RESUMO
Pendred syndrome (PDS) is an autosomal recessive disorder caused by mutations in the gene that encodes pendrin. Pendred thyroid tissue is supposedly altered by the absence of functional pendrin, but it is still unknown whether other iodide exchangers could compensate for the loss of the protein. Moreover, we have recently described that primary cilium, a conserved structure present at the apical surface of normal follicular cells, suffers different alterations in functional thyroid diseases. We aimed (1) to better understand the histopathological changes experienced by PDS thyroids, (2) to analyze the expression of different thyroid-specific genes and alternative iodide transporters and, finally, (3) to determine whether those changes may alter the morphological pattern of primary cilia in follicular cells. Thyroid samples from a series of four PDS patients were analyzed by immunohistochemistry, double immunofluorescence, and morphometry to evaluate changes in primary cilia frequency and length. We found thyroid follicular nodular disease in all PDS thyroids, frequently in association with follicular adenomas. There were only slight changes in the expression of thyroid-specific markers. Although no positivity for pendrin was found, cytoplasmic immunostaining for ANO-1, CLC-5, and CFTR was stronger in diffuse hyperplastic areas when compared to areas with highly cellular follicular nodules (HCFNs). HCFNs and follicular adenomas always showed diminished ciliary frequency and length. Our results suggest a direct relationship between the absence of functional pendrin and the loss of the normal thyroid architecture in PDS patients, which was also accompanied by differences in the expression of specific immunohistochemical markers and altered ciliogenesis. The present data may help the pathologist in screening for PDS.
Assuntos
Adenoma , Bócio Nodular , Perda Auditiva Neurossensorial , Doenças da Glândula Tireoide , Humanos , Iodetos/metabolismo , Bócio Nodular/genética , Bócio Nodular/metabolismo , Bócio Nodular/patologia , Perda Auditiva Neurossensorial/diagnóstico , Perda Auditiva Neurossensorial/genética , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Transportadores de SulfatoAssuntos
Carcinoma de Células Escamosas/metabolismo , Neoplasias Laríngeas/metabolismo , Neoplasias Nasofaríngeas/metabolismo , Via de Sinalização Wnt/fisiologia , Proteínas Adaptadoras de Transdução de Sinal/análise , Proteínas Adaptadoras de Transdução de Sinal/biossíntese , Idoso , Carcinoma , Carcinoma de Células Escamosas/química , Feminino , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/análise , Peptídeos e Proteínas de Sinalização Intercelular/biossíntese , Neoplasias Laríngeas/química , Masculino , Pessoa de Meia-Idade , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas/química , Proteínas Proto-Oncogênicas/análise , Proteínas Proto-Oncogênicas/biossíntese , Proteínas Repressoras/análise , Proteínas Repressoras/biossíntese , Proteínas Wnt/análise , Proteínas Wnt/biossíntese , Proteína Wnt-5a , Proteína Wnt1/análise , Proteína Wnt1/biossínteseRESUMO
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the digestive tract. Expression of CD117, DOG1 and PKCθ was investigated immunohistochemically in a series of 99 paraffin-embedded GISTs in order to determine the sensitivity and diagnostic value of these markers. KIT exons 9, 11, 13 and 17 and PDGFRA exons 12 and 18 were amplified by PCR and sequenced. A total of 94/99 (94%) GISTs stained positive for CD117, 81/99 (82%) for PKCθ and 90/99 (91%) for DOG-1. A significant correlation was noted between CD117 and DOG-1 expression (p=0.0001). All three markers were expressed in 74% (73/99) of GISTs. Of the five CD117-negative cases, two were PKCθ-negative/DOG1-negative and had mutations in KIT exon 11. Two were PKCθ-positive/DOG1-positive and had mutations in PDGFRA (one each in exons 12 and 18), and one was DOG1-negative/PKCθ-positive, with a PDGFRA exon 18 mutation. The most sensitive marker was CD117, followed by DOG-1 and PKCθ. Although PKCθ was less sensitive, and its staining is more challenging and difficult to interpret, the use of this marker is highly recommended, particularly in CD117-negative/DOG-1-negative GISTs.
Assuntos
Biomarcadores Tumorais/análise , Canais de Cloreto/análise , Tumores do Estroma Gastrointestinal/química , Isoenzimas/análise , Proteínas de Neoplasias/análise , Proteína Quinase C/análise , Proteínas Proto-Oncogênicas c-kit/análise , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anoctamina-1 , Biomarcadores Tumorais/genética , Distribuição de Qui-Quadrado , Análise Mutacional de DNA , Éxons , Feminino , Tumores do Estroma Gastrointestinal/enzimologia , Tumores do Estroma Gastrointestinal/genética , Tumores do Estroma Gastrointestinal/imunologia , Tumores do Estroma Gastrointestinal/patologia , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Mutação , Inclusão em Parafina , Reação em Cadeia da Polimerase , Valor Preditivo dos Testes , Prognóstico , Proteína Quinase C-theta , Proteínas Proto-Oncogênicas c-kit/genética , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Sensibilidade e Especificidade , Espanha , Análise Serial de Tecidos , Adulto JovemRESUMO
Abnormal Wnt signaling and impaired cell-cell adhesion due to abnormal E-cadherin and ß-catenin function have been implicated in many cancers, but have not been fully explored in laryngeal squamous cell carcinoma. In this study, ß-catenin cellular location and E-cadherin expression levels were analyzed in 16 laryngeal squamous cell carcinomas (LSCCs) (9 glottic and 7 supraglottic) and 11 samples of non-tumoral inflammatory larynx tissue, using immunohistochemical methods. All non-tumoral tissues showed equally strong membranous expression of ß-catenin, while cytoplasmic expression was found in only 3 of the 11 samples. By contrast, whereas 8/9 glottic LSCCs exhibited only membranous expression of ß-catenin, 6/7 supraglottic LSCCs displayed both membranous and cytoplasmic expression (p = 0.003). Strong E-cadherin staining was observed in 9/11 non-tumoral tissues and 7/9 glottic LSCCs, whereas 4/7 supraglottic LSCCs exhibited weak expression. Reduced membrane expression of E-cadherin and cytoplasmic retention of ß-catenin in supraglottic LSCC seems to be related with more aggressive biological behavior which has been described in clinical studies. Further research is required to clarify the involvement of ß-catenin in the mechanism associated with malignant transformation in laryngeal tissues.
Assuntos
Caderinas/biossíntese , Carcinoma de Células Escamosas/metabolismo , Neoplasias Laríngeas/metabolismo , beta Catenina/biossíntese , Adulto , Idoso , Biomarcadores Tumorais/metabolismo , Carcinoma de Células Escamosas/patologia , Progressão da Doença , Feminino , Humanos , Imuno-Histoquímica , Neoplasias Laríngeas/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Adulto JovemRESUMO
AIM: To characterize the differentially-activated mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K/Akt/mTOR) pathways in mutant (m) and wild-type (wt) GISTs and to investigate the role of insulin-like growth factor 1 receptor (IGF1R) expression. MATERIALS AND METHODS: Ninety-nine paraffin-embedded gastrointestinal stromal tumors (GISTs) were selected. CD117, IGF1R, phospho-ERK1/2, phospho-Akt, p70S6, eukaryotic initiation factor 4E-binding protein-1 (4EBP1) and pS6 expression were investigated using immunohistochemical methods. KIT exons 9, 11, 13 and 17 and platelet derived growth factor receptor alpha (PDGFRA) exons 12 and 18 were amplified by PCR and sequenced. RESULTS: Significant differences were found in the expression of phospho-ERK1/2 between mGISTs and wtGISTs. Complex evaluation of all PI3K/Akt/mTOR pathway markers revealed greater activation in mGISTs, particularly in PDGFRA-mutated GISTs. No significant correlation was observed between IGF1R expression and either mutational status or pathway activation. CONCLUSION: There appears to be no MAPK pathway activation in wtGISTs. Tumors harboring PDGFRA mutations tended to use the PI3K/Akt/mTOR signaling pathway. Most adult GISTs, irrespective of mutational status, displayed no IGFR1 expression; tumors positive for IGFR1 showed no preferential activation of the MAPK or AKT pathways.