RESUMO
GVHD as a complication of SOT presents both a diagnostic and therapeutic challenge. Typically affecting the skin, gastrointestinal tract, and liver, GVHD occurs when donor lymphocytes engrafted in recipient tissues are activated by host antigen-presenting cells resulting in cytokine release and donor cell-mediated cytotoxicity to host tissue. Here, we describe a 5-year-old girl who developed fatal, refractory GVHD after isolated intestinal transplantation when recipient immune cells failed to repopulate the allograft in the setting of CMV viremia. Persistence of the donor immune cells in the allograft mucosa, rather than engraftment in the recipient bone marrow, likely perpetuated this refractory GVHD. Early diagnosis and intervention are critical to reduce morbidity and mortality. Thus, periodic monitoring of peripheral blood and allograft mucosal chimerism with sensitive detection methods may allow early detection and potentially curative enterectomy in similar cases of refractory GVHD.
Assuntos
Doença Enxerto-Hospedeiro/imunologia , Mucosa Intestinal/imunologia , Intestinos/transplante , Síndrome do Intestino Curto/cirurgia , Medula Óssea/imunologia , Pré-Escolar , Quimerismo , Evolução Fatal , Feminino , Doença Enxerto-Hospedeiro/diagnóstico , Humanos , Mucosa Intestinal/transplante , Intestinos/imunologia , Masculino , Doadores de TecidosRESUMO
The mechanisms underlying the potential for aggressive behavior of prostate cancer (PCa) remain elusive. In this study, whole genome and/or transcriptome sequencing was performed on 19 specimens of PCa, matched adjacent benign prostate tissues, matched blood specimens, and organ donor prostates. A set of novel fusion transcripts was discovered in PCa. Eight of these fusion transcripts were validated through multiple approaches. The occurrence of these fusion transcripts was then analyzed in 289 prostate samples from three institutes, with clinical follow-up ranging from 1 to 15 years. The analyses indicated that most patients [69 (91%) of 76] positive for any of these fusion transcripts (TRMT11-GRIK2, SLC45A2-AMACR, MTOR-TP53BP1, LRRC59-FLJ60017, TMEM135-CCDC67, KDM4-AC011523.2, MAN2A1-FER, and CCNH-C5orf30) experienced PCa recurrence, metastases, and/or PCa-specific death after radical prostatectomy. These outcomes occurred in only 37% (58/157) of patients without carrying those fusion transcripts. Three fusion transcripts occurred exclusively in PCa samples from patients who experienced recurrence or PCaerelated death. The formation of these fusion transcripts may be the result of genome recombination. A combination of these fusion transcripts in PCa with Gleason's grading or with nomogram significantly improves the prediction rate of PCa recurrence. Our analyses suggest that formation of these fusion transcripts may underlie the aggressive behavior of PCa.
Assuntos
Fusão Gênica , Neoplasias da Próstata/genética , RNA Mensageiro/genética , Transcriptoma , Adulto , Idoso , Estudos de Coortes , Seguimentos , Biblioteca Gênica , Humanos , Hibridização in Situ Fluorescente , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Recidiva Local de Neoplasia , Prognóstico , Próstata/patologia , Prostatectomia , Neoplasias da Próstata/patologia , Alinhamento de Sequência , Análise de Sequência de DNA , Adulto JovemRESUMO
Anoctamin-1 (ANO1) (DOG1, TMEM16a) is a calcium-activated chloride channel initially described in gastrointestinal stromal tumors, but now known to be expressed in a variety of normal and tumor tissues including salivary tissue in murine models. We herein perform a comprehensive survey of DOG1 expression in 156 cases containing non-neoplastic human salivary tissues and tumors. ANO1 mRNA levels were significantly higher (8-fold increase, P<0.0001) in normal parotid tissue (n=6) as compared with squamous mucosa (n=15). By immunohistochemistry, DOG1 showed a diffuse moderate (2+) apical membranous staining pattern in normal serous acini, 1+ apical membranous pattern in mucous acini, and variable 1-2+ apical staining of distal intercalated ducts. Myoepithelial cells, striated and excretory ducts were invariably negative. All acinic cell carcinomas (n=28) were DOG1 positive demonstrating a complex mixture of intense (3+) apical membranous, cytoplasmic and complete membranous staining. Most ductal tumor types were negative or only showed a subset of positive cases. Within the biphasic tumor category, adenoid cystic carcinomas (18/24 cases) and epithelial-myoepithelial carcinomas (8/15 cases) were frequently positive, often showing a distinctive combined apical ductal and membranous/cytoplasmic myoepithelial staining profile. Thus, DOG1 staining is a marker of salivary acinar and to a lesser extent intercalated duct differentiation. Strong staining can be used to support the diagnosis of acinic cell carcinoma. DOG1 may also be a marker of a 'transformed' myoepithelial phenotype in a subset of biphasic salivary gland malignancies.
Assuntos
Biomarcadores Tumorais/análise , Carcinoma de Células Acinares/metabolismo , Diferenciação Celular , Canais de Cloreto/biossíntese , Proteínas de Neoplasias/biossíntese , Ductos Salivares/metabolismo , Neoplasias das Glândulas Salivares/metabolismo , Células Acinares/metabolismo , Células Acinares/patologia , Anoctamina-1 , Carcinoma/metabolismo , Carcinoma/patologia , Carcinoma de Células Acinares/patologia , Transformação Celular Neoplásica/metabolismo , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , RNA Mensageiro/análise , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Ductos Salivares/patologia , Neoplasias das Glândulas Salivares/patologiaRESUMO
Epidermal growth factor receptor (EGFR) expression and signaling contribute to glioma biological features and, thus, are a target for new drug development. The role, if any, of EGFR in routine surgical neuropathological diagnostics is less clear. Herein, we describe prospective EGFR IHC analysis in an adult cohort comprising 750 infiltrative gliomas. EGFR expression increased with World Health Organization grade but did not significantly differ between grade-matched astrocytic and oligodendroglial tumors. Survival did not significantly differ by EGFR expression among astrocytic tumors adjusted for World Health Organization grade. However, grade II oligodendrogliomas with strong EGFR expression and 1p/19q codeletion showed reduced survival, compared with their codeleted counterparts with weaker EGFR expression. Surprisingly, an inverse phenomenon was found with grade III anaplastic oligodendrogliomas, in which stronger EGFR expression was a favorable marker for survival. Among all gliomas, the likelihood of EGFR amplification, as viewed by fluorescence in situ hybridization, increased with the strength of EGFR expression, and <1% of cases with weak or no EGFR immunostaining showed amplification. These data suggest that EGFR IHC is useful in certain circumstances (ie, it may help supplement 1p/19q prognostic information in oligodendroglial tumors and screen out cases that would not benefit from more costly EGFR fluorescence in situ hybridization analysis).
Assuntos
Receptores ErbB/metabolismo , Oligodendroglioma/metabolismo , Oligodendroglioma/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Receptores ErbB/genética , Feminino , Amplificação de Genes , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Oligodendroglioma/genética , Análise de Sobrevida , Adulto JovemAssuntos
Proliferação de Células , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/patologia , Proteínas Proto-Oncogênicas c-myc/genética , Citogenética , Regulação Leucêmica da Expressão Gênica , Genes myc , Imuno-Histoquímica , Imunofenotipagem , Regulação para CimaRESUMO
Inactivation of Pten gene through deletions and mutations leading to excessive pro-growth signaling pathway activations frequently occurs in cancers. Here, we report a Pten derived pro-cancer growth gene fusion Pten-NOLC1 originated from a chr10 genome rearrangement and identified through a transcriptome sequencing analysis of human cancers. Pten-NOLC1 fusion is present in primary human cancer samples and cancer cell lines from different organs. The product of Pten-NOLC1 is a nuclear protein that interacts and activates promoters of EGFR, c-MET, and their signaling molecules. Pten-NOLC1 promotes cancer proliferation, growth, invasion, and metastasis, and reduces the survival of animals xenografted with Pten-NOLC1-expressing cancer cells. Genomic disruption of Pten-NOLC1 induces cancer cell death, while genomic integration of this fusion gene into the liver coupled with somatic Pten deletion produces spontaneous liver cancers in mice. Our studies indicate that Pten-NOLC1 gene fusion is a driver for human cancers.
Assuntos
Neoplasias Hepáticas/genética , Proteínas Nucleares/genética , PTEN Fosfo-Hidrolase/genética , Fosfoproteínas/genética , Proteínas Proto-Oncogênicas c-met/genética , Animais , Linhagem Celular Tumoral , Proliferação de Células/genética , Receptores ErbB/genética , Regulação Neoplásica da Expressão Gênica/genética , Genoma Humano/genética , Xenoenxertos , Humanos , Neoplasias Hepáticas/patologia , Camundongos , Proteínas de Fusão Oncogênica/genética , Transdução de Sinais/genéticaRESUMO
Homozygous deletion of CDKN2A (p16) is one of the most common genetic alterations in pleural mesotheliomas, occurring in up to 74% of cases. MTAP resides in the same gene cluster of the 9p21 region and is co-deleted in the majority of CDKN2A deleted cases. This study examines the genetic alterations in peritoneal mesotheliomas, which may have a different pathogenesis than their pleural counterparts. Twenty-six cases of peritoneal mesotheliomas in a triplicate tissue microarray were studied. Dual-color fluorescence in situ hybridization was performed with CDKN2A and MTAP locus-specific probes. Nine of 26 (35%) peritoneal mesotheliomas had homozygous deletion of CDKN2A; MTAP was co-deleted in every case. All cases with CDKN2A deletions had loss of p16 protein expression; five cases had loss of p16 protein without evidence of CDKN2A deletions. All patients with CDKN2A deletions were men (P, NS) and were significantly older (mean, 63 years) than the patients with no deletions (mean, 52 years) (P=0.033, t-test). An association with asbestos exposure could not be proved in this study. Similar to pleural mesotheliomas, patients with CDKN2A deletions and loss of p16 protein expression had worse overall and disease-specific survival (P=0.010 and 0.006, respectively; Kaplan-Meier log rank). Detection of CDKN2A-MTAP co-deletion in peritoneal mesotheliomas, coupled with a p16 immunohistochemical stain as an inexpensive screening tool, can help identify those patients who may have an unfavorable outcome after aggressive cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy and those who may respond to targeted therapy of the MTAP pathway.
Assuntos
Inibidor p16 de Quinase Dependente de Ciclina/biossíntese , Genes p16 , Mesotelioma/genética , Neoplasias Peritoneais/genética , Purina-Núcleosídeo Fosforilase/genética , Adulto , Idoso , Feminino , Deleção de Genes , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Estimativa de Kaplan-Meier , Masculino , Mesotelioma/metabolismo , Mesotelioma/mortalidade , Pessoa de Meia-Idade , Neoplasias Peritoneais/metabolismo , Neoplasias Peritoneais/mortalidade , Análise Serial de Tecidos , Adulto JovemRESUMO
PURPOSE: Papillary thyroid carcinoma (PTC), the most common thyroid malignancy, usually possesses BRAF mutation or rearranged in translation (RET)/PTC rearrangements. PTC usually possesses BRAF mutation or RET/PTC rearrangements. The mutation status of patients with recurrent PTC has never been characterized in a large population. EXPERIMENTAL DESIGN: Mutation status was determined in a cohort of 54 patients with recurrent PTC and analyzed for clinicopathologic relationships. BRAF and ras mutations were determined by PCR and sequencing of genomic DNA. RET/PTC rearrangements were analyzed by reverse transcription-PCR. RESULTS: BRAF mutation in exon 15 (V600E) was found in 42/54 (77.8%) recurrent PTC patients. The RET/PTC rearrangements were detected in 9 of 54 (16.7%) patients. In addition, 5 of 54 (9.3%) recurrent PTC patients had both a BRAF mutation and a RET/PTC rearrangement. The prevalence of tumors with dual mutations found in the recurrent population far exceeds the frequency historically reported for patients with primary PTC. Patients with dual mutations were significantly older (80% older than 45 years) than patients with a BRAF mutation alone (38% older than 45 years). CONCLUSIONS: Recurrent PTC is significantly associated with a predominant BRAF mutation. RET/PTC rearrangements, although commonly associated with primary PTCs in younger patients, are uncommonly found in recurrent PTC patients. In addition, the incidence of dual mutations was higher in patients with recurrent PTC than in those primary PTC, as reported by others.
Assuntos
Carcinoma Papilar/genética , Carcinoma Papilar/patologia , Mutação , Proteínas Proto-Oncogênicas B-raf/genética , Recidiva , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/patologia , Adulto , Sequência de Bases , Análise Mutacional de DNA , Éxons , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Proteínas ras/genéticaRESUMO
Lipomatous mesenchymal tumors constitute the most common type of soft tissue tumors. Well-differentiated liposarcoma (WDLS) can undergo dedifferentiation to a nonlipogenic sarcoma of variable histologic grade. In the recent literature, amplification of the murine double minute 2 (MDM2) oncogene, which has a role in cell cycle control, has been successful in distinguishing WDLS from benign lesions. We present a case of dedifferentiated liposarcoma diagnosed by fine-needle aspiration (FNA), using cytomorphology and ancillary studies (immunocytochemistry and fluorescent in-situ hybridization). An 85-year old female presented to our institution with a firm soft tissue mass of the right buttock. The FNA showed atypical spindle cells, osteoclast-like giant cells and extracellular dense matrix material. The cell block showed cellular groups of highly atypical spindle cells with osteoid and adipose tissue. Fluorescence in situ hybridization (FISH) studies performed on the cell block demonstrated amplification of the MDM2 gene. In addition, the findings were morphologically compatible with the previously resected retroperitoneal dedifferentiated liposarcoma with areas of osteosarcoma. This rare case illustrates the usefulness of FNA and ancillary studies in the diagnosis and subclassification of soft tissue tumors. To the best of our knowledge, this is the first report of MDM2 FISH positivity in a liposarcoma diagnosed by FNA.
RESUMO
Glutathione peroxidase 3 is a selenium-dependent enzyme playing a critical role in detoxifying reactive oxidative species and maintaining the genetic integrity of mammalian cells. In this report, we found that the expression of glutathione peroxidase 3 (GPx3) was widely inactivated in prostate cancers. Complete inactivation of GPx3 correlates with a poor clinical outcome. Deletions (hemizygous and homozygous) of GPx3 gene are frequent in prostate cancer samples, occurring in 39% of the samples studied. The rate of methylation of the GPx3 exon 1 region in prostate cancer samples reaches 90%. Overexpression of GPx3 in prostate cancer cell lines induced the suppression of colony formation and anchorage-independent growth of PC3, LNCaP, and Du145 cells. PC3 cells overexpressing GPx3 reduced invasiveness in Matrigel transmigration analysis by an average of 2.7-fold. Xenografted PC3 cells expressing GPx3 showed reduction in tumor volume by 4.8-fold, elimination of metastasis (0/16 versus 7/16), and reduction of animal death (3/16 versus 16/16). The tumor suppressor activity of GPx3 seems to relate to its ability to suppress the expression of c-met. The present findings suggest that GPx3 is a novel tumor suppressor gene.
Assuntos
Metilação de DNA , Deleção de Genes , Genes Supressores de Tumor , Glutationa Peroxidase/genética , Glutationa Peroxidase/metabolismo , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Animais , Sequência de Bases , Análise Mutacional de DNA , Progressão da Doença , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Camundongos , Camundongos SCID , Invasividade Neoplásica , Metástase Neoplásica , Proteínas Proto-Oncogênicas c-met/genética , Células Tumorais CultivadasRESUMO
The authors present the case of an elderly man with a primary dural-based intracranial synovial sarcoma. Histological and immunohistochemical profiles of the lesion were diagnostic for a synovial sarcoma, and molecular studies using fluorescence in situ hybridization were compatible with a synovial sarcoma. A wide array of spindle cell neoplasms has been described as originating in the dura. To the authors' knowledge, however, this is only the second primary dura-based intracranial synovial sarcoma ever reported, emphasizing the importance of a broad differential diagnosis when encountering spindle cell lesions of the meninges.
Assuntos
Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Repressoras/metabolismo , Sarcoma Sinovial/metabolismo , Sarcoma Sinovial/patologia , Idoso de 80 Anos ou mais , Neoplasias Encefálicas/diagnóstico , Diagnóstico Diferencial , Humanos , Hibridização in Situ Fluorescente , Masculino , Sarcoma/diagnóstico , Sarcoma Sinovial/diagnósticoRESUMO
INTRODUCTION: Sarcomas are heterogeneous, and their treatment and prognosis are driven by the morphologic subtype and the clinical stage. Classic cytogenetics and fluorescence in situ hybridization (FISH) analysis play an important role in their diagnostic work up. MATERIALS AND METHODS: Forty-six cases of soft-tissue sarcoma were reviewed that underwent karyotyping and simultaneous FISH analysis at initial diagnosis. They included 10 dedifferentiated liposarcomas, 10 myxoid liposarcomas, and 14 synovial sarcomas. Six tumors were investigated for EWSR1 rearrangement. Six high-grade miscellaneous sarcomas were also examined. RESULTS: The dedifferentiated liposarcoma had complex karyotypes and MDM2 amplification by FISH, and of these, 5 tumors with myxoid changes also had complex signals for DDIT3. All but 4 myxoid liposarcomas had complex karyotypes, in addition to the characteristic translocation. FISH analysis displayed DD1T3 rearrangement. All synovial sarcomas except 1 recurrence had a t(X;18) translocation by karyotyping and FISH. The EWSR1 rearrangement was present in all extraskeletal myxoid chondrosarcomas, angiomatoid fibrous histiocytoma, atypical Ewing sarcoma, and a clear-cell sarcoma, all of which had characteristic karyotypes. Seven high-grade sarcomas had no specific karyotype or rearrangements for DDIT3, SS18, and EWSR1 by FISH. CONCLUSIONS: There is good correlation between karyotyping and FISH. Complex FISH signals found in dedifferentiated liposarcomas may be related to an increased chromosome 12 copy number and ploidy. Karyotyping is an important baseline standard for the quality assurance of newly developed FISH probes. It also provides a global view of chromosomal changes and the opportunity to investigate the role of other genetic alterations and potential therapeutic targets.
Assuntos
Neoplasias Lipomatosas/patologia , Sarcoma Sinovial/patologia , Sarcoma/genética , Humanos , Hibridização in Situ Fluorescente , Neoplasias Lipomatosas/genética , Estudos Retrospectivos , Sarcoma/patologia , Sarcoma Sinovial/genéticaRESUMO
We evaluated epidermal growth factor receptor (EGFR) protein expression by immunohistochemical analysis and EGFR gene amplification by fluorescence in situ hybridization in 199 consecutive newly diagnosed and surgically treated patients with primary non-small cell lung carcinoma (NSCLC) and correlated results with clinicopathologic findings. EGFR protein expression was more common in squamous cell carcinoma (SCC; 17 [26.2%]) than in adenocarcinoma (14 [11.1%]; (P = .0076) and more frequently associated with EGFR amplification (8 [14.5%] vs 4 [3.6%] cases; P = .0208). Poor differentiation was associated with a higher average number of EGFR gene copies per cell (mean, 4.18; P = .0322) and a higher EGFR/chromosome 7 ratio (mean, 1.84; P = .0324). N0 disease showed a higher number of EGFR gene copies (mean, 4.196; P = .0163). SCCs demonstrated a higher EGFR/chromosome 7 ratio than adenocarcinomas (mean, 1.95 vs 1.47; P = .0324), particularly T1 tumors (mean, 1.79; P = .0243). Statistical analysis failed to show correlation between outcome and EGFR protein expression and gene amplification in early NSCLC. EGFR protein expression was uncoupled from gene amplification in most cases, although good correlation occurred in a subset of SCCs.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/metabolismo , Receptores ErbB/genética , Receptores ErbB/metabolismo , Amplificação de Genes , Neoplasias Pulmonares/metabolismo , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/secundário , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/metabolismo , Carcinoma de Células Grandes/genética , Carcinoma de Células Grandes/metabolismo , Carcinoma de Células Grandes/secundário , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/secundário , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/secundário , Cromossomos Humanos Par 7 , Intervalo Livre de Doença , Dosagem de Genes , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Estudos ProspectivosRESUMO
BACKGROUND: Xp11.2 or TFE3 translocation renal cell carcinomas (RCC) and alveolar soft part sarcoma (ASPS) are characterized by chromosome translocations involving the Xp11.2 breakpoint resulting in transcription factor TFE3 gene fusions. The most common translocations documented in TFE3 RCCs are t(X;1) (p11.2;q21) and t(X;17) (p11.2;q25) which leads to fusion of TFE3 gene on Xp11.2 with PRCC or ASPL respectively. TFE3 immunohistochemistry (IHC) has been inconsistent over time due to background staining problems in part related to fixation issues. Karyotyping to detect TFE3 gene rearrangement requires typically unavailable fresh tissue. Reverse transcriptase-polymerase chain reaction (RT-PCR) is generally very challenging due to degradation of RNA in archival material. The study objective was to develop and validate a TFE3 break-apart fluorescence in situ hybridization (FISH) assay to confirm Xp11 translocation RCCs and ASPS. METHODS: Representative sections of formalin-fixed paraffin-embedded tissue blocks were selected in 40 possible cases. Approximately 60 tumor cells were analyzed in the targeted region. The validation of TFE3 FISH was done with 11 negative and two positive cases. Cut off for a positive result was validated as >7.15 % positive nuclei with any pattern of break-apart signals. FISH evaluation was done blinded of the immunohistochemical or karyotype data. RESULTS: Three out of forty cases were positive for the TFE3 break-apart signals by FISH. The negative cases were reported as clear cell RCC with papillary features (10), clear cell RCC with sarcomatoid areas (2), Papillary RCC with clear cell areas (9), Chromophobe RCC (2), RCC, unclassified type (3) and renal medullary carcinoma (1). 3 of the negative cases were consultation cases for renal tumor with unknown histology. Seven negative cases were soft tissue tumor suspicious for ASPS. CONCLUSION: Our study validates the utility of TFE3 break-apart FISH on formalin-fixed paraffin-embedded tissue sections for diagnosis and confirmation of Xp11.2 translocation RCCs and ASPS.
Assuntos
Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/metabolismo , Carcinoma de Células Renais/patologia , Neoplasias Renais/patologia , Sarcoma Alveolar de Partes Moles/patologia , Neoplasias de Tecidos Moles/genética , Translocação Genética , Cromossomos Humanos X/metabolismo , Rearranjo Gênico/genética , Humanos , Imuno-Histoquímica/métodos , Hibridização in Situ Fluorescente/métodos , Sarcoma Alveolar de Partes Moles/diagnósticoRESUMO
Isolated high-grade prostatic intraepithelial neoplasia (HGPIN) on needle biopsy confers an increased risk of prostate carcinoma (CaP) on follow-up biopsy. The aim of this study is to determine whether paraffin-section fluorescence in situ hybridization (FISH) of specific chromosome/oncogene copy number abnormalities (CNAs) in biopsy specimens with isolated HGPIN increases the predictive value for CaP on repeat biopsy. Cases were divided into 3 groups: controls (n=8) and sextant biopsy specimens with isolated HGPIN without CaP (group A; n=11) and with CaP (group B; n=14) on follow-up biopsy. Dual-color FISH assessing c-myc, HER-2/neu, chromosome region 7q31 (D7S486), and corresponding chromosome centromeres was performed. An amplification ratio (AR) for each marker centromere was derived for each biopsy specimen, with AR ranges designated as no/low, low-intermediate, and high. Also calculated for each marker were the percentage of cells with marker amplification, hyperdiploidy, and monosomy. A composite score for each biopsy specimen was calculated based on these parameters, with a possible range of 0 to 15. The specific chromosomal oncogene CNAs were as follows: for chromosome 7/7q31, 2 of 11 (18%) in group A and 6 of 14 (43%) in group B; for chromosome 8/c-myc, 4 of 11 (36%) in group A and 9 of 13 (69%) in group B; and for chromosome 17/HER-2/neu, 10 of 10 (100%) in group A and 13 of 14 (93%) in group B. The mean composite score was 0 for controls, 2.5 for group A, and 4.7 for group B. Composite scores > or =4 for the 3 groups were 0 of 9 (0%) for controls, 1 of 11 (12%) for group A, and 8 of 14 (57%) for group B. These differences were statistically significant (P=0.015). One group A patient with a high composite score (6) had atypical small glands on follow-up biopsy at <1 year. Chromosome/oncogene CNAs are uncommon in control patients, occurring with increasing frequency and magnitude in patients with isolated HGPIN without and with follow-up CaP. Chromosome/oncogene CNAs in HGPIN are mostly of the low to intermediate level and display intercellular heterogeneity. HER-2/neu amplification is common in HGPIN with and without follow-up CaP. Chromosome 7 and 8 aneusomy and 7q31 and c-myc amplification are greater in HGPIN with follow-up CaP. Patients with isolated HGPIN and high composite score without follow-up CaP are uncommon; these patients may have a small, unsampled CaP. Although patients with HGPIN without CaP are more likely to have a low composite score, a subset of patients with follow-up CaP have low composite score, suggesting (1) mutational pathways independent of chromosomes 7, 8, and 17 and HER-2/neu, c-myc, and chromosome region 7q31 CNAs; (2) CaP derived from an independent, unsampled focus of HGPIN; or (3) CaP not derived from HGPIN.
Assuntos
Adenocarcinoma/patologia , Hibridização in Situ Fluorescente , Próstata/patologia , Neoplasia Prostática Intraepitelial/patologia , Neoplasias da Próstata/patologia , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Idoso , Biomarcadores Tumorais/análise , Biópsia por Agulha , Aberrações Cromossômicas , Cromossomos Humanos Par 7/genética , DNA de Neoplasias/análise , Seguimentos , Amplificação de Genes , Humanos , Interfase , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Próstata/metabolismo , Antígeno Prostático Específico/sangue , Neoplasia Prostática Intraepitelial/genética , Neoplasia Prostática Intraepitelial/metabolismo , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismoRESUMO
Sex-determining region Y-box 2 gene at 3q26.33 has been identified as oncogene in squamous cell carcinoma occurring at different anatomical sites including the lung. Sex-determining region Y-box 2 protein expression and gene amplification have been found in preinvasive squamous cell lesions such as dysplasia and carcinoma in situ. We sought to evaluate sex-determining region Y-box 2 expression and amplification in a spectrum of premalignant squamous lesions ranging from squamous metaplasia to low- and high-grade dysplasia to in situ and invasive squamous cell carcinoma of the lung. Each lesion was taken from 1 of 3 study groups: 18 patients with concurrent squamous cell carcinoma, 17 patients with prior squamous cell carcinoma undergoing surveillance biopsies, and 11 patients with no history of squamous cell carcinoma. Sex-determining region Y-box 2 amplification occurred only in a subset of invasive squamous cell carcinoma (3/5; 60%) and their associated high-grade dysplasia (3/4; 75%), but not in any of the low-grade dysplasias (0/1; 0%) or metaplasias (0/9; 0%). No sex-determining region Y-box 2 amplification was observed in squamous preneoplastic lesions in surveillance biopsies without current evidence of squamous cell carcinoma or in benign lungs. Sex-determining region Y-box 2 protein expression was seen in all squamous lesions regardless of presence or degree of dysplasia. Our results suggest that sex-determining region Y-box 2 amplification is not an early event in squamous carcinogenesis and is important for progression in a subset of squamous cell carcinoma. It appears that sex-determining region Y-box 2 gene amplification in lung squamous carcinogenesis is not the only regulator of sex-determining region Y-box 2 protein expression.
Assuntos
Carcinoma de Células Escamosas/genética , Amplificação de Genes , Neoplasias Pulmonares/genética , Lesões Pré-Cancerosas/genética , Fatores de Transcrição SOXB1/genética , Humanos , Fatores de Transcrição SOXB1/biossínteseRESUMO
The assessment of hormone receptors, including estrogen receptor and progesterone receptor, has become a standard practice in breast cancer management. However, the need for multiple sections to evaluate each receptor individually by conventional immunohistochemistry may preclude the analysis on some core biopsies with a limited amount of tumors. The aim of the study was to validate the quantitative analysis of nuclear markers estrogen receptor and progesterone receptor by quantum dot-based immunohistochemistry using a multispectral imaging system in ductal carcinoma in situ of the breast. Consecutive sections from a total of 17 cases of ductal carcinoma in situ with excisional biopsies or mastectomies were stained with conventional immunohistochemistry and quantum dot-based, single- and double-labeled immunohistochemistry for estrogen receptor and progesterone receptor. The semiquantitative results from double-labeled, quantum dot-based immunohistochemistry were compared with those from single-labeled, quantum dot-based immunohistochemistry as well as from conventional immunohistochemistry. There was good concordance between double- and single-labeled quantum dot-based immunohistochemistry, and quantum dot-based immunohistochemistry correlated well with conventional immunohistochemistry (Spearman correlation coefficient range from 0.884 to 0.958, P < .001). The findings proved the validity and accuracy of quantum dot-based multiplex, multispectral technique in detecting 2 tumor markers in the same cellular compartment simultaneously on a single slide. This technique may enhance our ability to assess multiple breast tumor markers in specimens with limited available tissue. However, several technical and logistic issues await significant improvement before this novel technique can be justified for routine clinical application.
Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/patologia , Carcinoma Intraductal não Infiltrante/patologia , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Neoplasias da Mama/cirurgia , Carcinoma Intraductal não Infiltrante/cirurgia , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Imuno-Histoquímica/métodos , Mastectomia , Inclusão em Parafina , Prognóstico , Pontos Quânticos , Estatísticas não ParamétricasRESUMO
Cyclin D1 expression, usually absent in chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), has been described in the proliferation centers (PC) of some CLL/SLL. The prevalence of this finding is uncertain, as is the explanation for its occurrence and whether these cases have any other unique features. Cyclin D1 immunohistochemical staining was therefore investigated in 57 extramedullary CLL/SLL biopsies. In 6 cases, cyclin D1 immunofluorescence followed by CCND1 fluorescence in situ hybridization (FISH) and PC targeted analysis was performed using a Bioview Duet system. Excluding the prospectively selected cases that had the targeted FISH studies, cyclin D1+ PC were identified in 20% of cases. The cyclin D1+ CLL did not appear pathologically or phenotypically distinctive, though 46% had an interfollicular growth pattern. The cyclin D1+ PCs were SOX11- and lacked CCND1 translocations and gains in 5 of 5 informative cases. The recognition of cyclin D1 expression in PC of a significant minority of CLL/SLL can be a diagnostic aid and should not lead to the diagnosis of focal mantle cell lymphoma.
Assuntos
Ciclina D1/genética , Centro Germinativo/metabolismo , Leucemia Linfocítica Crônica de Células B/diagnóstico , Fatores de Transcrição SOXC/genética , Idoso , Idoso de 80 Anos ou mais , Ciclina D1/metabolismo , Feminino , Centro Germinativo/patologia , Humanos , Hibridização in Situ Fluorescente , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/patologia , Masculino , Pessoa de Meia-Idade , Fatores de Transcrição SOXC/metabolismo , Translocação GenéticaRESUMO
1p/19q codeletion is a favorable prognostic marker of oligodendrogliomas. Although fluorescence in situ hybridization (FISH) and microsatellite-based polymerase chain reaction (PCR) for loss of heterozygosity (LOH) are common methods to test for 1p/19q codeletion, it is unclear which test is better at prognostic stratification. This study analyzed outcomes of 111 oligodendrogliomas with both 1p/19q FISH and LOH done at the time of diagnosis. Overall concordance between the 2 assays was 81.1%. In grade III oligodendrogliomas, LOH was better than FISH at survival stratification (p < 0.0001 for LOH vs p = 0.02 for FISH), although increasing the stringency of FISH interpretation criteria improved concordance and prognostic power. Oligodendrogliomas that were 1p/19q-codeleted by FISH but also had 10q LOH were negative for 1p/19q codeletion by PCR analysis in more than 70% of cases, with very poor survival in the grade III subset. Thus, although PCR-based LOH is a better stratifier of 1p/19q status, FISH still has clinical and prognostic utility, especially if 10q data can be incorporated.
Assuntos
Cromossomos Humanos Par 10/genética , Cromossomos Humanos Par 19/genética , Cromossomos Humanos Par 1/genética , Perda de Heterozigosidade/genética , Repetições de Microssatélites/genética , Oligodendroglioma/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Humanos , Hibridização in Situ Fluorescente/métodos , Masculino , Pessoa de Meia-Idade , Oligodendroglioma/patologia , Reação em Cadeia da Polimerase/métodos , Estudos ProspectivosRESUMO
We assessed 103 resected gastroesophageal adenocarcinomas for HER2 amplification by fluorescence in situ hybridization (FISH) and 2 commercial immunohistochemical assays. Of 103, 30 (29%) were FISH-amplified. Both immunohistochemical assays had greater than 95% concordance with FISH. However, as a screening test for FISH amplification, the Ventana Medical Systems (Tucson, AZ) 4B5 antibody demonstrated superior sensitivity (87%) compared with the DAKO (Carpinteria, CA) A0485 (70%). Of the cases, 28 were immunohistochemically 3+ or immunohistochemically 2+/FISH-amplified with the 4B5 assay compared with only 22 cases with the A0485 assay, representing a large potential difference in patient eligibility for anti-HER2 therapy. Cases with low-level FISH amplification (HER2/CEP17, 2.2-4.0) express lower levels of HER2 protein compared with cases with high-level amplification (HER2/CEP17, ≥4.0), raising the possibility of a differential response to anti-HER2 therapy. The H score and digital image analysis may have a limited role in improving HER2 test performance.