RESUMO
BACKGROUND: Evaluation of mismatch repair (MMR) deficiency is conducted via immunohistochemistry or by microsatellite instability (MSI) analysis. Heterogeneous immunohistochemistry staining for MMR proteins may show different patterns; however, according to current guidelines, all of those patterns should be interpreted as MMR proficient. This conclusion might lead to false negative results because although most cases of heterogeneity stem from technical factors and biological variability, other types of heterogeneity represent true MMR deficiency. OBJECTIVES: To identify a unique heterogeneity pattern that is associated with true MMR loss. METHODS: We analyzed 145 cases of colorectal carcinoma. Immunohistochemistry staining for MLH1, PMS2, MSH2, and MSH6 were performed. We defined geographic heterogeneity as areas of tumor nuclear staining adjacent to areas of loss of tumor nuclear staining with intact staining in the surrounding stroma. All cases were evaluated for the presence of geographic heterogeneity. In addition, 24 cases were also evaluated by MSI testing. RESULTS: Of the 145 cases, 24 (16.5%) were MMR deficient. Of the 24 cases for which MSI analysis was also available, 10 cases (41.7%) demonstrated biological heterogeneity, 5 (20.8%) demonstrated technical heterogeneity, and 2 (8.3%) demonstrated geographic heterogeneity. Only the two cases with geographic heterogeneity were MSI-high via MSI analysis. In addition, a germline mutation in MSH-6 was identified in one of these cases. CONCLUSIONS: Geographic heterogeneity may raise a suspicion for a MMR-deficient case, which should be further analyzed using additional methodologies such as MSI analysis.
Assuntos
Reparo de Erro de Pareamento de DNA/genética , Proteínas MutS/genética , Adenoma/genética , Adenoma/patologia , Adulto , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Corantes , Heterogeneidade Genética , Humanos , MasculinoRESUMO
Germline biallelic mismatch repair deficiency (bMMRD) results in a unique cancer predisposition syndrome in which the affected children are susceptible to the development of malignancies, especially brain, gastrointestinal, and lymphoid cancers. Acute myeloblastic leukemia is rarely reported in this syndrome. Here we report the decision-making challenges in a bMMRD child with acute myeloblastic leukemia. Our experience should alert physicians to include bMMRD in the differential diagnosis of a child with hyper/hypopigmented spots and leukemia. Furthermore, the presence of the above and consanguinity emphasizes the need to rule out bMMRD when an allogeneic bone marrow transplant is considered and to enable the surveillance of other family members for earlier detection of cancers in these children.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Encefálicas/genética , Neoplasias Colorretais/genética , Transplante de Células-Tronco de Sangue do Cordão Umbilical , Proteínas de Ligação a DNA/genética , Leucemia Mieloide Aguda/terapia , Síndromes Neoplásicas Hereditárias/genética , Proteínas Nucleares/genética , Aloenxertos/virologia , Neoplasias Encefálicas/diagnóstico , Manchas Café com Leite/diagnóstico , Manchas Café com Leite/genética , Pré-Escolar , Neoplasias Colorretais/diagnóstico , Terapia Combinada , Transplante de Células-Tronco de Sangue do Cordão Umbilical/efeitos adversos , Diagnóstico Diferencial , Evolução Fatal , Feminino , Mutação em Linhagem Germinativa , Humanos , Leucemia Mieloide Aguda/genética , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/etiologia , Linfoma Difuso de Grandes Células B/virologia , Masculino , Síndromes Neoplásicas Hereditárias/diagnóstico , Nucleofosmina , RecidivaRESUMO
BACKGROUND: The prognostic value of skin and blood T-cell receptor clonality in mycosis fungoides is a matter of debate. Our aim was to ascertain the relation between the presence of a monoclonal T-cell population in the blood and in the skin with response to treatment in patients with mycosis fungoides. PATIENTS AND METHODS: Clinical features and follow-up data were retrospectively collected and analyzed in 94 patients with mycosis fungoides seen at a cutaneous lymphoma clinic in a single tertiary center. All patients had results of polymerase chain reaction analysis of T-cell receptor gamma gene rearrangement in lesional skin and in peripheral blood at time of diagnosis. Association of response to treatment with clonality in the tissue and in the blood was assessed. RESULTS: T-cell monoclonality was detected in the skin in 30 of 94 patients, in the blood in 12 of 94 cases and the same clone was found in both tissues in 6 of 94 patients. The presence of a polyclonal T-cell population in the circulation was associated with complete response (P = .006). Lack of response to treatment (stable disease or progression of disease) was associated with T-cell clonality in skin (P = .009), in blood (P = .002) and in both tissues (P < .001). A multivariate analysis showed that T-cell monoclonality in the skin is independently associated with lack of response of mycosis fungoides to therapy. CONCLUSION: Blood and skin should be studied for T-cell clonality as part of the routine initial workup, even in patients with early-stage disease.
Assuntos
Micose Fungoide , Neoplasias Cutâneas , Humanos , Linfócitos T , Estudos Retrospectivos , Rearranjo Gênico da Cadeia gama dos Receptores de Antígenos dos Linfócitos T , Reação em Cadeia da Polimerase/métodos , Micose Fungoide/diagnóstico , Micose Fungoide/terapia , Neoplasias Cutâneas/patologiaRESUMO
BACKGROUND & AIMS: Chronic hepatitis C virus (HCV) infection is strongly associated with insulin resistance and diabetes mellitus. Peroxisome proliferator-activated receptor-gamma co-activator 1α (PGC-1α) is a transcriptional co-activator involved in the initiation of gluconeogenesis in the liver. Increased hepatic expression of PGC-1α has been implicated in insulin resistance. We investigated whether modulation of PGC-1α levels following HCV infection underlies HCV-associated hepatic insulin resistance. METHODS: HCV genomes were expressed in hepatoma cells followed by analysis of PGC-1α and gluconeogenesis levels. RESULTS: PGC-1α was robustly induced in HCV infected cells. PGC-1α induction was accompanied by an elevated expression of the gluconeogenic gene glucose-6 phosphatase (G6Pase) and increased glucose production. The induction of gluconeogenesis is HCV dependent, since interferon treatment abolishes PGC-1α and G6Pase elevation and decreases glucose output. Moreover, PGC-1α knockdown resulted in a significant reduction of G6Pase levels in HCV full length replicon cells, emphasizing the central role of PGC-1α in the exaggerated gluconeogenic response observed in HCV patients. Treatment of HCV replicon cells with the antioxidant N-acetylcysteine resulted in reduction of PGC-1α levels, suggesting that HCV-induced oxidative stress promoted PGC-1α upregulation. Finally, both PGC-1α and G6Pase RNA levels were significantly elevated in liver samples of HCV infected patients, highlighting the clinical relevance of these results. CONCLUSIONS: PGC-1α is robustly induced following HCV infection, resulting in an upregulated gluconeogenic response, thereby linking HCV infection to hepatic insulin resistance. Our results suggest that PGC-1α is a potential molecular target for the treatment of HCV-associated insulin resistance.
Assuntos
Proteínas de Choque Térmico/genética , Proteínas de Choque Térmico/metabolismo , Hepacivirus/metabolismo , Hepatite C Crônica/metabolismo , Resistência à Insulina , Fígado/virologia , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Acetilcisteína/farmacologia , Linhagem Celular Tumoral , Eletroporação , Técnicas de Silenciamento de Genes , Genótipo , Gluconeogênese/genética , Glucose-6-Fosfatase/genética , Glucose-6-Fosfatase/metabolismo , Hepacivirus/genética , Hepacivirus/fisiologia , Humanos , Interferon-alfa/farmacologia , Fígado/citologia , Fígado/metabolismo , Estresse Oxidativo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo , RNA Mensageiro/metabolismo , RNA Viral/metabolismo , Replicon , Ativação Transcricional/efeitos dos fármacos , Regulação para Cima , Replicação ViralRESUMO
Inflammatory Myofibroblastic Tumors (IMTs) are rare fibroblastic/myofibroblastic neoplasms that affect predominately pediatric patients and young adults. Almost half of the patients with IMTs have a chromosomal abnormality in the Anaplastic Lymphoma Kinase 1 gene on chromosome 2p23. Although these tumors occur primarily in the lung, lesions have been reported in a variety of intra-abdominal organs like the liver, spleen, and mesentery. Small bowel IMTs are particularly rare. IMTs generally pursue a benign clinical course, however intra-abdominal and retroperitoneal tumors have typically shown higher local recurrence and even distant metastases. The most common presenting symptoms of an intra-abdominal IMT are abdominal pain and change in bowel habits. Laboratory results are nonspecific and can include anemia and minor elevation of inflammatory markers like C-reactive protein. We report an unusual case of IMT in the small bowel causing the obstruction.
Assuntos
Granuloma de Células Plasmáticas , Proteínas Tirosina Quinases , Criança , Granuloma de Células Plasmáticas/diagnóstico , Granuloma de Células Plasmáticas/genética , Granuloma de Células Plasmáticas/patologia , Humanos , Intestino Delgado/diagnóstico por imagem , Proteínas Tirosina Quinases/genética , Proteínas Tirosina Quinases/metabolismo , Proteínas Proto-Oncogênicas , Receptores Proteína Tirosina QuinasesRESUMO
Inflammatory myofibroblastic tumor (IMT) is a lesion of intermediate biological potential with local recurrences and rare metastases found in multiple anatomical locations. We present a case of a pure intraarticular IMT of the knee, a location that has not been previously documented, with genetic confirmation of ALK-CARS fusion detected with next-generation sequencing. A 20-year-old healthy male was admitted to the orthopedic oncology department due to several months of pain and restriction in movement of his left knee. On magnetic resonance imaging, multiple intraarticular nodular lesions were seen. The patient underwent 2 synovectomies within the course of 1 year. The initial biopsy was interpreted as nodular fasciitis. The second biopsy revealed exuberant tissue displaying compact fascicles of spindle cells intermixed with myxoid areas in a background of inflammatory cells, highly suggestive for IMT. Due to the unusual intraarticular location, equivocal ALK immunostaining and the differential diagnosis with nodular fasciitis, we performed targeted next-generation sequencing using Archer FusionPlex Sarcoma panel, which can identify multiple fusions in a single assay. An ALK-CARS fusion was found, supporting the diagnosis of IMT. This report emphasizes the added value of broad molecular analysis in cases with unusual clinical presentation, equivocal immunohistochemistry, and a wide differential diagnosis.
Assuntos
Articulação do Joelho/patologia , Proteínas de Fusão Oncogênica/genética , Neoplasias de Tecidos Moles/diagnóstico , Membrana Sinovial/patologia , Aminoacil-tRNA Sintetases/genética , Quinase do Linfoma Anaplásico/genética , Biópsia , Procedimentos Cirúrgicos de Citorredução , Diagnóstico Diferencial , Fasciite/diagnóstico , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Articulação do Joelho/diagnóstico por imagem , Articulação do Joelho/imunologia , Articulação do Joelho/cirurgia , Imageamento por Ressonância Magnética , Masculino , Neoplasias de Tecidos Moles/genética , Neoplasias de Tecidos Moles/imunologia , Neoplasias de Tecidos Moles/cirurgia , Sinovectomia , Membrana Sinovial/diagnóstico por imagem , Membrana Sinovial/imunologia , Adulto JovemRESUMO
BACKGROUND: Patients with multiple (< 100) colorectal adenomatous polyps are at increased risk for colorectal cancer. Genetic evaluation of those patients who test negative forAPCgene mutation is both a clinical and economic burden but is critical for counseling and surveillance. In Israel, this is confounded by the fact that national health insurance does not fully cover genetic evaluation of APC gene exon 16. OBJECTIVES: To perform a comprehensive genetic evaluation of APC gene mutation-negative polyposis patients with the aim of developing a future evaluation protocol. METHODS: Genetic analyses were performed in 29 APC gene mutation-negative Jewish individuals with 5 to > or = 40 colonic adenomas who did not fulfill Amsterdam (clinical) criteria for Lynch syndrome. Analyses included completion of APC gene exon 16 sequencing, analysis for APC gene copy number variations (deletions or duplications), MUTYH gene sequencing, and microsatellite instability in CRC patients fulfilling "Bethesda" (laboratory investigation) criteria for Lynch syndrome. RESULTS: Completion of APC gene exon 16 sequencing revealed one patient with the E1317Q polymorphism. All were normal by APC multiplex ligation-dependent probe amplification analysis. Pathogenic MUTYH mutations were found in three patients, all of North African origin; two additional patients had variants of unknown significance. One of six patients with Bethesda-positive criteria was MSI-High with immunohistology consistent with MLH1 mutation. CONCLUSIONS: Based on this small but well-characterized cohort with multiple colorectal adenomas, Lynch syndrome needs to be excluded if there are compatible criteria; otherwise MUTYH sequencing is probably the first step in evaluating APC-negative patients, especially for Jews of North African descent. Completing APC exon 16 sequencing and copy number variations analysis should probably be the last evaluations.
Assuntos
Polipose Adenomatosa do Colo/genética , Neoplasias Colorretais/genética , DNA Glicosilases/genética , Testes Genéticos , Mutação/genética , Polimorfismo Genético/genética , Polipose Adenomatosa do Colo/patologia , Adulto , Idoso , Estudos de Coortes , Neoplasias Colorretais/patologia , Feminino , Genes APC , Humanos , Israel , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Adulto JovemAssuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Cromossomos Humanos Par 11/genética , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Mieloide Aguda/etiologia , Leucemia Mieloide Aguda/genética , Proteína de Leucina Linfoide-Mieloide/genética , Segunda Neoplasia Primária/etiologia , Segunda Neoplasia Primária/genética , Anticorpos Monoclonais Murinos/administração & dosagem , Anticorpos Monoclonais Murinos/efeitos adversos , Sequência de Bases , Cromossomos Humanos Par 9/genética , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Sondas de DNA/genética , Rearranjo Gênico , Histona-Lisina N-Metiltransferase , Humanos , Hibridização in Situ Fluorescente , Masculino , Pessoa de Meia-Idade , Rituximab , Translocação Genética , Vidarabina/administração & dosagem , Vidarabina/efeitos adversos , Vidarabina/análogos & derivadosRESUMO
Lynch Syndrome is caused by mutations in DNA mismatch repair genes. Diagnosis is not always trivial and may be costly. Information regarding incidence, genotype-phenotype correlation, spectrum of mutations and genes involved in specific populations facilitate the diagnostic process and contribute to clinical work-up. To report gene distribution, mutations detected and co-occurrence of related syndromes in a cohort of Ashkenazi Jews in Israel. Patients were identified in dedicated high risk clinics in 3 medical centers in Israel. Diagnostic process followed a multi-step scheme. It included testing for founder mutations, tumor testing, gene sequencing and MLPA. Lynch Syndrome was defined either by positive mutation testing, or by clinical criteria and positive tumor analysis. We report a cohort of 75 Ashkenazi families suspected of Lynch Syndrome. Mutations were identified in 51/75 (68%) families: 38 in MSH2, 9 in MSH6, and 4 in MLH1. 37/51 (73%) of these families carried one of the 3 'Ashkenazi' founder mutations in MSH2 or MSH6. Each of the other 14 families carried a private mutation. 3 (6%) were large deletions. Only 20/51 (39%) families were Amsterdam Criteria positive; 42 (82%) were positive for the Bethesda guidelines and 9 (18%) did not fulfill any Lynch Syndrome criteria. We report C-MMRD and co-occurrence of BRCA and Lynch Syndrome in our cohort. Mutation spectra and gene distribution among Ashkenazi Jews are unique. Three founder Lynch Syndrome mutations are found in 73% families with known mutations. Among the three, MSH2 and MSH6 are the most common. These features affect the phenotype, the diagnostic process, risk estimation, and genetic counseling.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Neoplasias Colorretais Hereditárias sem Polipose/genética , Proteínas de Ligação a DNA/genética , Judeus/genética , Proteína 2 Homóloga a MutS/genética , Mutação , Proteínas Nucleares/genética , Antígenos de Neoplasias/genética , Moléculas de Adesão Celular/genética , Molécula de Adesão da Célula Epitelial , Efeito Fundador , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Israel , Proteína 1 Homóloga a MutLRESUMO
Clinical features usually initiate evaluation for Lynch Syndrome (LS) but some colorectal cancer (CRC) histopathology findings are compatible with high microsatellite instability (MSI-H) that also occurs in LS. This led to the suggestion that pathologists request MSI analysis, which is an expensive addition to routine histology. We aimed to see if a Gastrointestinal Pathologist could identify MSI-H features with reproducibility and high (95%) specificity (MSI-H 95%). Histopathology of all CRCs received during 2005 and 4 MSI-H controls were scored using 2 published methods, "MsScore" and "PathScore". MSI analysis was performed on CRCs scored by either method as probable MSI-H 95% and results compared. To examine reproducibility of histopathology, 100 coded slides, including 25 scored MSI-H 95% and 75 scored low, were re-examined to now identify those needing MSI analysis. Costs were evaluated for identifying MSI-H with or without scoring. All 227 CRCs were scored for possible MSI-H 95%; 24 had high scores and MSI analysis. DNA analysis proved 14 MSI-H, PathScore identified 13 (95%), MsPath identified 9 (64%), histopathology alone identified 7 (50%). Reproducibility for identifying histopathology characteristics of MSI-H at re-examination, without scoring, was "moderate agreement" (Kappa statistic = 0.4615). Costs for identifying MSI-H by PathScore were the lowest, $436/identification. Conclusions; PathScore identified the most proven MSI-H CRCs at lowest cost and even an experienced gastrointestinal pathologist has difficulties identify MSI-H without scoring. So, scoring can be facilitated by a computerized evaluation form for routine CRC histology, prompting score computation and recommendation for MSI analysis with high specificity.
Assuntos
Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Instabilidade de Microssatélites , Patologia Clínica/métodos , Idoso , Neoplasias Colorretais Hereditárias sem Polipose/genética , Neoplasias Colorretais Hereditárias sem Polipose/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Patologia Clínica/economia , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
BACKGROUND: High rates of extrapancreatic malignancies (EPM) have been observed in patients with intraductal papillary mucinous neoplasm (IPMN). IPMN in patients with familial pancreatic cancer have also been reported. Our purpose was to evaluate the association of IPMN with EPM, malignancies in family members, and germline BRCA1 and BRCA2 mutations. METHODS: Using retrospective analysis on prospectively collected data from 82 patients with IPMN and direct contact for familial cancer history, data were compared with those of 150 patients with pancreatic ductal adenocarcinoma (PDAC). The common germline mutations in the BRCA1 and BRCA2 genes were evaluated on available IPMN patients. RESULTS: EPM rates were greater in IPMN than PDAC patients (P = .002). Malignancies in first-degree relatives, specifically pancreatic cancer, were more common among IPMN than PDAC patients (P = .028). IPMN patients with EPM had high rates of relatives with colorectal cancer (31%). Two of the 51 genetically tested patients (4%) were BRCA2 mutation carriers, and both had first-degree relatives with pancreatic cancer. One patient fulfilled the Amsterdam criteria for hereditary nonpolyposis colon cancer; however, the neoplasm was microsatellite stable. CONCLUSION: Our results demonstrated high rates of EPM among IPMN patients. There was an increased rate of cancer in families of IPMN patients, specifically pancreatic cancer. A high rate of colorectal cancer in families of IPMN patients who have EPM was also observed. These findings suggest a genetic component in the pathogenesis of IPMN. Possible genetic changes include BRCA2 mutations, which are found in 25% of IPMN patients with a family history of pancreatic cancer.
Assuntos
Adenocarcinoma/epidemiologia , Neoplasias Primárias Múltiplas/epidemiologia , Neoplasias Pancreáticas/epidemiologia , Adenocarcinoma/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Análise Mutacional de DNA , Feminino , Genes BRCA1 , Genes BRCA2 , Predisposição Genética para Doença , Humanos , Israel/epidemiologia , Masculino , Pessoa de Meia-Idade , Neoplasias Primárias Múltiplas/genética , Neoplasias Pancreáticas/genética , Estudos RetrospectivosRESUMO
Blood oxygenation level dependence (BOLD) imaging under either hypercapnia or hyperoxia has been used to study neuronal activation and for assessment of various brain pathologies. We evaluated the benefit of a combined protocol of BOLD imaging during both hyperoxic and hypercapnic challenges (termed hemodynamic response imaging (HRI)). Nineteen healthy controls and seven patients with primary brain tumors were included: six with glioblastoma (two newly diagnosed and four with recurrent tumors) and one with atypical-meningioma. Maps of percent signal intensity changes (ΔS) during hyperoxia (carbogen; 95%O2+5%CO2) and hypercapnia (95%air+5%CO2) challenges and vascular reactivity mismatch maps (VRM; voxels that responded to carbogen with reduced/absent response to CO2) were calculated. VRM values were measured in white matter (WM) and gray matter (GM) areas of healthy subjects and used as threshold values in patients. Significantly higher response to carbogen was detected in healthy subjects, compared to hypercapnia, with a GM/WM ratio of 3.8 during both challenges. In patients with newly diagnosed/treatment-naive tumors (n = 3), increased response to carbogen was detected with substantially increased VRM response (compared to threshold values) within and around the tumors. In patients with recurrent tumors, reduced/absent response during both challenges was demonstrated. An additional finding in 2 of 4 patients with recurrent glioblastoma was a negative response during carbogen, distant from tumor location, which may indicate steal effect. In conclusion, the HRI method enables the assessment of blood vessel functionality and reactivity. Reference values from healthy subjects are presented and preliminary results demonstrate the potential of this method to complement perfusion imaging for the detection and follow up of angiogenesis in patients with brain tumors.