RESUMO
(1) Background: BRAF mutations affect 4-5% of lung adenocarcinomas. This study aimed to analyze the clinicopathological features of lung carcinomas with BRAF mutations, focusing on V600E vs. non-V600E and the presence of co-mutations. (2) Methods: All BRAF-mutated lung carcinomas were retrieved from a molecular diagnostic unit (the reference unit for four different hospitals). The samples were analyzed using next-generation sequencing. Statistical analyses included log-rank tests for overall survival (OS) and progression-free survival (PFS). (3) Results: In total, 60 BRAF-mutated lung carcinomas were retrieved: 24 (40.0%) with V600E and 36 (60.0%) with non-V600E mutations, and 21 (35.0%) with other co-mutations and 39 (65.0%) with only BRAF mutations. Survival data were available for 54/60 (90.0%) cases. Targeted therapy was documented in 11 cases. Patients with V600E mutations exhibited a better prognosis than patients with non-V600E mutations (p = 0.008 for OS, p = 0.018 for PFS); this was confirmed in PFS (p = 0.036) when considering only patients who received no targeted therapy. Patients with co-mutations displayed no prognostic difference compared to patients carrying only BRAF mutations (p = 0.590 for OS, p = 0.938 for PFS). (4) Conclusions: BRAF-mutated lung carcinomas with V600E (40.0%) had a better prognosis than those without V600E. Concomitant co-mutations (35.0%) did not affect the prognosis.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Proteínas Proto-Oncogênicas B-raf , Humanos , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/patologia , Mutação , Proteínas Proto-Oncogênicas B-raf/genéticaRESUMO
The majority of patients with Follicular Lymphoma (FL) experience subsequent phases of remission and relapse, making the disease "virtually" incurable. To predict the outcome of FL patients at diagnosis, various clinical-based prognostic scores have been proposed; nonetheless, they continue to fail for a subset of patients. Gene expression profiling has highlighted the pivotal role of the tumor microenvironment (TME) in the FL prognosis; nevertheless, there is still a need to standardize the assessment of immune-infiltrating cells for the prognostic classification of patients with early or late progressing disease. We studied a retrospective cohort of 49 FL lymph node biopsies at the time of the initial diagnosis using pathologist-guided analysis on whole slide images, and we characterized the immune repertoire for both quantity and distribution (intrafollicular, IF and extrafollicular, EF) of cell subsets in relation to clinical outcome. We looked for the natural killer (CD56), T lymphocyte (CD8, CD4, PD1) and macrophage (CD68, CD163, MA4A4A)-associated markers. High CD163/CD8 EF ratios and high CD56/MS4A4A EF ratios, according to Kaplan-Meier estimates were linked with shorter EFS (event-free survival), with the former being the only one associated with POD24. In contrast to IF CD68+ cells, which represent a more homogeneous population, higher in non-progressing patients, EF CD68+ macrophages did not stratify according to survival. We also identify distinctive MS4A4A+CD163-macrophage populations with different prognostic weights. Enlarging the macrophage characterization and combining it with a lymphoid marker in the rituximab era, in our opinion, may enable prognostic stratification for low-/high-grade FL patients beyond POD24. These findings warrant validation across larger FL cohorts.
Assuntos
Linfoma Folicular , Humanos , Intervalo Livre de Progressão , Linfoma Folicular/genética , Linfoma Folicular/patologia , Estudos Retrospectivos , Recidiva Local de Neoplasia , Rituximab , Microambiente TumoralRESUMO
Immune checkpoint inhibitors have recently been approved for the treatment of advanced head and neck squamous cell carcinoma (HNSCC). The determination of PD-L1 using the combined positive score (CPS) is of utmost importance in the selection of patients. However, it is unclear which material should be examined. This study aimed to compare PD-L1 CPS in the resections of primary tumors and metastatic lymph nodes, and in the biopsies of the primary tumors.We collected 30 resected HNSCCs with lymph node metastases; in 17 of these, preoperative biopsies were retrieved. PD-L1 immunostaining of 75 samples was performed using the Dako 22C3 antibody on the Ventana ULTRA platform. An appropriate internal control was performed on each slide. CPS was calculated for each reaction. Concordance values and k were calculated for each patient. CPS cut-off values were fixed at 0 and 20.Tumors were resected from the oral cavity (4), oropharynx (17), hypopharynx (1), and larynx (8). The overall concordance of CPS between tumor resection and lymph node metastasis was 76.7% (k = 0.593). The overall concordance of CPS between tumor resection and tumor biopsy was 86.7% (k = 0.688). The agreement was moderate to substantial for each comparison.PD-L1 CPS may be correctly determined not only in resected primary tumors, but also in removed lymph node metastases, as well as in preoperative biopsies.
Assuntos
Antígeno B7-H1 , Neoplasias de Cabeça e Pescoço , Antígeno B7-H1/biossíntese , Antígeno B7-H1/metabolismo , Biomarcadores Tumorais/análise , Biópsia , Neoplasias de Cabeça e Pescoço/metabolismo , Neoplasias de Cabeça e Pescoço/cirurgia , Humanos , Metástase Linfática , Carcinoma de Células Escamosas de Cabeça e Pescoço/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/cirurgiaRESUMO
Prognosis of gastric cancer is dramatically improved by early diagnosis. Correa's cascade correlates the expression of some molecular markers with the progression of preneoplastic lesions toward carcinoma. This article reviews the diagnostic and prognostic values of molecular markers in complete (MUC2) and incomplete (MUC2, MUC5AC, and MUC6) intestinal metaplasia, gastric dysplasia/intra-epithelial neoplasia, and early gastric cancer. In particular, considering preinvasive neoplasia and early gastric cancer, some studies have demonstrated a correlation between molecular alterations and prognosis, for example, mucins phenotype in gastric dysplasia, and GATA6, TP53 mutation/LOH and MUC6 in early gastric cancer. Moreover, this review considers novelties from the literature regarding the (immuno)histochemical characterization of diffuse-type/signet ring cell gastric cancer, with particular attention to clinical outcomes of patients. The aim of this review is the evaluation of the state of the art regarding suitable biomarkers used in the pre-surgical phase, which can distinguish patients with different prognoses and help decide the best therapeutic strategy.
Assuntos
Neoplasias Gástricas/metabolismo , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/genética , Detecção Precoce de Câncer , Fator de Transcrição GATA6/análise , Fator de Transcrição GATA6/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Intestinos , Metaplasia/diagnóstico , Metaplasia/genética , Metaplasia/metabolismo , Mucina-5AC/análise , Mucina-5AC/genética , Mucina-2/análise , Mucina-2/genética , Mucina-6/análise , Mucina-6/genética , Mutação , Prognóstico , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/genética , Proteína Supressora de Tumor p53/análise , Proteína Supressora de Tumor p53/genéticaRESUMO
Circulating tumor cells (CTCs) are a rare population of cells found in the bloodstream and represent key players in the metastatic cascade. Their analysis has proved to provide further core information concerning the tumor. Herein, we aim at investigating CTCs isolated from a 32-year-old patient diagnosed with triple negative spindle-shaped metaplastic breast cancer (MpBC), a rare tumor poorly responsive to therapies and with a dismal prognosis. The molecular analysis performed on the primary tumor failed to underline effective actionable targets to address the therapeutic strategy. Besides the presence of round-shaped CTCs, cells with a spindle shape were present as well, and through molecular analysis, we confirmed their malignant nature. This aspect was coherent with the primary tumor histology, proving that CTCs are released regardless of their morphology. Copy number aberration (CNA) profiling and variant analysis using next-generation sequencing (NGS) showed that these cells did not harbor the alterations exhibited by the primary tumor (PIK3CA G1049A mutation, MYC copy number gain). However, despite the great heterogeneity observed, the amplification of regions involved in metastasis emerged (8q24.22-8q24.23). Our findings support the investigation of CTCs to identify alterations that could have a role in the metastatic process. To the best of our knowledge, this is the first examination of CTCs in an MpBC patient.
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Carcinomas with apocrine differentiation (CAD) of the breast are rare tumours typically presenting high immunohistochemical expression of androgen receptor (AR) which is a target molecule for personalised therapy. To date, no studies have evaluated the genetic changes that are associated with AR immunohistochemical expression in CADs. The present work aims to characterise AR status in CADs. Twenty CAD tumours were studied with immunohistochemistry, in situ fluorescence hybridization and DNA methylation analysis, to evaluate AR expression and its regulator status. All tumours demonstrated high AR immunohistochemical expression, with over 95% of the neoplastic cells showing AR positivity in 19/20 cases. CADs showed AR gene copy loss in a percentage of neoplastic cells ranging from 5 to 84% (mean 48.93%). AR regulator genes, including the MAGE family, UXT and FLNA, presented variable methylation levels, but were mainly hypomethylated and therefore all transcriptionally active. The results of this study indicate that CADs present AR monosomy, paralleled by higher transcriptional activity of the gene with potential to influence response to AR deprivation therapy.
Assuntos
Biomarcadores Tumorais/genética , Neoplasias da Mama/genética , Carcinoma/genética , Cromossomos Humanos X , Variações do Número de Cópias de DNA , Dosagem de Genes , Receptores Androgênicos/genética , Aberrações dos Cromossomos Sexuais , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/patologia , Carcinoma/patologia , Diferenciação Celular , Metilação de DNA , Feminino , Regulação Neoplásica da Expressão Gênica , Predisposição Genética para Doença , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Irlanda , Itália , Pessoa de Meia-Idade , Monossomia , FenótipoRESUMO
BACKGROUND: Early Gastric Cancer (EGC) reaches 25% of the gastric cancers surgically treated in some areas of Northeastern Italy and is usually characterized by a good prognosis. However, among EGCs classified according to Kodama's criteria, Pen A subgroup is characterized by extensive submucosal invasion, lymph node metastases and worse prognosis, whereas Pen B subgroup by better prognosis. The aim of the study was to characterize the differences between Pen A, Pen B and locally advanced gastric cancer (T3N0) in order to identify biomarkers involved in aggressiveness and clinical outcome. METHODS: We selected 33 Pen A, 34 Pen B and 20 T3N0 tumors and performed immunohistochemistry of mucins, copy number variation analysis of a gene panel, microsatellite instability (MSI), TP53 mutation and loss of heterozygosity (LOH) analyses. RESULTS: Pen A subgroup was characterized by MUC6 overexpression (p = 0.021). Otherwise, the Pen B subgroup was significantly associated with the amplification of GATA6 gene (p = 0.002). The higher percentage of MSI tumors was observed in T3N0 group (p = 0.002), but no significant differences between EGC types were found. Finally, TP53 gene analysis showed that 32.8% of Pen tumors have a mutation in exons 5-8 and 50.0% presented LOH. Co-occurrence of TP53 mutation and LOH mainly characterized Pen A tumors (p = 0.022). CONCLUSIONS: Our analyses revealed that clinico-pathological parameters, microsatellite status and frequency of TP53 mutations do not seem to distinguish Pen subgroups. Conversely, the amplification of GATA6 was associated with Pen B, as well as the overexpression of MUC6 and the TP53mut/LOH significantly characterized Pen A.
Assuntos
Detecção Precoce de Câncer/métodos , Mucinas Gástricas/genética , Invasividade Neoplásica/genética , Neoplasias Gástricas/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Variações do Número de Cópias de DNA/genética , Feminino , Mucosa Gástrica/metabolismo , Mucosa Gástrica/patologia , Humanos , Imuno-Histoquímica , Itália , Perda de Heterozigosidade , Metástase Linfática/genética , Masculino , Instabilidade de Microssatélites , Repetições de Microssatélites/genética , Pessoa de Meia-Idade , Mutação , Prognóstico , Estudos Retrospectivos , Proteína Supressora de Tumor p53/genéticaRESUMO
Breast cancer (BC) is the most diagnosed carcinoma and the leading cause of cancer death in female over 100 countries. Thanks to the advance in therapeutic strategies, patients' survival has improved. However, the lack of response to treatments and drug resistance are still a main concern, demanding for new therapeutic approaches, in particular for the advanced stages of the disease. Androgen receptor (AR) is gaining increasing interest as a fourth targetable receptor in BC, however, its regulation in BC cells is still poorly understood. MicroRNAs (miRNAs) regulate gene expression post-transcriptionally. Here, we identified miR-9-5p as an inhibitor of AR expression, we validated the inverse correlation between miR-9-5p and AR in primary BC samples and we further identified a feedback loop in which androgen agonists of AR up-regulate miR-9-5p. We also provided evidence that miR-9-5p elicits anti-proliferative effects in BC cell lines regardless of their estrogen receptor status. Finally, we showed that miR-9-5p can revert AR-downstream signaling even in presence of AR-agonists, highlighting the role of this miR in the hormonal response of BC. In conclusion, this study supports the role of miR-9-5p as an anti-proliferative miR in BC and as a central modulator of AR-signaling response to circulating androgens in BC.
RESUMO
Oesophageal and gastro-oesophageal junction (GOJ) neoplasms, and their predisposing conditions, may be encountered by the practicing pathologist both as biopsy samples and as surgical specimens in daily practice. Changes in incidence of oesophageal squamous cell carcinomas (such as a decrease in western countries) and in oesophageal and GOJ adenocarcinomas (such as a sharp increase in western countries) are being reported globally. New modes of treatment have changed our histologic reports as specific aspects must be detailed such as in post endoscopic resections or with regards to post neo-adjuvant therapy tumour regression grades. The main aim of this overview is therefore to provide an up-to-date, easily available and clear diagnostic approach to neoplastic and pre-neoplastic conditions of the oesophagus and GOJ, based on the most recent available guidelines and literature.
Assuntos
Neoplasias Esofágicas , Lesões Pré-Cancerosas , Adenocarcinoma/diagnóstico , Adenocarcinoma/epidemiologia , Adenocarcinoma/patologia , Esôfago de Barrett/diagnóstico , Esôfago de Barrett/epidemiologia , Esôfago de Barrett/patologia , Neoplasias Esofágicas/diagnóstico , Neoplasias Esofágicas/epidemiologia , Neoplasias Esofágicas/patologia , Neoplasias Esofágicas/terapia , Esôfago/patologia , Humanos , Incidência , Metaplasia/patologia , Gradação de Tumores , Lesões Pré-Cancerosas/diagnóstico , Lesões Pré-Cancerosas/patologia , Fatores de Risco , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/epidemiologia , Neoplasias Gástricas/patologia , Neoplasias Gástricas/terapiaRESUMO
Gastric cancer accounts for about 6% of cancers worldwide, being the fifth most frequently diagnosed malignancy and the third leading cause of cancer related death. Gastric carcinogenesis is a multistep and multifactorial process and is the result of the complex interplay between genetic susceptibility and environmental factors. The identification of predisposing conditions and of precancerous lesions is the basis for screening programs and early stage treatment. Furthermore, although most gastric cancers are sporadic, familial clustering is observed in up to 10% of patients. Among them, hereditary cases, related to known cancer susceptibility syndromes and/or genetic causes are thought to account for 1-3% of all gastric cancers. The pathology report of gastric resections specimens therefore requires a standardized approach as well as in depth knowledge of prognostic and treatment associated factors.
Assuntos
Síndromes Neoplásicas Hereditárias , Lesões Pré-Cancerosas , Neoplasias Gástricas , Adenocarcinoma , Predisposição Genética para Doença , Humanos , Incidência , Síndromes Neoplásicas Hereditárias/diagnóstico , Síndromes Neoplásicas Hereditárias/epidemiologia , Síndromes Neoplásicas Hereditárias/genética , Síndromes Neoplásicas Hereditárias/patologia , Prognóstico , Estômago/patologia , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/epidemiologia , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologiaRESUMO
We discussed the potentialities of tumor mutation burden (TMB) as a predictive marker for immunotherapy in breast cancer, also highlighting the limits that have hindered its introduction in the clinical practice. Although some studies have demonstrated the possibility to select patients more responsive to immune-checkpoint inhibitors by evaluating TMB, some issues emerged regarding the complexity of the methodologies for its determination, the costs of the analysis, and the necessity to improve the TMB determination with that of neoantigen identification.
Assuntos
Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/genética , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Terapia de Alvo Molecular , Mutação , Biomarcadores Tumorais/antagonistas & inibidores , Neoplasias da Mama/imunologia , Neoplasias da Mama/patologia , Análise Mutacional de DNA , Feminino , Humanos , PrognósticoRESUMO
Extracranial metastases from atypical meningioma are rare, and even more so in the liver. We report a case of a 68-years-old patient with atypical meningioma, treated with partial surgical resection in 2012, and gamma knife radiotherapy in 2014 in another hospital, exhibiting a liver metastasis 6 years after the initial surgical resection.
Assuntos
Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/secundário , Neoplasias Meníngeas/diagnóstico por imagem , Meningioma/diagnóstico por imagem , Idoso , Neoplasias Encefálicas/cirurgia , Humanos , Neoplasias Hepáticas/cirurgia , Neoplasias Meníngeas/cirurgia , Meningioma/cirurgiaRESUMO
AIMS: Glycogen synthase kinase-3 beta (GSK-3ß) is a serine/threonine kinase involved in glycogen metabolism, cell cycle progression, differentiation, embryogenesis, migration, metabolism, survival and cellular senescence. Its main biological function is to inhibit ß-catenin by sequestration and promotion of its proteasomal degradation in the Wnt canonical pathway; however, GSK-3ß interacts with multiple signalling pathways, and aberrant expression of the enzyme was reported in many solid neoplasms. This study aimed to investigate the biological relevance of GSK-3ß in classical Hodgkin lymphomas (cHL). METHODS AND RESULTS: We analysed the functional status of GSK-3ß enzyme in cHL by using antibodies raised against fixation-resistant epitopes of phospho Y216 GSK-3ß (active form), phospho S9 GSK-3ß (inactive form) and ß-catenin protein. We first detected the pY216 GSK-3ß active form of the enzyme in 100 of 100 (100%) of the cases, and in line with the latter expression profile, the ß-catenin protein was found in only 12 of 100 (12%) of the samples. As reported previously in bladder cancer, pancreatic adenocarcinoma and chronic lymphocytic leukaemia, we showed an aberrant nuclear localization in the neoplastic clone of active pY216 GSK-3ß in 78 of 100 (78%) of cHL cases. CONCLUSIONS: We demonstrated the activation of GSK-3ß in cHL resulting in inhibition of the Wnt/ß-catenin signal cascade and the aberrant accumulation of its activated form in nuclei of Hodgkin Reed-Sternberg and Hodgkin cells. These findings may be relevant for future clinical studies, identifying GSK-3ß as a potential therapeutic target for cHL.