RESUMO
The study of the immune response in thyroid autoimmunity has been mostly focused on the autoantibodies and lymphocytes, but there are indications that intrinsic features of thyroid tissue cells may play a role in disrupting tolerance that needs further investigation. The overexpression of HLA and adhesion molecules by thyroid follicular cells (TFC) and our recent demonstration that PD-L1 is also moderately expressed by TFCs in autoimmune thyroid indicates that TFCs they may activate but also inhibit the autoimmune response. Intriguingly, we have recently found that in vitro cultured TFCs are able to suppress the proliferation of autologous lymphocyte T in a contact-dependent manner which is independent of the PD-1/PD-L1 signaling pathway. To get a more comprehensive picture of TFC activating and inhibitory molecules/pathways driving the autoimmune response in the thyroid glands, preparations of TFCs and stromal cells from five Graves' disease (GD) and four control thyroid glands were compared by scRNA-seq. The results confirmed the previously described interferon type I and type II signatures in GD TFCs and showed unequivocally that they express the full array of genes that intervene in the processing and presentation of endogenous and exogeneous antigens. GD TFCs lack however expression of costimulatory molecules CD80 and CD86 required for priming T cells. A moderate overexpression of CD40 by TFCs was confirmed. GD Fibroblasts showed widespread upregulation of cytokine genes. The results from this first single transcriptomic profiling of TFC and thyroid stromal cells provides a more granular view of the events occurring in GD. The new data point at an important contribution of stromal cells and prompt a major re-interpretation of the role of MHC over-expression by TFC, from deleterious to protective. Most importantly this re-interpretation could also apply to other tissues, like pancreatic beta cells, where MHC over-expression has been detected in diabetic pancreas.
Assuntos
Autoimunidade , Doença de Graves , Humanos , Antígeno B7-H1/genética , Transcriptoma , Doença de Graves/genética , Moléculas de Adesão Celular/genéticaRESUMO
Immune Checkpoint Receptors include a number of inhibitory receptors that limit tissue damage during immune responses; blocking PD-1/PD-L1 checkpoint receptor axis led to a paradigm shift in cancer immunotherapy but also to autoimmune adverse effects, prominently thyroid autoimmunity. Although PD-L1 is known to be expressed on thyroid follicular cells (TFCs) of autoimmune glands the role on PD-1/PD-L1 in the interaction between T cells and thyroid cells in the tissue has not been investigated. Here we report that autologous primary TFCs, but not transformed TFCs, inhibit CD4 and CD8 T cell proliferation but no cytokine production. This effect is not, however, mediated by PD-1/PD-L1 nor locally produced cytokines. Beta galactosidase analysis excluded culture-induced senescence as an explanation. High resolution flow cytometry demonstrated that autologous TFC/T cells co-culture induced the expansion of several clusters of double negative (DN) T cells characterized by high expression of activation markers and negative immune checkpoints. Single cell transcriptomic profiling demonstrated that dissociated TFC express numerous candidate molecules for mediating this suppressive activity, including CD40, E-Cadherin and TIGIT ligands. These ligands directly or through the generation of a suppressor population of DN T cells, and not the PD-1/PD-L1 axis, are most likely the responsible of TFC immunosuppressive activity. These results contribute to reveal the complex network of inhibitory mechanism that operate at the tissue level to restrain autoimmunity but also point to pathways, other that PD-1/PD-L1, that can contribute to tumor evasion.
Assuntos
Antígeno B7-H1 , Glândula Tireoide , Antígeno B7-H1/metabolismo , Receptor de Morte Celular Programada 1/metabolismo , Linfócitos T CD8-Positivos , Proliferação de CélulasRESUMO
Background: Autoimmune thyroid diseases are the most common types of autoimmune diseases, but their physiopathology is still relatively unexplored. Genotype-tissue expression (GTEx) is a publicly available repository containing RNAseq data, including profiles from thyroid. Approximately 14.8% of these glands were affected by focal lymphocytic thyroiditis and 6.3% were annotated as Hashimoto. We interrogated these data to improve the characterization of infiltrating cells and to identify new molecular pathways active in autoimmune thyroiditis. Materials and Methods: Histological GTEx images of 336 thyroid samples were classified into three categories, that is, non-infiltrated thyroid, small focal infiltrated thyroid, and extensive lymphoid infiltrated thyroid. Differentially expressed genes among these categories were identified and subjected to in silico pathway enrichment analysis accordingly. CIBERSORTx deconvolution was used to characterize infiltrating cells. Results: As expected, most of the transcriptional changes were dependent on tissue infiltration. Upregulated genes in tissues include-in addition to lineage-specific B and T cell genes-a broad representation of inhibitory immune checkpoint receptors expressed by B and T lymphocytes. CIBERSORTx analysis identified 22 types of infiltrating cells showed that T cells predominate 3:1 over B cells in glands with small infiltrates, only by 1.7:1 in those with large infiltrates. Follicular helper and memory CD4 T cells were significantly more abundant in glands with large infiltrates (p < 0.0001), but the most prominent finding in these glands was an almost sixfold increase in the number of naive B cells (p < 0.0001). A predominance of M2 macrophages over M1 and M0 macrophages was observed in the three gland categories (p < 0.001). Conclusions: Analysis of transcriptomic RNA-seq profiles constitutes a rich source of information for the analysis of autoimmune tissues. High-resolution transcriptomic data analysis of thyroid glands indicates the following: (a) in all infiltrated glands, active autoimmune response coexists with suppressor counteracting mechanisms involving several inhibitory checkpoint receptor pairs, (b) glands with small infiltrates contain an unexpected relatively high proportion of B lymphocytes, and (c) in highly infiltrated glands, there is a distinct transcriptomic signature of active tertiary lymphoid organs. These results support the concept that the autoimmune response is amplified in the thyroid tissue.
Assuntos
Doença de Hashimoto , Tireoidite Autoimune , Tireoidite , Linfócitos B , Humanos , TranscriptomaRESUMO
BACKGROUND AND OBJECTIVE: The risk of recurrence in papillary thyroid carcinoma (PTC) is likely related to the amount of tumour in the metastatic lymph node (LN). Therefore, the current TNM classification (N0/N1) make it necessary to find a method to quantify the LN metastasis (LNM). We propose that the quantitative molecular assay One-Step Nucleic-Acid Amplification (OSNA), which measures the number of cytokeratin-19 (CK-19) mRNA copies as a marker of LNM, could play this role. Our objective was to describe the characteristics of the LNs from PTC, and to compare the morphological characteristics that have been claimed as criteria for metastatic burden with OSNA. PATIENTS AND METHOD: Prospective study of LNs from 42 patients. All of the LNs were measured, weighed and analysed by OSNA and also by imprint cytology. RESULTS: A total of 573 LNs were included, 187 (32.6%) of them were OSNA-positives. The global consistency between cytology and OSNA was 87.4%. Significant differences were observed in the CK-19 copy number between the LNMs<0.2cm and those >3cm, as well as between those from 0.2 to 3cm with respect to those >3cm, but not between those <0.2cm and those between 0.2 and 3cm. The total tumour load per neck dissection showed no differences based on whether there were ≤5 or >5 LNMs. CONCLUSIONS: In our series the LNMs >3cm show an increased tumour load, but it is unclear if it is necessary to sub-classify the smaller ones as well as the relevance of the number of metastatic nodes according to the cut-off of 5 nodes. We consider that the OSNA analysis avoids the bias of nodal histology and allows for a greater understanding of its real oncological potential.
Assuntos
Metástase Linfática , Câncer Papilífero da Tireoide , Neoplasias da Glândula Tireoide , Humanos , Queratina-19 , Metástase Linfática/diagnóstico , Estudos Prospectivos , RNA Mensageiro , Câncer Papilífero da Tireoide/genética , Neoplasias da Glândula Tireoide/genéticaRESUMO
PURPOSE: To determine the rate of non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) in a multi-institutional series from the Iberian Peninsula and describing this NIFTP cohort. METHODS: Retrospective study of papillary thyroid carcinoma (PTC) or well-differentiated tumours of uncertain malignant potential (WDT-UMP) diagnosed between 2005 and 2015 and measuring ≥5 mm in adult patients from 17 hospitals. Pathological reports were reviewed to determine the cases that fulfil the original criteria of NIFTP and histology was reassessed. Rates were correlated with the number of PTC and its follicular variant (FVPTC) of each institution. Demographic data, histology, management, and follow-up of the reclassified NIFTP cohort were recorded. RESULTS: A total of 182 cases with NIFTP criteria were identified: 174/3372 PTC (rate: 5.2%; range: 0-12.1%) and 8/19 WDT-UMP (42.1%). NIFTP rate showed linear correlation with total PTC (p: 0.03) and FVPTC (p: 0.007) identified at each centre. Ultrasound findings were non-suspicious in 60.1%. Fine-needle cytology or core biopsy diagnoses were undetermined in 49.7%. Most patients were treated with total thyroidectomy. No case had nodal disease. Among patients with total thyroidectomy, 89.7% had an excellent response evaluated 1 year after surgery. There were no structural persistence or relapses. Five patients showed residual thyroglobulin after 90 months of mean follow-up. CONCLUSIONS: NIFTP rate is low but highly variable in neighbouring institutions of the Iberian Peninsula. This study suggests pathologist's interpretation of nuclear alterations as the main cause of these differences. Patients disclosed an excellent outcome, even without using the strictest criteria.
Assuntos
Adenocarcinoma Folicular , Neoplasias da Glândula Tireoide , Adenocarcinoma Folicular/diagnóstico por imagem , Adulto , Seguimentos , Humanos , Recidiva Local de Neoplasia , Patologistas , Estudos Retrospectivos , Neoplasias da Glândula Tireoide/diagnóstico por imagemRESUMO
BACKGROUND AND OBJECTIVE: The risk of recurrence in papillary thyroid carcinoma (PTC) is likely related to the amount of tumour in the metastatic lymph node (LN). Therefore, the current TNM classification (N0/N1) make it necessary to find a method to quantify the LN metastasis (LNM). We propose that the quantitative molecular assay One-Step Nucleic-Acid Amplification (OSNA), which measures the number of cytokeratin-19 (CK-19) mRNA copies as a marker of LNM, could play this role. Our objective was to describe the characteristics of the LNs from PTC, and to compare the morphological characteristics that have been claimed as criteria for metastatic burden with OSNA. PATIENTS AND METHOD: Prospective study of LNs from 42 patients. All of the LNs were measured, weighed and analysed by OSNA and also by imprint cytology. RESULTS: A total of 573 LNs were included, 187 (32.6%) of them were OSNA-positives. The global consistency between cytology and OSNA was 87.4%. Significant differences were observed in the CK-19 copy number between the LNMs<0.2cm and those >3cm, as well as between those from 0.2 to 3cm with respect to those >3cm, but not between those <0.2cm and those between 0.2 and 3cm. The total tumour load per neck dissection showed no differences based on whether there were ≤5 or >5 LNMs. CONCLUSIONS: In our series the LNMs >3cm show an increased tumour load, but it is unclear if it is necessary to sub-classify the smaller ones as well as the relevance of the number of metastatic nodes according to the cut-off of 5 nodes. We consider that the OSNA analysis avoids the bias of nodal histology and allows for a greater understanding of its real oncological potential.
RESUMO
Several biomarkers have been suggested to have prognostic value in differentiated thyroid carcinomas (DTC) with no validation in the refractory setting, including all tumor subtypes. We aim to correlate RNA expression profiles with survival based on patients included in the DECISION trial. We obtained 247 samples from the 417 patients included in the DECISION study and performed RNAseq analysis (77 million paired-end reads for each sample on HiSeq2000). After quality control, 125 samples were included in the secondary analysis and mapped against the human reference genome (GRCh38) with STAR (v2.5.1b) using ENCODE parameter. Survival analysis was calculated using the Kaplan-Meier method and log-rank test was used for statistical comparison. In this post hoc analysis, we identified three groups of tumors based on their gene expression profile: BRAF-like, RAS-like, and non-BRAF-non-RAS-like (NoBRaL). No significant correlation with sorafenib responders was observed. However, we identified a statistically significant correlation between the RNA-expression profiles and progression-free survival. The BRAF-like profile had a significantly better outcome compared with RAS-like and NoBRaL (11.8, 6.2, and 5.5 months, respectively) [HR: 0.31, 95% confidence interval (CI), 0.17-0.60; P < 0.001 and HR: 0.36 (95% CI, 0.21-0.63); P < 0.001] and HR: 0.36 (95% CI, 0.21-0.63; P < 0.001) and maintained significance as an independent prognostic factor for overall survival in the multivariate analysis for papillary thyroid cancers. To our knowledge, this is the first comprehensive RNA-seq analysis of all histologic subtypes of DTC. The RNA expression profiles identified may suggest a new prognostic parameter to be considered before recommendation of systemic therapies or the design of stratification factors for future clinical trials.
Assuntos
Neoplasias da Glândula Tireoide/radioterapia , Linhagem Celular Tumoral , Feminino , Humanos , Radioisótopos do Iodo/uso terapêutico , Masculino , Prognóstico , Transcriptoma , Resultado do TratamentoRESUMO
Context: Global DNA hypomethylation is a major event for the development and progression of cancer, although the significance in thyroid cancer remains unclear. Therefore, we aimed to investigate its role in thyroid cancer progression and its potential as a prognostic marker. Methods: Global hypomethylation of Alu repeats was used as a surrogate marker for DNA global hypomethylation, and was assessed using the Quantification of Unmethylated Alu technique. Mutations in BRAF and RAS were determined by Sanger sequencing. Results: Ninety primary thyroid tumors were included [28 low-risk differentiated thyroid cancer (DTC), 13 pediatric DTC, 33 distant metastatic DTC, 7 poorly differentiated thyroid cancer (PDTC), and 9 anaplastic thyroid cancer (ATC)], as well as 24 distant metastases and 20 normal thyroid tissues. An increasing hypomethylation was found for distant metastatic DTC [median, 4.0; interquartile range (IQR), 3.1 to 6.2] and PDTC/ATC (median, 9.3; IQR, 7.0 to 12.1) as compared with normal thyroid tissue (median, 2.75; IQR, 2.30 to 3.15), whereas low-risk and pediatric DTC were not affected by hypomethylation. Alu hypomethylation was similar between distant metastases and matched primary tumors. Within distant metastatic DTC, Alu hypomethylation was increased in BRAF vs RAS mutated tumors. Kaplan-Meier and Cox regression analyses showed that thyroid cancer-related and all-cause mortality were associated with tumor hypomethylation, but this association was lost after adjustment for thyroid cancer risk category. Conclusion: Distant metastatic DTC, PDTC, and ATC were increasingly affected by global Alu hypomethylation, suggesting that this epigenetic entity may be involved in thyroid cancer progression and dedifferentiation.
Assuntos
Adenocarcinoma/genética , Adenocarcinoma/patologia , Metilação de DNA , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Linhagem Celular Tumoral , Criança , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Metástase NeoplásicaAssuntos
Síndrome de ACTH Ectópico/tratamento farmacológico , Neoplasias das Glândulas Suprarrenais/tratamento farmacológico , Medula Suprarrenal/patologia , Síndrome de Cushing/tratamento farmacológico , Peptídeos Cíclicos/efeitos adversos , Somatostatina/análogos & derivados , Síndrome de ACTH Ectópico/complicações , Síndrome de ACTH Ectópico/diagnóstico , Neoplasias das Glândulas Suprarrenais/complicações , Neoplasias das Glândulas Suprarrenais/diagnóstico , Medula Suprarrenal/metabolismo , Adrenalectomia , Hormônio Adrenocorticotrópico/análise , Hormônio Adrenocorticotrópico/metabolismo , Terapia Combinada , Síndrome de Cushing/diagnóstico , Progressão da Doença , Feminino , Ganglioneuroma/química , Ganglioneuroma/cirurgia , Terapia de Reposição Hormonal , Humanos , Hidrocortisona/sangue , Hidrocortisona/uso terapêutico , Cetoconazol/uso terapêutico , Pessoa de Meia-Idade , Neoplasias Primárias Múltiplas/química , Neoplasias Primárias Múltiplas/cirurgia , Peptídeos Cíclicos/uso terapêutico , Neoplasias Retroperitoneais/química , Neoplasias Retroperitoneais/cirurgia , Somatostatina/efeitos adversos , Somatostatina/uso terapêuticoRESUMO
INTRODUCTION: Lymphadenectomy is recommended during surgery for papillary thyroid carcinoma when there is evidence of cervical lymph node metastasis (therapeutic) or in high-risk patients (prophylactic) such as those with T3 and T4 tumors of the TNM classification. Selective sentinel lymph node biopsy may improve preoperative diagnosis of nodal metastases. OBJECTIVE: To analyze the results of selective sentinel lymph node biopsy in a group of patients with papillary thyroid carcinoma and no evidence of nodal involvement before surgery. PATIENTS AND METHOD: A retrospective, single-center study in patients with papillary thyroid carcinoma and no clinical evidence of lymph node involvement who underwent surgery between 2011 and 2013. The sentinel node was identified by scintigraphy. When the sentinel node was positive, the affected compartment was removed, and when sentinel node was negative, central lymph node dissection was performed. RESULTS: Forty-three patients, 34 females, with a mean age of 52.3 (±17) years, were enrolled. Forty-six (27%) of the 170 SNs resected from 24 (55.8%) patients were positive for metastasis. In addition, 94 (15.6%) out of the 612 lymph nodes removed in the lymphadenectomies were positive for metastases. Twelve of the 30 (40%) low risk patients (cT1N0 and cT2N0) changed their stage to pN1, whereas 12 of 13 (92%) high risk patients (cT3N0 and cT4N0) changed to pN1 stage. CONCLUSIONS: Selective sentinel lymph node biopsy changes the stage of more than 50% of patients from cN0 to pN1. This confirms the need for lymph node resection in T3 and T4 tumors, but reveals the presence of lymph node metastases in 40% of T1-T2 tumors.
Assuntos
Metástase Linfática/patologia , Estadiamento de Neoplasias/métodos , Câncer Papilífero da Tireoide/secundário , Neoplasias da Glândula Tireoide/patologia , Adulto , Idoso , Reações Falso-Negativas , Feminino , Humanos , Excisão de Linfonodo , Metástase Linfática/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Cuidados Pré-Operatórios , Estudos Retrospectivos , Biópsia de Linfonodo Sentinela/métodos , Tomografia Computadorizada com Tomografia Computadorizada de Emissão de Fóton Único , Agregado de Albumina Marcado com Tecnécio Tc 99m , Câncer Papilífero da Tireoide/diagnóstico por imagem , Câncer Papilífero da Tireoide/patologia , Câncer Papilífero da Tireoide/cirurgia , Neoplasias da Glândula Tireoide/cirurgia , TireoidectomiaRESUMO
BACKGROUND: Current methods based on fine-needle aspiration biopsy (FNAB) are not sufficient to distinguish among follicular thyroid lesions, follicular adenoma (FA), follicular thyroid carcinoma (FTC), and the follicular variant of papillary thyroid cancer (FVPTC). Furthermore, none of the immunohistochemical markers currently available are sensitive or specific enough to be used in the clinical setting, necessitating a diagnostic hemithyroidectomy. The aim of this study was to identify proteins of value for differential diagnosis between benign and malignant thyroid follicular lesions. METHODS: This retrospective analysis is based on an assessment of the immunoexpression of 19 proteins on 81 benign thyroid lesions (FA) and 50 malignant tumors (FTC/FVPTC). The resulting expression profile allowed the design of a scoring system model to improve the differential diagnosis of benign and malignant thyroid lesions. The model was validated using an independent series of 69 FA and 40 FTC and an external series of 40 nodular hyperplasias, and was further tested in a series of 38 FNAB cell blocks. RESULTS: A model based on the nuclear and cytoplasmic expression of APLP2, RRM2, and PRC1 discriminated between benign and malignant lesions with 100% sensitivity in both main and validation groups, with specificities of 71.3% and 50.7%, respectively. For the nodular hyperplasia series, specificity reached 94.8%. Finally, in FNAB samples, the sensitivity was 100% and the specificity was 45% for discrimination between benign and malignant lesions. CONCLUSIONS: These findings suggest that the identified APLP2, RRM2, and PRC1 signature could be useful for distinguishing between benign (FA) and malignant (FTC and FVPTC) tumors of the thyroid follicular epithelium.
Assuntos
Adenoma/diagnóstico , Precursor de Proteína beta-Amiloide/metabolismo , Carcinoma Papilar/diagnóstico , Proteínas de Ciclo Celular/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Ribonucleosídeo Difosfato Redutase/metabolismo , Glândula Tireoide/metabolismo , Neoplasias da Glândula Tireoide/diagnóstico , Adenoma/metabolismo , Adenoma/patologia , Adulto , Biomarcadores Tumorais/metabolismo , Biópsia por Agulha Fina , Carcinoma Papilar/metabolismo , Carcinoma Papilar/patologia , Diagnóstico Diferencial , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Sensibilidade e Especificidade , Glândula Tireoide/patologia , Neoplasias da Glândula Tireoide/metabolismo , Neoplasias da Glândula Tireoide/patologiaRESUMO
Tumor resection in papillary thyroid carcinoma (PTC) is often accompanied by lymph node (LN) removal of the central and lateral cervical compartments. One-step nucleic acid amplification (OSNA) is a polymerase chain reaction-based technique that quantifies cytokeratin 19 (CK19) messenger RNA copies. Our aim is to assess the value of OSNA in detection of LN metastases in PTC, in comparison with imprints and microscopic analysis of formalin-fixed, paraffin-embedded (FFPE) tissue. A total of 387 LNs from 37 patients were studied. From each half LN, 2 imprints were taken and analyzed with hematoxylin and eosin (H&E) and CK19 immunostaining. One half of the LN was submitted to OSNA and one half to FFPE processing and H&E and CK19 staining. For concordance analysis, every single LN was considered as a case. A group of 11 cases with discordant results between OSNA and H&E/CK19 FFPE sections were subjected to additional FFPE serial sectioning and H&E and CK19 staining. We found a high degree of concordance between the assays used, with sensitivities ranging from 0.81 to 0.95, and specificities ranging from 0.87 and 0.98. OSNA allowed upstaging of patients from pN0 to pN1, in comparison with standard pathologic analysis. Identification of a metastatic LN with more than 15000 CK19 messenger RNA copies predicted the presence of a second LN with macrometastasis (<5000 copies). In summary, the study shows that OSNA application in sentinel or suspicious LN may be helpful in assessing nodal status in PTC patients.
Assuntos
Carcinoma/patologia , Queratina-19/análise , Metástase Linfática/diagnóstico , Estadiamento de Neoplasias/métodos , Reação em Cadeia da Polimerase/métodos , Neoplasias da Glândula Tireoide/patologia , Área Sob a Curva , Biomarcadores Tumorais/análise , Carcinoma Papilar , Humanos , Inclusão em Parafina , Curva ROC , Sensibilidade e Especificidade , Coloração e Rotulagem , Câncer Papilífero da TireoideRESUMO
UNLABELLED: Purpouse: One Step Nucleic Acid Amplification (OSNA) has been previously proposed for the diagnosis of lymph node metastases (LNMs) from several malignant conditions by quantifying the number of copies of cytokeratin 19 mRNA. Our aim was to evaluate the results obtained by OSNA in the lymph nodes of patients with papillary thyroid carcinoma (PTC) by comparing our results with the findings observed using standard pathological examination. MATERIALS AND METHODS: Fifty human lymph nodes (from five patients with diagnosed PTC) were studied. Each node was divided into two: one half was used for molecular study ("OSNA-node"), and the other half was used for conventional staining with hematoxylin and eosin ("HE-non-OSNA node"). Three cytological imprints using Papanicolaou and May-Grunwald-Giemsa strains were obtained from both node halves. The results from each technique were compared, and ROC analysis was performed. RESULTS: The OSNA study showed 22 positive samples for LNM (44%), which demonstrate a high concordance rate with the results observed using conventional pathological examination (cytology of "OSNA-node" and HE of "Non-OSNA node") with specificity and sensitivity values greater than 86% and 89%, respectively. However, both comparisons differed in the number of copies of mRNA as the best cut-off (260 copies in the first case and 93 in the second case). CONCLUSIONS: The OSNA results for the detection of LNM in patients with PTC are comparable with those observed using conventional techniques. However, its quantitative nature could be useful to more accurately detect lymph node involvement.
Assuntos
Carcinoma/patologia , Linfonodos/patologia , Neoplasias da Glândula Tireoide/patologia , Adulto , Idoso , Carcinoma Papilar , Feminino , Humanos , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Técnicas de Amplificação de Ácido Nucleico , Câncer Papilífero da Tireoide , Adulto JovemRESUMO
PURPOSE: Lymphadenectomy in papillary thyroid carcinoma (PTC) continues to be controversial. A better staging method is needed to provide adequate individual surgical treatment. SPECT/CT lymphoscintigraphy and sentinel lymph node (SLN) biopsy may improve lymphatic staging and surgical treatment. Our main objectives were to describe the lymphatic drainage of PTC using lymphoscintigraphy, to evaluate the lymphatic spread (comparing SLN and lymphadenectomy results) and to analyse the impact of SLN identification in surgery. METHODS: We prospectively studied 24 consecutive patients with PTC (19 women; mean age 52.7 years, range 22-81 years). The day before surgery, lymphoscintigraphy with ultrasound-guided intratumoral injection ((99m)Tc-nanocolloid, 148 MBq) was performed, obtaining planar and SPECT/CT images. All patients underwent total thyroidectomy, SLN biopsy (hand-held gamma probe) with perioperative analysis, central compartment node dissection, or laterocervical lymphadenectomy if perioperative stage N1b or positive SLNs in this lymphatic basin. RESULTS: Lymphoscintigraphy revealed at least one SLN in 19 of 24 patients (79 %) on planar and SPECT/CT images, and in 23 of 24 patients (96 %) during surgery using a hand-held gamma probe. Lymph node metastases were detected with classical perioperative techniques (ultrasound guidance and surgical inspection) in 3 of 24 patients, by perioperative SLN analysis in 10 of 23, and by definitive histology in 13 of 24. The false-negative (FN) ratio for SLN was 7.7 % (one patient with bulky lymph nodes). The FN ratio for perioperative frozen sections was 15.4 % (two patients, one with micrometastases, the other with bilateral SLN). Lymphatic drainage was only to the central compartment in 6 of 24 patients (3 of the 6 with positive SLNs for metastases), only to the laterocervical basin in 5 of 24 patients (all unilateral, 2 of 5 positive SLNs) and to the central and laterocervical compartments in 12 of 24 patients (6 of 12 and 3 of 12 positive SLNs, respectively). CONCLUSION: Lymphoscintigraphy reveals the lymph node drainage in a high proportion of patients. It detects laterocervical drainage in a significant percentage of patients, allowing the detection of occult lymph node metastases and improving the surgical management in PTC.
Assuntos
Carcinoma/diagnóstico por imagem , Excisão de Linfonodo , Biópsia de Linfonodo Sentinela , Neoplasias da Glândula Tireoide/diagnóstico por imagem , Tomografia Computadorizada de Emissão de Fóton Único , Tomografia Computadorizada por Raios X , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma/diagnóstico , Carcinoma/patologia , Carcinoma/cirurgia , Carcinoma Papilar , Feminino , Humanos , Metástase Linfática/diagnóstico , Metástase Linfática/diagnóstico por imagem , Metástase Linfática/patologia , Masculino , Pessoa de Meia-Idade , Imagem Multimodal , Estadiamento de Neoplasias , Câncer Papilífero da Tireoide , Neoplasias da Glândula Tireoide/diagnóstico , Neoplasias da Glândula Tireoide/patologia , Neoplasias da Glândula Tireoide/cirurgiaRESUMO
BACKGROUND: Pancreatic adenosquamous carcinoma (PASC) is a rare subtype of pancreatic cancer characterized by a dual histological component and aggressive behavior. This form is not well known, its histogenesis is uncertain, and there are different opinions on the diagnostic histopathological criteria. The differential diagnosis with more common ductal adenocarcinoma, squamous cell carcinoma, squamous or adenosquamous metastases is complex. The available therapies do not improve the poor prognosis and it is difficult to find long-term survivors (more than 1 year), even after demolitive surgery with complementary therapies. CASE REPORT: We report a case of advanced PASC with excellent progression-free survival and overall survival, 20 months and 29 months, respectively. Furthermore, an almost complete response was obtained to first-line chemotherapy with gemcitabine/oxaliplatin (GEMOX) followed by maintenance gemcitabine. CONCLUSION: GEMOX followed by gemcitabine as maintenance could be an effective treatment for this pancreatic entity. Further reports are needed to confirm this outcome.
Assuntos
Antimetabólitos Antineoplásicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Adenoescamoso/tratamento farmacológico , Desoxicitidina/análogos & derivados , Neoplasias Pancreáticas/tratamento farmacológico , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Carcinoma Adenoescamoso/secundário , Desoxicitidina/administração & dosagem , Intervalo Livre de Doença , Esquema de Medicação , Humanos , Masculino , Compostos Organoplatínicos/administração & dosagem , Neoplasias Pancreáticas/patologia , Resultado do Tratamento , GencitabinaRESUMO
PURPOSE: To analyze the expression of PTOV1 in high-grade prostatic intraepithelial neoplasia (HG-PIN) and to explore its usefulness to predict prostate cancer in patients with isolated HG-PIN in needle biopsy (prostate needle biopsy). EXPERIMENTAL DESIGN: PTOV1 expression in HG-PIN lesions from 140 patients was analyzed by immunohistochemistry in a semiquantitative manner (Histo-score). HG-PIN derived from 79 radical prostatectomies for prostate cancer and from 11 cistoprostatectomies for bladder cancer without prostate cancer were used as positive and negative controls, respectively. Fifty patients with HG-PIN without concomitant cancer at their first prostate needle biopsy were chosen as the study group. Patients were followed by a mean of 2.5 repeated prostate needle biopsies (1-5), during a mean period of 12.4 months (1-39). RESULTS: PTOV1 expression in HG-PIN from radical prostatectomies showed a significantly higher Histo-score (162.6) compared with specimens from cistoprostatectomies (67.0). In the study group, PTOV1 expression was significantly higher in samples with cancer in the follow-up (11 patients, 22%) compared with samples in which cancer was not detected (151.4 versus 94.6). PTOV1 expression was the only independent predictor of cancer in the multivariate analysis and the area under the curve was 0.803 (95% confidence interval, 0.728-0.878). A threshold of 100 for PTOV1 expression provided 90.9% sensitivity, 51.3% specificity, 34.5% positive predictive value, and 95.2% negative predictive value. CONCLUSIONS: PTOV1 is overexpressed in HG-PIN associated with cancer and is a potential marker for studying the carcinogenesis and progression of prostate cancer. Prostate needle biopsy with PTOV1 expression in HG-PIN above a threshold of 100 should be repeated immediately for the likely presence of undiagnosed cancer.
Assuntos
Biomarcadores Tumorais/metabolismo , Proteínas de Neoplasias/metabolismo , Neoplasia Prostática Intraepitelial/metabolismo , Neoplasias da Próstata/metabolismo , Biópsia por Agulha , Humanos , Masculino , Próstata/metabolismo , Próstata/patologia , Neoplasia Prostática Intraepitelial/diagnóstico , Neoplasia Prostática Intraepitelial/patologia , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/patologia , Sensibilidade e Especificidade , Análise Serial de TecidosRESUMO
In an attempt to identify molecules that clearly reflect the oncogenic role of cell signaling pathways in human tumors, we propose a concept we term "funnel factor", a factor where several oncogenic signals converge and drive the proliferative signal downstream. In studies done in various tumor types, the expression of key cell signaling factors, including Her1 and Her2 growth factor receptors, as well as the RAS-RAF-mitogen-activated protein kinase and the phosphatidylinositol 3-kinase-AKT-mammalian target of rapamycin pathways was correlated with the associated clinicopathologic characteristics of these tumors. The downstream factors p70, S6, 4E-binding protein 1 (4E-BP1), and eukaryotic translation initiation factor 4E, which play a critical role in the control of protein synthesis, survival, and cell growth, were also analyzed. We found that phosphorylated 4E-BP1 (p-4E-BP1) expression in breast, ovary, and prostate tumors is associated with malignant progression and an adverse prognosis regardless of the upstream oncogenic alterations. Thus, p-4E-BP1 seems to act as a funnel factor for an essential oncogenic capability of tumor cells, self-sufficiency in growth signals, and could be a highly relevant molecular marker of malignant potential. Further investigation into this concept may identify additional funnel factors in the oncogenic pathways and provide potential therapeutic targets.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Neoplasias/metabolismo , Fosfoproteínas/metabolismo , Proteínas de Ciclo Celular , Humanos , Neoplasias/patologia , Transdução de SinaisRESUMO
BACKGROUND: Intraductal papillary mucinous tumors (IPMT) account for 5% of pancreatic neoplasms. Preoperative identification is important because of their frequent multifocal or diffuse involvement in pancreatic ducts, which makes extensive surgery necessary even in benign cases. To the authors' knowledge, the cytologic features of this entity in fine-needle aspiration biopsy (FNAB) specimens have seldom been described and are poorly standardized. METHODS: Eleven consecutive cases of surgically proven IPMT with previous endoscopic ultrasonography (EUS)-guided FNAB were collected for retrospective analysis. EUS-FNAB had been performed with on-site attendance of a cytopathologist in all cases. Macroscopic and microscopic appearance of mucin, cellular type and arrangement, presence of nuclear grooves, and degree of nuclear atypia were recorded. RESULTS: Final diagnosis was benign IPMT (B) in four cases, borderline IPMT (Bo) in two cases, malignant IPMT (M) in one case, and IPMT associated with invasive carcinoma (Ca) in four. Retrospective analysis found moderate to high levels of extracellular mucin in 10 of the 11 cases. The other case (one Ca) showed a small amount of thick mucin. In all cases, epithelial cells were identified, although cellularity was very low in four cases (three B and one Bo). Atypia was absent in two cases (two B) slight in two cases (two B), moderate in three cases (one Bo and two Ca), and severe in four cases (one Bo, one M, and two Ca). Mucinous epithelium was found in nine cases and nonmucinous epithelium in five cases (one Bo and four Ca). Papillary structures were observed in five cases (two Bo and three Ca), sheets in eight cases (four B, one Bo, one M, and two Ca), single atypical cells in five cases (one Bo and four Ca), irregular clusters in three cases (one Bo and two Ca), and nuclear grooves in two cases (one B and one Bo). CONCLUSIONS: The most common features of IPMT were extracellular mucin and sheets of mucinous epithelium. Papillae and nuclear grooves were not consistently found. Nonmucinous epithelium, severe atypia, single atypical cells, and irregular clusters indicated a high probability of malignant transformation. Even in the absence of atypia, a clinically significant diagnostic orientation can be established in most cases on the basis of the characteristic cytologic picture.
Assuntos
Adenocarcinoma Mucinoso/diagnóstico , Adenocarcinoma Mucinoso/patologia , Carcinoma Ductal Pancreático/diagnóstico , Carcinoma Ductal Pancreático/patologia , Adulto , Idoso , Biópsia por Agulha , Transformação Celular Neoplásica , Técnicas Citológicas , Diagnóstico Diferencial , Endossonografia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mucinas/análise , Estudos RetrospectivosRESUMO
Helical computerized tomography (CT) and magnetic resonance imaging (MRI) are used for staging of hepatocellular carcinoma (HCC) prior to curative treatments but underestimate tumor extension in 30% to 50% of cases when compared with pathologic explants. This study compares a new technology, MRI angiography (MRA), with triphasic helical CT in detection of HCC. Fifty cirrhotic patients, 29 with HCC, undergoing liver transplantation were analyzed. MRA was performed with a 3-D breath-hold fast spoiled gradient-echo sequence by using an effective section thickness of 2 to 2.5 mm. The gold standard was the pathologic examination (liver cut into 5-mm slices). One hundred twenty-seven lesions were identified at the explant: 76 HCC, 13 high-grade dysplastic nodules, 31 macroregenerative nodules, 7 hemangiomas. Diameter of the main HCC nodules was 29 +/- 14 mm and 11 +/- 7 mm for the 47 additional nodules. On a per nodule basis, sensitivity of MRA was superior to CT (58/76 [76%] vs. 43/70 [61%], respectively, P =.001). Sensitivity of MRA for detection of additional nodules decreased with size (>20 mm: 6/6 [100%]; 10-20 mm: 16/19 [84%]; <10 mm: 7/22 [32%]) and was superior to CT for nodules 10 to 20 mm (84% vs. 47%, P =.016). Nonspecific hypervascular nodules >5 mm at MRA were HCC in two thirds of the cases. In conclusion, MRA has a high diagnostic accuracy for HCC > or =10 mm and is more sensitive than triphasic helical CT in nodules sized 10 to 20 mm. MRA is the optimal technique for HCC staging prior to curative therapies.