FISH) to renal FNA specimens. All percutaneous renal FNAs performed during 2005 through 2008 were identified from the electronic pathology database. Results of cytogenetic and FISH analyses were correlated with the final diagnoses of the renal FNAs. A total of 303 renal FNAs were performed. During an onsite assessment, a portion of the cytology specimen was allocated for cytogenetic analysis in 74 cases. Karyotypic analysis or FISH was successful in 44 (59%) of these. Characteristic chromosomal abnormalities were observed in 27 cases. In 17 cases, a ...
Numerical and structural centrosome abnormalities are detected in various human malignancies and ... more Numerical and structural centrosome abnormalities are detected in various human malignancies and have been implicated in the formation of multipolar mitoses, chromosome missegregation, and chromosomal instability. Despite this association between centrosome abnormalities and cancerous growth, a causative role of centrosome aberrations in generating chromosomal instability and aneuploidy has not been universally established. We report here excessive numerical and structural centrosome abnormalities in a malignant Burkitt's lymphoma harboring the characteristic t(8;14) chromosomal translocation. Using conventional karyotyping and fluorescence in situ hybridization (FISH), we detected no signs of ongoing numerical chromosome instability, although the tumor displayed sporadic multipolar metaphases. These findings demonstrate that centrosome abnormalities are not a universal surrogate marker for chromosomal instability in malignant tumors. Moreover, our results suggest a model in whi...
Benign uterine leiomyomata are the most common tumors in women of reproductive age. One recurring... more Benign uterine leiomyomata are the most common tumors in women of reproductive age. One recurring chromosomal aberration in uterine leiomyomata is rearrangement of 10q22. Chromosome 10 breakpoints were mapped by fluorescence in situ hybridization to intervals ranging from 8.9 to 72.1 kb within the third intron of MORF (monocytic leukemia zinc finger protein-related factor or MYST4) in four uterine leiomyomata tested. Additional Southern hybridization experiments confirmed that the breakpoint lies within the third intron and narrowed the interval to 2.1 kb in one uterine leiomyomata. MORF is a member of the MYST family of histone acetyltransferase and previously has been found rearranged in some types of acute myeloid leukemia (AML). This is the first instance in which disruption of a histone acetyltransferase has been reported in another tumor type. The breakpoints in uterine leiomyomata would fall in the NH2-terminal portion of the protein between a conserved domain found in histon...
BACKGROUND:Adult “translocation” renal cell carcinoma (RCC), bearing transcription factor E3 (TFE... more BACKGROUND:Adult “translocation” renal cell carcinoma (RCC), bearing transcription factor E3 (TFE3) gene fusions at Xp11.2, is a recently recognized, unique entity for which prognosis and therapy remain poorly understood. In the current study, the authors investigated the effect of vascular endothelial growth factor (VEGF)‐targeted therapy in this distinct subtype of RCC.METHODS:A retrospective review was conducted to describe the clinical characteristics and outcome of adult patients with metastatic Xp11.2 RCC who had strong TFE3 nuclear immunostaining and received anti‐VEGF therapy. Tumor response to anti‐VEGF therapy was evaluated using Response Evaluation Criteria in Solid Tumors (RECIST) criteria. The Kaplan‐Meier method was used to estimate progression‐free survival (PFS) and overall survival (OS) distributions.RESULTS:Fifteen patients were identified, of whom 10, 3, and 2 received sunitinib, sorafenib, and monoclonal anti‐VEGF antibodies, respectively. The median follow‐up wa...
Cytogenetic analysis has not only provided important information on the pathogenesis of soft tiss... more Cytogenetic analysis has not only provided important information on the pathogenesis of soft tissue tumors but, by disclosing distinct chromosomal rearrangements in different histopathological entities, has also come to serve as a valuable diagnostic tool. Little is known as yet about the potential prognostic impact of cytogenetic features detected in these tumors. A total of 239 benign and 221 malignant soft tissue tumors with clonal chromosome aberrations were subdivided according to general karyotypic features, such as degree of complexity and ploidy level, and rearrangements of specific chromosomal regions. The cytogenetic variables were analyzed regarding clinical outcome, using time to metastasis as the end point. Selected variables were then compared with established clinicopathological predictors of metastasis development. When the entire material was considered, 167 of 268 investigated cytogenetic variables were associated with clinical outcome. Focusing on the subset of 151 patients with high-grade sarcoma, 17 variables were identified that, besides grade and size, were associated with increased risk of metastasis development. A final Cox regression analysis identified five independent cytogenetic predictors of adverse outcome; breakpoints in chromosome regions 1p1, 1q4, 14q1, and 17q2, and gain of regions 6p1/p2. An increasing effect on metastatic risk was seen with increasing involvement of the selected cytogenetic variables, even when different histopathological types were studied separately. We conclude that cytogenetic data provide independent prognostic information in soft tissue sarcomas. Furthermore, our results point to specific areas of the genome harboring genes that may influence the metastatic potential of sarcoma cells.
Ordinary lipomas are cytogenetically characterized by a variety of balanced rearrangements involv... more Ordinary lipomas are cytogenetically characterized by a variety of balanced rearrangements involving chromosome segment 12ql3-15, and atypical lipomatous tumors (ALT) by supernumerary ring chromosomes or giant markers known to contain amplified 12q sequences. In a series of 228 cytogenetically analyzed and histopathologically reexamined ordinary lipomas and ALT, 10 tumors showed unbalanced chromosome-12 aberrations. All 4 tumors with loss of segments from 12q were classified as ordinary lipomas, whereas 5 of the 6 tumors showing gain of 12q material were diagnosed as ALT. One or three extra copies of 12q15-q24 were present in all 5 ALT. We conclude that duplication of 12q sequences may be a sufficient level of amplification for development of the microscopic appearance that characterizes ALT.
A nonrandom occurrence of trisomy 8 and of trisomy 20 in desmoid tumors has been recently reporte... more A nonrandom occurrence of trisomy 8 and of trisomy 20 in desmoid tumors has been recently reported. The finding of trisomy 8 in nondividing desmoid tumor cells by in situ hybridization prompted us to evaluate, in a similar way, the occurrence of trisomy 20 and the possible occurrence of both trisomies together because their co-existence was cytogenetically observed in a few cases. Double fluorescence in situ hybridization (FISH) with centromeric probes for chromosomes 8 and 20 was performed on 16 single cell suspensions of desmoid tumors. FISH confirmed the occurrence of trisomy 8 or 20 in a single cell suspension of desmoid tumors. Both individual trisomies, and even more their association in the same cells, are rare to extremely rare in solid tumors in general and in mesenchymal tumors in particular, and are only known to occur in infantile fibrosarcoma.
Lipoblastomas are pediatric neoplasms resulting from transformation of adipocytes. These benign t... more Lipoblastomas are pediatric neoplasms resulting from transformation of adipocytes. These benign tumors are typically composed of adipose cells in different stages of maturation within a variably myxoid matrix, and they contain clonal rearrangements of chromosome band 8q12. Because lipoblastomas resemble embryonic adipose tissue, characterization of their transforming mechanisms might reveal biological pathways in physiological adipogenesis. Herein, we demonstrate that lipoblastoma chromosome 8q12 rearrangements bring about promoter-swapping events in the PLAG1 oncqgene. We show that the hyaluronic acid synthase 2 (HAS2) or collagen 1 alpha 2 (COL1A2) gene promoter regions are fused to the entire PLAG1 coding sequence in each of four lipoblastomas. PLAG1 is a developmentally regulated zinc finger gene whose tumorigenic function has been shown previously only in epithelial salivary gland cells. Our findings reveal that PLAG1 activation, presumably resulting from transcriptional up-regulation, is a central oncogenic event in lipoblastoma.
Inflammatory pseudotumors or inflammatory myofibroblastic tumors (IMT) are lesions of extreme het... more Inflammatory pseudotumors or inflammatory myofibroblastic tumors (IMT) are lesions of extreme heterogeneity showing a highly variable mixture of bland-looking spindle cells, inflammatory cells, and collagen fibers. We describe our results of molecular cytogenetic and rapid amplification of cDNA ends (RACE-PCR) studies on an IMT characterized by a translocation involving 12q15. Chromosomal aberrations involving this region are very frequent among other benign tumors, such as lipomas, uterine leiomyomas, or pulmonary chondroid hamartomas. Recently, we have shown that, by these structural chromosomal aberrations, the HMGIC gene is affected. Fluorescence in situ hybridization (FISH) analysis and 3' RACE-PCR on cells of the present case of an inflammatory myofibroblastic tumor indicated an intragenic rearrangement of HMGIC, resulting in an aberrant transcript of that gene. Clonal cytogenetic aberrations have been described in very few cases of IMT. The results presented herein indicate that this case of IMT represents a true benign mesenchymal neoplasm associated with, or due to, a rearrangement of HMGIC.
Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc, May 19, 2016
Intravenous leiomyomatosis is an unusual smooth muscle neoplasm with quasi-malignant intravascula... more Intravenous leiomyomatosis is an unusual smooth muscle neoplasm with quasi-malignant intravascular growth but a histologically banal appearance. Herein, we report expression and molecular cytogenetic analyses of a series of 12 intravenous leiomyomatosis cases to better understand the pathogenesis of intravenous leiomyomatosis. All cases were analyzed for the expression of HMGA2, MDM2, and CDK4 proteins by immunohistochemistry based on our previous finding of der(14)t(12;14)(q14.3;q24) in intravenous leiomyomatosis. Seven of 12 (58%) intravenous leiomyomatosis cases expressed HMGA2, and none expressed MDM2 or CDK4. Colocalization of hybridization signals for probes from the HMGA2 locus (12q14.3) and from 14q24 by interphase fluorescence in situ hybridization (FISH) was detected in a mean of 89.2% of nuclei in HMGA2-positive cases by immunohistochemistry, but in only 12.4% of nuclei in negative cases, indicating an association of HMGA2 expression and this chromosomal rearrangement (P=...
Proceedings of the National Academy of Sciences, 2000
It has long been known that rearrangements of chromosomes through breakage-fusion-bridge (BFB) cy... more It has long been known that rearrangements of chromosomes through breakage-fusion-bridge (BFB) cycles may cause variability of phenotypic and genetic traits within a cell population. Because intercellular heterogeneity is often found in neoplastic tissues, we investigated the occurrence of BFB events in human solid tumors. Evidence of frequent BFB events was found in malignancies that showed unspecific chromosome aberrations, including ring chromosomes, dicentric chromosomes, and telomeric associations, as well as extensive intratumor heterogeneity in the pattern of structural changes but not in tumors with tumor-specific aberrations and low variability. Fluorescence in situ hybridization analysis demonstrated that chromosomes participating in anaphase bridge formation were involved in a significantly higher number of structural aberrations than other chromosomes. Tumors with BFB events showed a decreased elimination rate of unstable chromosome aberrations after irradiation compared...
Percutaneous fine-needle aspiration (FNA) cytology is an important diagnostic test for the evalua... more Percutaneous fine-needle aspiration (FNA) cytology is an important diagnostic test for the evaluation and management of selected renal masses. Cytogenetic analysis of cytology specimens can serve as an adjunct for precise classification because certain tumors are associated with specific chromosomal aberrations. This study summarizes our experience with the application of conventional cytogenetics and fluorescence in situ hybridization (FISH) to renal FNA specimens. All percutaneous renal FNAs performed during 2005 through 2008 were identified from the electronic pathology database. Results of cytogenetic and FISH analyses were correlated with the final diagnoses of the renal FNAs. A total of 303 renal FNAs were performed. During an onsite assessment, a portion of the cytology specimen was allocated for cytogenetic analysis in 74 cases. Karyotypic analysis or FISH was successful in 44 (59%) of these. Characteristic chromosomal abnormalities were observed in 27 cases. In 17 cases, a ...
Numerical and structural centrosome abnormalities are detected in various human malignancies and ... more Numerical and structural centrosome abnormalities are detected in various human malignancies and have been implicated in the formation of multipolar mitoses, chromosome missegregation, and chromosomal instability. Despite this association between centrosome abnormalities and cancerous growth, a causative role of centrosome aberrations in generating chromosomal instability and aneuploidy has not been universally established. We report here excessive numerical and structural centrosome abnormalities in a malignant Burkitt's lymphoma harboring the characteristic t(8;14) chromosomal translocation. Using conventional karyotyping and fluorescence in situ hybridization (FISH), we detected no signs of ongoing numerical chromosome instability, although the tumor displayed sporadic multipolar metaphases. These findings demonstrate that centrosome abnormalities are not a universal surrogate marker for chromosomal instability in malignant tumors. Moreover, our results suggest a model in whi...
Benign uterine leiomyomata are the most common tumors in women of reproductive age. One recurring... more Benign uterine leiomyomata are the most common tumors in women of reproductive age. One recurring chromosomal aberration in uterine leiomyomata is rearrangement of 10q22. Chromosome 10 breakpoints were mapped by fluorescence in situ hybridization to intervals ranging from 8.9 to 72.1 kb within the third intron of MORF (monocytic leukemia zinc finger protein-related factor or MYST4) in four uterine leiomyomata tested. Additional Southern hybridization experiments confirmed that the breakpoint lies within the third intron and narrowed the interval to 2.1 kb in one uterine leiomyomata. MORF is a member of the MYST family of histone acetyltransferase and previously has been found rearranged in some types of acute myeloid leukemia (AML). This is the first instance in which disruption of a histone acetyltransferase has been reported in another tumor type. The breakpoints in uterine leiomyomata would fall in the NH2-terminal portion of the protein between a conserved domain found in histon...
BACKGROUND:Adult “translocation” renal cell carcinoma (RCC), bearing transcription factor E3 (TFE... more BACKGROUND:Adult “translocation” renal cell carcinoma (RCC), bearing transcription factor E3 (TFE3) gene fusions at Xp11.2, is a recently recognized, unique entity for which prognosis and therapy remain poorly understood. In the current study, the authors investigated the effect of vascular endothelial growth factor (VEGF)‐targeted therapy in this distinct subtype of RCC.METHODS:A retrospective review was conducted to describe the clinical characteristics and outcome of adult patients with metastatic Xp11.2 RCC who had strong TFE3 nuclear immunostaining and received anti‐VEGF therapy. Tumor response to anti‐VEGF therapy was evaluated using Response Evaluation Criteria in Solid Tumors (RECIST) criteria. The Kaplan‐Meier method was used to estimate progression‐free survival (PFS) and overall survival (OS) distributions.RESULTS:Fifteen patients were identified, of whom 10, 3, and 2 received sunitinib, sorafenib, and monoclonal anti‐VEGF antibodies, respectively. The median follow‐up wa...
Cytogenetic analysis has not only provided important information on the pathogenesis of soft tiss... more Cytogenetic analysis has not only provided important information on the pathogenesis of soft tissue tumors but, by disclosing distinct chromosomal rearrangements in different histopathological entities, has also come to serve as a valuable diagnostic tool. Little is known as yet about the potential prognostic impact of cytogenetic features detected in these tumors. A total of 239 benign and 221 malignant soft tissue tumors with clonal chromosome aberrations were subdivided according to general karyotypic features, such as degree of complexity and ploidy level, and rearrangements of specific chromosomal regions. The cytogenetic variables were analyzed regarding clinical outcome, using time to metastasis as the end point. Selected variables were then compared with established clinicopathological predictors of metastasis development. When the entire material was considered, 167 of 268 investigated cytogenetic variables were associated with clinical outcome. Focusing on the subset of 151 patients with high-grade sarcoma, 17 variables were identified that, besides grade and size, were associated with increased risk of metastasis development. A final Cox regression analysis identified five independent cytogenetic predictors of adverse outcome; breakpoints in chromosome regions 1p1, 1q4, 14q1, and 17q2, and gain of regions 6p1/p2. An increasing effect on metastatic risk was seen with increasing involvement of the selected cytogenetic variables, even when different histopathological types were studied separately. We conclude that cytogenetic data provide independent prognostic information in soft tissue sarcomas. Furthermore, our results point to specific areas of the genome harboring genes that may influence the metastatic potential of sarcoma cells.
Ordinary lipomas are cytogenetically characterized by a variety of balanced rearrangements involv... more Ordinary lipomas are cytogenetically characterized by a variety of balanced rearrangements involving chromosome segment 12ql3-15, and atypical lipomatous tumors (ALT) by supernumerary ring chromosomes or giant markers known to contain amplified 12q sequences. In a series of 228 cytogenetically analyzed and histopathologically reexamined ordinary lipomas and ALT, 10 tumors showed unbalanced chromosome-12 aberrations. All 4 tumors with loss of segments from 12q were classified as ordinary lipomas, whereas 5 of the 6 tumors showing gain of 12q material were diagnosed as ALT. One or three extra copies of 12q15-q24 were present in all 5 ALT. We conclude that duplication of 12q sequences may be a sufficient level of amplification for development of the microscopic appearance that characterizes ALT.
A nonrandom occurrence of trisomy 8 and of trisomy 20 in desmoid tumors has been recently reporte... more A nonrandom occurrence of trisomy 8 and of trisomy 20 in desmoid tumors has been recently reported. The finding of trisomy 8 in nondividing desmoid tumor cells by in situ hybridization prompted us to evaluate, in a similar way, the occurrence of trisomy 20 and the possible occurrence of both trisomies together because their co-existence was cytogenetically observed in a few cases. Double fluorescence in situ hybridization (FISH) with centromeric probes for chromosomes 8 and 20 was performed on 16 single cell suspensions of desmoid tumors. FISH confirmed the occurrence of trisomy 8 or 20 in a single cell suspension of desmoid tumors. Both individual trisomies, and even more their association in the same cells, are rare to extremely rare in solid tumors in general and in mesenchymal tumors in particular, and are only known to occur in infantile fibrosarcoma.
Lipoblastomas are pediatric neoplasms resulting from transformation of adipocytes. These benign t... more Lipoblastomas are pediatric neoplasms resulting from transformation of adipocytes. These benign tumors are typically composed of adipose cells in different stages of maturation within a variably myxoid matrix, and they contain clonal rearrangements of chromosome band 8q12. Because lipoblastomas resemble embryonic adipose tissue, characterization of their transforming mechanisms might reveal biological pathways in physiological adipogenesis. Herein, we demonstrate that lipoblastoma chromosome 8q12 rearrangements bring about promoter-swapping events in the PLAG1 oncqgene. We show that the hyaluronic acid synthase 2 (HAS2) or collagen 1 alpha 2 (COL1A2) gene promoter regions are fused to the entire PLAG1 coding sequence in each of four lipoblastomas. PLAG1 is a developmentally regulated zinc finger gene whose tumorigenic function has been shown previously only in epithelial salivary gland cells. Our findings reveal that PLAG1 activation, presumably resulting from transcriptional up-regulation, is a central oncogenic event in lipoblastoma.
Inflammatory pseudotumors or inflammatory myofibroblastic tumors (IMT) are lesions of extreme het... more Inflammatory pseudotumors or inflammatory myofibroblastic tumors (IMT) are lesions of extreme heterogeneity showing a highly variable mixture of bland-looking spindle cells, inflammatory cells, and collagen fibers. We describe our results of molecular cytogenetic and rapid amplification of cDNA ends (RACE-PCR) studies on an IMT characterized by a translocation involving 12q15. Chromosomal aberrations involving this region are very frequent among other benign tumors, such as lipomas, uterine leiomyomas, or pulmonary chondroid hamartomas. Recently, we have shown that, by these structural chromosomal aberrations, the HMGIC gene is affected. Fluorescence in situ hybridization (FISH) analysis and 3' RACE-PCR on cells of the present case of an inflammatory myofibroblastic tumor indicated an intragenic rearrangement of HMGIC, resulting in an aberrant transcript of that gene. Clonal cytogenetic aberrations have been described in very few cases of IMT. The results presented herein indicate that this case of IMT represents a true benign mesenchymal neoplasm associated with, or due to, a rearrangement of HMGIC.
Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc, May 19, 2016
Intravenous leiomyomatosis is an unusual smooth muscle neoplasm with quasi-malignant intravascula... more Intravenous leiomyomatosis is an unusual smooth muscle neoplasm with quasi-malignant intravascular growth but a histologically banal appearance. Herein, we report expression and molecular cytogenetic analyses of a series of 12 intravenous leiomyomatosis cases to better understand the pathogenesis of intravenous leiomyomatosis. All cases were analyzed for the expression of HMGA2, MDM2, and CDK4 proteins by immunohistochemistry based on our previous finding of der(14)t(12;14)(q14.3;q24) in intravenous leiomyomatosis. Seven of 12 (58%) intravenous leiomyomatosis cases expressed HMGA2, and none expressed MDM2 or CDK4. Colocalization of hybridization signals for probes from the HMGA2 locus (12q14.3) and from 14q24 by interphase fluorescence in situ hybridization (FISH) was detected in a mean of 89.2% of nuclei in HMGA2-positive cases by immunohistochemistry, but in only 12.4% of nuclei in negative cases, indicating an association of HMGA2 expression and this chromosomal rearrangement (P=...
Proceedings of the National Academy of Sciences, 2000
It has long been known that rearrangements of chromosomes through breakage-fusion-bridge (BFB) cy... more It has long been known that rearrangements of chromosomes through breakage-fusion-bridge (BFB) cycles may cause variability of phenotypic and genetic traits within a cell population. Because intercellular heterogeneity is often found in neoplastic tissues, we investigated the occurrence of BFB events in human solid tumors. Evidence of frequent BFB events was found in malignancies that showed unspecific chromosome aberrations, including ring chromosomes, dicentric chromosomes, and telomeric associations, as well as extensive intratumor heterogeneity in the pattern of structural changes but not in tumors with tumor-specific aberrations and low variability. Fluorescence in situ hybridization analysis demonstrated that chromosomes participating in anaphase bridge formation were involved in a significantly higher number of structural aberrations than other chromosomes. Tumors with BFB events showed a decreased elimination rate of unstable chromosome aberrations after irradiation compared...
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