RESUMO
Epithelial-myoepithelial carcinoma (EMC) is a rare salivary gland cancer characterized by biphasic tubular structures composed of inner ductal and outer clear myoepithelial cells. Because of its histologic variety and overlap of histologic features with other salivary gland tumors, there are broad differential diagnoses. The HRAS Q61R mutation has been reported to be frequent in and specific to EMC. We evaluated the usefulness of RAS Q61R mutant-specific immunohistochemical (IHC) staining for detecting this genetic alteration in EMC. We investigated 83 EMC cases and 66 cases of salivary gland tumors with an EMC-like component, including pleomorphic adenoma, adenoid cystic carcinoma, basal cell adenoma/adenocarcinoma, and myoepithelial carcinoma. Sanger sequencing was performed for HRAS, KRAS, and NRAS. The diffuse and membranous/cytoplasmic RAS Q61R IHC expression was observed in 65% of EMC cases, in which all cases harbored the HRAS Q61R mutation. IHC-positive cases were present only in de novo EMCs (54/76 cases, 71%) but not in EMCs ex pleomorphic adenoma. The immunoreactivity was almost always restricted to the myoepithelial cells. Conversely, all EMC cases lacking the HRAS Q61R mutation were negative on IHC. In addition, only 3% of EMC-like tumors showed the abovementioned immunopositivity. None of the cases examined carried KRAS or NRAS mutations. IHC for RAS Q61R is highly sensitive and specific for detecting the HRAS Q61R mutation in EMC. Since significant immunopositivity was almost exclusively identified in nearly two thirds of EMCs but seldom in the histologic mimics, the IHC of RAS Q61R is a useful tool for diagnosing EMC in general pathology laboratories.
Assuntos
Biomarcadores Tumorais/genética , Análise Mutacional de DNA , Imuno-Histoquímica , Mutação , Mioepitelioma/genética , Neoplasias Epiteliais e Glandulares/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Neoplasias das Glândulas Salivares/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Diagnóstico Diferencial , Feminino , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Mioepitelioma/patologia , Neoplasias Epiteliais e Glandulares/patologia , Valor Preditivo dos Testes , Reprodutibilidade dos Testes , Estudos Retrospectivos , Neoplasias das Glândulas Salivares/patologiaRESUMO
Mammary analogue secretory carcinoma (MASC) is a recently described salivary gland neoplasm that is defined by ETV6-NTRK3 gene fusion. There have been few case reports on the cytopathologic features of MASC to date. We examined the clinicopathological and cytological features of seven cases of MASC defined by RT-PCR analysis of the ETV6-NTRK3 fusion gene. The cases occurred in three men and four women aged between 39 and 68 years, with a mean of 51.6 years. In five of these seven cases, the tumor involved the parotid gland. Histologically, all cases displayed predominantly microcystic patterns, often a mixture of follicular and papillary-cystic structures. All tumors were immunoreactive for mammaglobin, S-100 protein, and vimentin. Available fine-needle aspiration cytology smears were cellular and exhibited many loosely cohesive syncytial clusters or isolated cells. Many histiocytes, some of which contained hemosiderin pigments, and variously shaped mucinous material were evident in the background or within the epithelial clusters. The majority of cases showed small to medium-sized follicular structures with secreted materials. Papillary clusters were occasionally found. Tumor cells exhibited small to medium-sized round to oval nuclei, with a smooth contour and indistinct or small nucleoli, and vacuolated cytoplasm. No tumor cells had obvious intracytoplasmic zymogen granules. It appeared that clusters of small to medium-sized follicular and papillary configurations consisting of bland tumor cells with vacuolated cytoplasm, but lack of intracytoplasmic zymogen granules, in a mucinous or hemosiderin-laden histiocyte-rich background, were a characteristic cytological feature highly suggestive of MASC.
Assuntos
Carcinoma/patologia , Neoplasias Parotídeas/patologia , Adulto , Idoso , Biópsia por Agulha Fina , Carcinoma/diagnóstico , Carcinoma/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Parotídeas/diagnóstico , Neoplasias Parotídeas/metabolismo , Proteínas S100/genética , Proteínas S100/metabolismo , Secretoglobinas/genética , Secretoglobinas/metabolismo , Vimentina/genética , Vimentina/metabolismoRESUMO
We herein report a case of intrapelvic gastrointestinal stromal tumor (GIST) of undetermined origin in a 48-year-old male who presented with dysuria. An enlarged tumor was detected on digital rectal examination. Imaging studies showed a solid and lobular homogenous tumor of 7.0 cm in diameter. The tumor was attached to the right dorsal aspect of the prostate with compression of the seminal vesicles and rectum. It was considered that the tumor had arisen from the prostate, although the patient's serum prostate-specific antigen level was low (0.436 ng/mL). The histological diagnosis by prostate needle biopsy was a spindle cell tumor. At cystoprostatectomy, the tumor was confirmed to be separated from the prostate by a fibrous band, and showed spindle cells with a fascicular growth pattern, but without necrotic areas. Mitotic figures were noted in 12 of 50 high-power fields. The tumor cells were immunoreactive for the KIT protein (CD117), CD34, Discovered on GIST-1 (DOG-1), and vimentin. In contrast, they were negative for desmin, α-smooth muscle actin, pancytokeratin (AE1/AE3), and S100 protein. The Ki-67 labeling index was 5%. The genetic analyses targeting the c-kit gene revealed a point mutation at codon 559 (GTTâGAT). The diagnosis of GIST was confirmed on the basis of the morphological features, immunoprofile, and results of the molecular analyses. Since extraintestinal GIST can resemble a prostatic tumor clinically, KIT (CD117) and DOG-1 should be considered for inclusion in the immunohistochemical panel for spindle cell tumors obtained by prostate needle biopsy.
Assuntos
Tumores do Estroma Gastrointestinal/diagnóstico , Neoplasias Primárias Desconhecidas/diagnóstico , Próstata/patologia , Anoctamina-1 , Antígenos CD34/metabolismo , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Biópsia por Agulha , Canais de Cloreto/metabolismo , Análise Mutacional de DNA , DNA de Neoplasias/análise , Tumores do Estroma Gastrointestinal/genética , Tumores do Estroma Gastrointestinal/metabolismo , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/metabolismo , Neoplasias Primárias Desconhecidas/genética , Neoplasias Primárias Desconhecidas/metabolismo , Pelve , Mutação Puntual , Próstata/metabolismo , Prostatectomia , Proteínas Proto-Oncogênicas c-kit/genética , Resultado do TratamentoRESUMO
Immunotherapy against beta-amyloid peptide (Abeta) is a leading therapeutic direction for Alzheimer disease (AD). Experimental studies in transgenic mouse models of AD have demonstrated that Abeta immunization reduces Abeta plaque pathology and improves cognitive function. However, the biological mechanisms by which Abeta antibodies reduce amyloid accumulation in the brain remain unclear. We provide evidence that treatment of AD mutant neuroblastoma cells or primary neurons with Abeta antibodies decreases levels of intracellular Abeta. Antibody-mediated reduction in cellular Abeta appears to require that the antibody binds to the extracellular Abeta domain of the amyloid precursor protein (APP) and be internalized. In addition, treatment with Abeta antibodies protects against synaptic alterations that occur in APP mutant neurons.
Assuntos
Doença de Alzheimer/terapia , Precursor de Proteína beta-Amiloide/imunologia , Anticorpos Monoclonais/farmacocinética , Neurônios/patologia , Sinapses/patologia , Doença de Alzheimer/imunologia , Secretases da Proteína Precursora do Amiloide/metabolismo , Precursor de Proteína beta-Amiloide/química , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Especificidade de Anticorpos , Complexo Antígeno-Anticorpo/metabolismo , Linhagem Celular Tumoral , Endocitose , Imunização/métodos , Camundongos , Camundongos Transgênicos , Neuroblastoma , Estrutura Terciária de Proteína , TemperaturaRESUMO
Increasing evidence links intraneuronal beta-amyloid (Abeta42) accumulation with the pathogenesis of Alzheimer's disease (AD). In Abeta precursor protein (APP) mutant transgenic mice and in human AD brain, progressive intraneuronal accumulation of Abeta42 occurs especially in multivesicular bodies (MVBs). We hypothesized that this impairs the MVB sorting pathway. We used the trafficking of the epidermal growth factor receptor (EGFR) and TrkB receptor to investigate the MVB sorting pathway in cultured neurons. We report that, during EGF stimulation, APP mutant neurons demonstrated impaired inactivation, degradation, and ubiquitination of EGFR. EGFR degradation is dependent on translocation from MVB outer to inner membranes, which is regulated by the ubiquitin-proteasome system (UPS). We provide evidence that Abeta accumulation in APP mutant neurons inhibits the activities of the proteasome and deubiquitinating enzymes. These data suggest a mechanism whereby Abeta accumulation in neurons impairs the MVB sorting pathway via the UPS in AD.
Assuntos
Peptídeos beta-Amiloides/metabolismo , Inibidores de Proteassoma , Vesículas Sinápticas/metabolismo , Ubiquitina/antagonistas & inibidores , Peptídeos beta-Amiloides/análise , Precursor de Proteína beta-Amiloide/análise , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Células Cultivadas , Fator de Crescimento Epidérmico/metabolismo , Receptores ErbB/análise , Receptores ErbB/metabolismo , Hipocampo/química , Hipocampo/enzimologia , Hipocampo/metabolismo , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Complexo de Endopeptidases do Proteassoma/análise , Complexo de Endopeptidases do Proteassoma/metabolismo , Ratos , Ratos Sprague-Dawley , Vesículas Sinápticas/química , Vesículas Sinápticas/enzimologia , Ubiquitina/análise , Ubiquitina/metabolismoRESUMO
Accumulation of beta-amyloid (Abeta) peptides in the cerebral cortex is considered a key event in the pathogenesis of Alzheimer's disease (AD). Presenilin 1 (PS1) plays an essential role in the gamma-secretase cleavage of the amyloid precursor protein (APP) and the generation of Abeta peptides. Reduction of Abeta generation via the inhibition of gamma-secretase activity, therefore, has been proposed as a therapeutic approach for AD. In this study, we examined whether genetic inactivation of PS1 in postnatal forebrain-restricted conditional knock-out (PS1 cKO) mice can prevent the accumulation of Abeta peptides and ameliorate cognitive deficits exhibited by an amyloid mouse model that overexpresses human mutant APP. We found that conditional inactivation of PS1 in APP transgenic mice (PS1 cKO;APP Tg) effectively prevented the accumulation of Abeta peptides and formation of amyloid plaques and inflammatory responses, although it also caused an age-related accumulation of C-terminal fragments of APP. Short-term PS1 inactivation in young PS1 cKO;APP Tg mice rescued deficits in contextual fear conditioning and serial spatial reversal learning in a water maze, which were associated with APP Tg mice. Longer-term PS1 inactivation in older PS1 cKO;APP Tg mice, however, failed to rescue the contextual memory and hippocampal synaptic deficits and had a decreasing ameliorative effect on the spatial memory impairment. These results reveal that in vivo reduction of Abeta via the inactivation of PS1 effectively prevents amyloid-associated neuropathological changes and can, but only temporarily, improve cognitive impairments in APP transgenic mice.