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BACKGROUND: Tumor-Stroma Ratio (TSR) has been recognized as a valuable prognostic indicator in various solid tumors. This study aimed to examine the clinicopathological relevance of TSR in Merkel cell carcinoma (MCC) using artificial intelligence (AI)-based parameterization of the stromal landscape and validate TSR scores generated by our AI model versus human-assessed. METHODS: 112 MCC cases with Whole Slide Images (WSIs) were collected from four different institutions. WSIs were first partitioned into 128x128-pixel "mini-patches" then classified by a novel framework, termed Pre-TumOr And STroma (Pre-TOAST) and TOAST, whose output equaled the probability of the mini-patch representing tumor cells rather than stroma. Hierarchical random samplings of 50 mini-patches per region were performed throughout 50 regions per slide. TSR and Tumor-Stromal Landscape (TSL) parameters were estimated by the maximum-likelihood algorithm. RESULTS: Receiver Operating Characteristic (ROC) curves showed the areas under the curve (AUCs) of Pre-TOAST in discriminating classed of interest (COI) including tumor cells, collagenous stroma, and lymphocytes from non-classes of interest (non-COI) including hemorrhage, space, and necrosis were 1.00. AUCs of TOAST in differentiating tumor cells from related stroma were 0.93. MCC stroma was categorized into TSR-high (TSR≥50%) and TSR-low (TSR<50%) using both AI- and human pathology-based methods. AI-based TSR-high subgroup exhibited notably shorter Metastasis-Free Survival (MFS) with a statistical significance of p=0.029. Interestingly, pathologist-determined TSR subgroups lacked statistical significance in Recurrence-Free Survival (RFS), MFS, and Overall Survival (OS) (p>0.05). Density-based spatial clustering of applications with noise (DBSCAN) analysis identified two distinct Tumor-Stroma Landscape (TSL) clusters: TSL1 and TSL2. TSL2 showed significantly shorter RFS (p=0.045) and markedly reduced MFS (p<0.001) compared to TSL1. CONCLUSION: TSL classification appears to offer better prognostic discrimination than traditional TSR evaluation in MCC. TSL can be reliably calculated using an AI-based classification framework and predict various prognostic features of MCC.
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INTRODUCTION: PReferentially expressed Antigen in MElanoma (PRAME) has shown utility in differentiating benign from malignant melanocytic neoplasms. In this study, we investigated the clinical significance of PRAME expression in dysplastic nevi (DN) and nevus-associated melanoma in situ (MIS). METHODS: We included 172 DN and 38 nevus-associated MIS from our institutional archive. PRAME positive expression was defined as nuclear staining in at least 75% of melanocytes. In addition, relevant studies from PubMed and Web of Science were incorporated into a meta-analysis using the random-effects model to assess PRAME expression in MIS and DN. RESULTS: Our institutional data revealed that 71.1% of nevus-associated MIS cases exhibited positive PRAME expression in the MIS components, whereas all DN components were negative for PRAME. 5.7% of cases diagnosed as DN in our cohort demonstrated diffuse positivity for PRAME. Notably, MIS associated with DN displaying epidermal and dermal components displayed a higher likelihood of PRAME positivity compared to those arising on a background of DN with solely epidermal (junctional) components (84% vs. 46%, p = 0.024). The meta-analysis indicated that the pooled PRAME positivity in MIS and DN was 54.5% and 1.9%, respectively. CONCLUSION: PRAME is a valuable immunohistochemical marker for differentiating MIS from DN, particularly in the context of nevus-associated MIS.
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INTRODUCTION: Sparsely granulated somatotroph adenoma/tumor (SGST) is thought to be more clinically aggressive than densely granulated somatotroph adenoma/tumor (DGST). However, the literature is not entirely consistent as to the disparate demographic and behavioral features of these subtypes. In this study, we conducted a meta-analysis to further clarify the demographic, clinicopathological, prognostic, and molecular characteristics of SGST versus DGST. METHODS: We accessed two electronic databases to search for potential data. Pooled estimates of odds ratio (OR), mean difference (MD), and corresponding 95% confidence interval (CI) were calculated using the random-effect model. RESULTS: SGST was associated with younger patient age and lower male-to-female ratio (p < 0.001) compared to DGST. Clinically, SGST had larger tumor size and high rate of cavernous sinus and suprasellar extension (p < 0.001) than DGST. During postoperative follow-up, SGST was associated with a lower endocrinological remission rate (OR 0.60; 95% CI 0.40 to 0.90; p = 0.01) and a poorer response rate to SRL (OR 0.16; 95% CI 0.08-0.35; p < 0.001) in comparison to DGST. The prevalence of GSP mutations was significantly lower in SGST (OR 0.36; 95% CI 0.17 to 0.79; p = 0.01). CONCLUSION: SGST and DGST were demographically, clinicopathologically, and molecularly different from each other with the former associated with adverse treatment outcomes and poor response to medical therapy. There are still gaps in translational studies that could help us better understand the behavior of these tumors and identify potential targets in the treatment of sparsely granulated tumors.
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Adenoma , Adenoma Hipofisário Secretor de Hormônio do Crescimento , Neoplasias Hipofisárias , Masculino , Humanos , Feminino , Adenoma Hipofisário Secretor de Hormônio do Crescimento/patologia , Neoplasias Hipofisárias/genética , Neoplasias Hipofisárias/patologia , Adenoma/cirurgia , Prognóstico , Resultado do TratamentoRESUMO
BACKGROUND: H3G34-mutant diffuse hemispheric glioma (DHG) is recognized as a new, distinct entity in the latest World Health Organization classification for central nervous system tumors and is associated with a particularly aggressive course. The authors performed a systematic review and pooled analysis to investigate the frequency of genetic events in these tumors and to determine whether these events were associated with survival trends. METHODS: Two electronic databases were accessed to search for relevant data. Included criteria were studies that had individual patient data on H3.3 G34-mutant gliomas. To analyze the impact of genetic events on overall survival, Kaplan-Meier analysis and Cox regression models were used, and corresponding hazard ratios and 95% confidence intervals were computed. RESULTS: In total, 20 studies with 257 H3G34-mutant DHGs were included for integrated analyses. The H3 glycine-to-valine (H3G34V) mutation showed a significantly worse prognosis than the glycine-to-arginine (H3G34R) mutation (median overall survival, 9.9 vs 14.8 months; hazard ratio, 3.040; 95% confidence interval, 1.208-7.651; P = .018), and this result remained statistically significant in the multivariate Cox regression model. Among H3G34 DHGs, TP53 mutation was the most common genetic alteration (94.9%), followed by ATRX alterations (87.5%), MGMT methylation (79.5%), and PDGFRA alterations (33.2%). The presence of PDGFRA amplification or EGFR amplification conferred poor survival. After adjusting for age and sex, these alterations were still independent indicators for adverse outcomes. CONCLUSIONS: The authors highlight the important role of molecular stratification of H3G34 DHGs, which may help refine our understanding of the natural history of this group of malignant tumors.
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Neoplasias Encefálicas , Glioma , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Genótipo , Glioma/patologia , Glicina/genética , Humanos , PrognósticoRESUMO
INTRODUCTION: Gliosarcomas are extremely rare malignant brain tumors, which can be classified as primary gliosarcoma (PGS) if the tumors arise de novo or secondary gliosarcoma (SGS) in patients who had previously been treated for glioblastoma. Given their rarity, it is unclear if PGS is clinically and genetically different from SGS. This meta-analysis aimed to investigate the clinicopathological features, prognostic survivals, and molecular profiles of these rare tumors. METHODS: We searched PubMed and Web of Science for relevant studies. Odds ratio (OR), hazard ratio (HR), and their 95% confidence intervals (CI) were pooled using the random-effect model. RESULTS: We included eight studies with 239 PGS and 79 SGS for meta-analyses. Compared to PGS, SGS occurred at a younger age and had lower rates of gross total resection and radiation therapy. Bevacizumab was more commonly administered in SGS. SGS patients had a significantly worse PFS (HR 0.60; 95% CI 0.40-0.89) and OS (HR 0.46; 95% CI 0.31-0.68) in comparison to PGS. The incidences of EGFR mutation, IDH mutation, and MGMT methylation were not statistically different between PGS and SGS. CONCLUSION: Our results demonstrated that PGS and SGS had distinct clinicopathological profiles and prognoses but shared similar genetic profiles. This study facilitates our understanding of how these two malignant brain tumors behave clinically, but future studies will be required to elucidate the genetic pathways of PGS and SGS.
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Neoplasias Encefálicas , Glioblastoma , Gliossarcoma , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/terapia , Glioblastoma/patologia , Gliossarcoma/genética , Gliossarcoma/patologia , Gliossarcoma/terapia , Humanos , Mutação , PrognósticoRESUMO
INTRODUCTION: Diffuse midline gliomas (DMGs) are infiltrative midline gliomas harboring H3K27M mutations and are generally associated with poor outcomes. H3K27M mutations include mutations in HIST1H3B/C (H3.1), HIST2H3B/D (H3.2), or H3F3A (H3.3) genes. It is still unclear whether these mutations each portend a universally poor prognosis, or if there are any factors which modulate outcome. The main objective of this study was to study overall survival (OS) of H3.1 versus H3.3 K27M-mutant DMGs in pediatric and adult patients. METHODS: PubMed and Web of Science were searched, and we included studies if they have individual patient data of DMGs with available H3K27M genotype. Kaplan-Meier analysis and Cox regression models were used to analyze the survival of H3.1 and H3.3 mutations in each subgroup. RESULTS: We included 26 studies with 102 and 529 H3.1 and H3.3-mutant DMGs, respectively. The H3.1 mutation was more commonly seen in younger age. In pediatric population, H3.3 mutation conferred a shorter survival (median OS of 10.1 vs 14.2 months; p < 0.001) in comparison to H3.1-positive patients, which was further confirmed in the multivariate Cox analysis. Conversely, H3.3 was associated with a prolonged survival in adult patients as compared with H3.1 mutation (median OS of 14.4 vs 1.7 months; p = 0.019). CONCLUSION: We demonstrated that the prognosis of H3.1 and H3.3 K27M mutation in DMG patients is modulated by patient age. Routine H3K27M mutation genotyping in newly diagnosed DMGs may further stratify patients with these difficult tumors.
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Neoplasias Encefálicas , Glioma , Adulto , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Criança , Glioma/patologia , Histonas/genética , Humanos , Mutação , PrognósticoRESUMO
BACKGROUND: Emphysematous pyelonephritis (EP) is a severe necrotizing infection of the renal parenchyma which is associated with significant case mortality. We sought to identify the incidence and predictive risk factors associated with EP mortality. METHODS: Two electronic databases, PubMed and Web of Science, were searched from their inception until June 06, 2021 for relevant articles. Two independent teams reviewed abstracts and extracted data from the selected manuscripts. A meta-analysis has been reported in line with PRISMA 2020 and AMSTAR Guidelines. RESULTS: Of the 1080 retrieved abstracts, 79 underwent full-text review and 45 studies were included in the final analysis, comprising a total cohort of 1303 patients and 177 mortalities. The pooled prevalence of mortality among the patients with EP disease was 13%. Our analysis found a significantly decreasing trend in mortality rates, an increasing trend in minimally invasive intervention and decreasing trends in emergency nephrectomy in the EP studies from 1985 to 2020. Significant risk factors that were associated with a negative impact on survival of EP patients included sepsis (OR = 15.99), shock (OR = 15.57), disturbance of consciousness (OR = 12.11), thrombocytopenia (OR 7.85), acute renal failure (OR = 5.41), Wan classification I (OR = 4.57), emergency nephrectomy (OR = 3.73), Huang-Tseng classification III-IV (OR = 2.4) and medical management alone (OR = 2.04). Female sex (OR = 0.52) and minimally invasive intervention (OR = 0.47) (percutaneous nephrostomy or ureteral stent placement) were associated with decreased mortality rates. CONCLUSIONS: Our study results demonstrated several significant risk factors that could help guide treatment to reduce the mortality risk of EP patients. Clinically, early treatment with a combination of minimally invasive intervention and appropriate medical management may be protective for reducing mortality risk in EP patients.
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Enfisema , Pielonefrite , Enfisema/complicações , Enfisema/epidemiologia , Feminino , Humanos , Nefrectomia , Prevalência , Pielonefrite/complicações , Pielonefrite/epidemiologia , Fatores de RiscoRESUMO
INTRODUCTION: Esthesioneuroblastoma (ENB) is an uncommon primary sinonasal tumor which can extend intracranially. Exactly how to classify them pathologically still remains discrepant; the Hyams grading system, for example, has not been universally adopted. This individual patient data (IPD) meta-analysis aimed to investigate the prognostic implication of each Hyams grade on patient outcomes. METHODS: We accessed two electronic databases including PubMed and Web of Science. Raw patient data from potential articles were extracted. To examine the associations of various clinicopathological factors with the Hyams grades, we utilized Chi-square, t-test, and Mann-Whitney, as appropriate. Log-rank test and Cox regression analysis were used to elucidate the impact of the Hyams grades on recurrence-free survival (RFS), metastasis-free survival (MFS), and overall survival (OS) of ENB patients. RESULTS: We included 33 studies with 492 ENB patients. We found significant associations of Kadish stages, Dulguerov stages, rates of recurrence, metastasis, and patient mortality with Hyams grade. Log-rank tests and Cox regression models demonstrated significant differences in RFS and OS of Hyams grade I - II, grade III, and grade IV patients. There was no statistical difference in RFS and OS of Hyams grade I and II. Radiotherapy was only effective in grade III - IV ENBs and chemotherapy showed no benefits to patients. CONCLUSION: We verify that the Hyams grading system appears to be a reliable prognostic indicator to assess ENB patient outcomes. Consolidating the Hyams grading system into a three-tier system based on similar clinical outcomes of grades I and II may simplify this classification schema.
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Estesioneuroblastoma Olfatório , Cavidade Nasal , Neoplasias Nasais , Estesioneuroblastoma Olfatório/patologia , Estesioneuroblastoma Olfatório/terapia , Humanos , Cavidade Nasal/patologia , Estadiamento de Neoplasias , Neoplasias Nasais/patologia , Neoplasias Nasais/terapia , Prognóstico , Estudos RetrospectivosRESUMO
INTRODUCTION: H3K27M-mutated diffuse midline gliomas (H3-DMGs) are aggressive tumors with a fatal outcome. This study integrating individual patient data (IPD) from published studies aimed to investigate the prognostic impact of different genetic alterations on survival of these patients. METHODS: We accessed PubMed and Web of Science to search for relevant articles. Studies were included if they have available data of follow-up and additional molecular investigation of H3-DMGs. For survival analysis, Kaplan-Meier analysis and Cox regression models were utilized, and corresponding hazard ratios (HR) and 95% confidence intervals (CI) were computed to analyze the impact of genetic events on overall survival (OS). RESULT: We included 30 studies with 669 H3-DMGs. TP53 mutations were the most common second alteration among these neoplasms. In univariate Cox regression model, TP53 mutation was an indicator of shortened survival (HR 1.446; 95% CI 1.143-1.829) whereas ACVR1 (HR 0.712; 95% CI 0.518-0.976) and FGFR1 mutations (HR 0.408; 95% CI 0.208-0.799) conferred prolonged survival. In addition, ATRX loss was also associated with a better OS (HR 0.620; 95% CI 0.386-0.996). Adjusted for age, gender, and tumor location, the presence of TP53 mutations, the absence of ACVR1 or FGFR1 mutations remained significantly poor prognostic factors. CONCLUSIONS: We outlined the prognostic importance of additional genetic alterations in H3-DMGs and recommended that these neoplasms should be further molecularly segregated. This may aid neuro-oncologists in appropriate risk stratification.
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Neoplasias Encefálicas , Glioma , Neoplasias Encefálicas/genética , Glioma/genética , Histonas/genética , Humanos , Mutação , PrognósticoRESUMO
INTRODUCTION: Spindle cell oncocytoma (SCO) is an extremely rare sellar neoplasm. No observational studies have been reported so far to investigate the prognostic factors of this tumor entity. This systematic review aimed to elucidate the risk factors for tumor recurrence/progression of SCO. METHODS: We searched for relevant articles in PubMed and Web of Science. Studies providing individual patient data with follow-up information of SCO cases were included. Pearson's Chi square and Fisher's exact test were used for categorical variables while t test or Mann-Whitney tests were applied for continuous variables, if applicable. We used the Cox regression model to assess the effects of suspected variables on progression-free survival (PFS). RESULTS: A total of 38 case reports and case series comprising of 67 SCOs were included for final analyses. Recurrent/progressive tumors were noted in 38.8% of cases. Among the clinicopathological factors, only the extent of surgery was a significant risk factor for tumor recurrence/progression. SCO patients with a subtotal resection had a significantly higher risk for tumor relapse in comparison with complete removal (HR 7.51; 95% CI 1.75-32.31; p = 0.007). CONCLUSION: Our study demonstrated the characteristic clinicopathological features of SCOs with a high recurrence/progression rate and outlined the predictor for tumor relapse. Failure to achieve gross total resection is the only risk factor for tumor recurrence/progression.
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Adenoma Oxífilo , Neoplasias Hipofisárias , Adenoma Oxífilo/cirurgia , Humanos , Recidiva Local de Neoplasia , Hipófise , Neoplasias Hipofisárias/cirurgia , Fatores de RiscoRESUMO
BACKGROUND: There are controversial results concerning the prognostic implication of TERT promoter mutation in glioma patients concerning MGMT status. In this meta-analysis, we investigated whether there are any interactions of these two genetic markers on the overall survival (OS) of glioma patients. METHODS: Electronic databases including PubMed and Web of Science were searched for relevant studies. Hazard ratio (HR) and its 95% confidence interval (CI) for OS adjusted for selected covariates were calculated from the individual patient data (IPD), Kaplan-Meier curve (KMC), or directly obtained from the included studies. RESULTS: A total of nine studies comprising 2819 glioma patients were included for meta-analysis. Our results showed that TERT promoter mutation was associated with a superior outcome in MGMT-methylated gliomas (HR = 0.73; 95% CI = 0.55-0.98; p-value = 0.04), whereas this mutation was associated with poorer survival in gliomas without MGMT methylation (HR = 1.86; 95% CI = 1.54-2.26; p-value < 0.001). TERT-mutated glioblastoma (GBM) patients with MGMT methylation benefited from temozolomide (TMZ) treatment (HR = 0.33; 95% CI = 0.23-0.47; p-value < 0.001). MGMT methylation was not related with any improvement in OS in TERT-wild type GBMs (HR = 0.80; 95% CI = 0.56-1.15; p-value = 0.23). CONCLUSIONS: The prognostic value of TERT promoter mutation may be modulated by MGMT methylation status. Not all MGMT-methylated GBM patients may benefit from TMZ; it is possible that only TERT-mutated GBM with MGMT methylation, in particular, may respond.
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Neoplasias Encefálicas/genética , Metilação de DNA , Metilases de Modificação do DNA/genética , Enzimas Reparadoras do DNA/genética , Glioma/genética , Telomerase/genética , Proteínas Supressoras de Tumor/genética , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/mortalidade , Metilases de Modificação do DNA/metabolismo , Enzimas Reparadoras do DNA/metabolismo , Feminino , Glioma/metabolismo , Glioma/mortalidade , Humanos , Masculino , Mutação , Prognóstico , Análise de Sobrevida , Telomerase/metabolismo , Proteínas Supressoras de Tumor/metabolismoRESUMO
Objective: It is still controversial as to how the reclassification of noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) affects the risk of malignancy (ROM) in The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC). This meta-analysis was aimed to investigate the impact of NIFTP on the ROM in each TBSRTC category. Methods: We accessed three electronic databases including PubMed, Web of Science, and Scopus to search for relevant data from January, 2016 to July, 2018. Relative risk and meta-analysis of proportions using the DerSimonian-Laird method, and each corresponding 95% confidence interval (CI) was pooled using a random-effect model. Results: A total of 14 studies consisting of 14,153 resected nodules were included for meta-analyses. Overall, there was a significant reduction in ROM in all TBSRTC categories following the NIFTP reclassification, except TBSRTC category I. The largest absolute and relative decrease in ROM was observed in TBSRTC category V (16%; 95% CI = 8 to 24) and category III (32%; 95% CI = 24 to 39), respectively. There was a positive correlation between the rate of NIFTP and resection rate (r = 0.83; P = .02). The decreases in ROM were more prominent in Western than in Asian cohorts. Conclusion: We confirmed the decrease in ROM due to the NIFTP reclassification for most of TBSRTC categories, which was more significant in Western than in Asian practice. The incidence of NIFTP was higher in institutions where surgical resection rates were high in patients with indeterminate cytology nodules. Abbreviations: AUS/FLUS = atypia of undetermined significance/follicular lesion of undetermined significance; CI = confidence interval; FNA = fine-needle aspiration; FN/SFN = follicular neoplasm/suspicious for follicular neoplasm; NIFTP = noninvasive follicular thyroid neoplasm with papillary-like nuclear features; NI-FVPTC = noninvasive follicular variant of papillary thyroid carcinoma; ROM = risk of malignancy; RR = relative risk; SM = suspicious for malignancy; TBSRTC = The Bethesda System for Reporting Thyroid Cytopathology.
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Adenocarcinoma Folicular , Neoplasias da Glândula Tireoide , Nódulo da Glândula Tireoide , Biópsia por Agulha Fina , HumanosRESUMO
AIMS: CD10 is an endopeptidase that degrades various bioactive peptides in the extracellular matrix. In addition to enzymatic degradation, it affects multiple intracellular signal transduction pathways. CD10 expression has been extensively studied in human epithelial cancers of numerous organs and sites. However, its presence in thyroid carcinomas, especially in anaplastic thyroid carcinoma (ATC), has not been fully determined. An actual CD10 expression in thyroid lesions including a large series of ATC was evaluated. METHODS AND RESULTS: We examined CD10 by immunohistochemistry (IHC) in 152 thyroid lesions: nine adenomatous goitres (AGs) and 143 tumours, including 47 anaplastic carcinomas. IHC showed diffuse and strong positivity for CD10 in the epithelial components of almost all ATCs. However, epithelia with squamous metaplasia and oncocytic change from AGs, follicular adenomas and differentiated carcinomas had focal CD10 reactivity. Some papillary thyroid carcinomas (PTCs), along with the PTC components of some ATCs, showed CD10 positivity in fibroblast-like stromal cells and fibrous material. CONCLUSION: Our results imply that the CD10 expression pattern depended on the histotypes of thyroid lesions. When possible metastatic tumours and non-epithelial tumours are excluded, high CD10 expression may be useful in determining whether a primary thyroid carcinoma includes an anaplastic component.
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Biomarcadores Tumorais/análise , Neprilisina/biossíntese , Carcinoma Anaplásico da Tireoide/patologia , Neoplasias da Glândula Tireoide/patologia , Humanos , Imuno-Histoquímica , Neprilisina/análise , Carcinoma Anaplásico da Tireoide/metabolismo , Neoplasias da Glândula Tireoide/metabolismoRESUMO
INTRODUCTION: Distant metastasis (DM) is not a frequent event in differentiated thyroid carcinoma (DTC) but has an adverse impact on mortality of patients with DTC. In the current study, we aimed to conduct a comprehensive systematic review and meta-analysis to investigate the risk factors for DM in DTCs and for each histological subtype. METHODS: Five electronic databases were searched from inception to December 2016 for relevant articles. Pooled odd ratios and 95% confidence interval were calculated using random-effect model. RESULTS: Thirty-four articles with 73,219 patients were included for meta-analyses. In DTCs, male gender, age ≥45 years, tumor size ≥4 cm, multifocality, vascular invasion (VI), extrathyroidal extension (ETE), lymph node metastasis (LNM), and lateral LNM were demonstrated to be associated with significant risks for DM. In addition, several clinicopathological factors such as age ≥45 years, VI, ETE, and LNM were shown to be significant risk factors for DM in both PTC and FTC subgroups. CONCLUSION: Our study demonstrated the promising value of several clinicopathological factors such as male gender, older age, VI, ETE, and LNM in predicting DM in PTCs and FTCs. Our study affirms the value of the selected clinicopathological factors for tumor risk stratification and assessment of patients' prognosis.
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Carcinoma/secundário , Neoplasias da Glândula Tireoide/patologia , Bases de Dados Factuais , Humanos , Metástase Linfática , Modelos Estatísticos , Invasividade Neoplásica , Metástase Neoplásica , Razão de Chances , Prognóstico , Fatores de RiscoRESUMO
INTRODUCTION: The use of molecular markers, especially BRAF and TERT promoter mutations, for risk stratification in papillary thyroid carcinoma (PTC) is subject to continuing debate. In this study, we aimed to investigate the clinicopathological implication of each genotype when combining BRAF and TERT promoter mutations in PTCs. METHODS: We searched four electronic databases including PubMed, Scopus, Web of Science and Virtual Health Library for relevant studies. Pooled estimates of odds ratios and corresponding 95% confidence intervals were calculated using random-effect model. RESULTS: From 111 results, we finally included 11 studies with 3911 PTC patients for meta-analyses. Our results demonstrated that PTCs with concurrent BRAF and TERT promoter mutations were associated with increased tumour aggressiveness in comparison with PTCs harbouring BRAF or TERT promoter mutation alone. The combination of BRAF and TERT promoter mutations could classify PTCs into four distinct risk groups with decreasing aggressiveness as follows: coexisting BRAF and TERT > TERT alone=BRAF alone > no mutations. CONCLUSION: The risk stratification of PTC based on these four genotypes can help improve the clinical management of PTCs by identifying the group of PTCs with the highest aggressiveness.
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Carcinoma Papilar/diagnóstico , Proteínas Proto-Oncogênicas B-raf/genética , Telomerase/genética , Neoplasias da Glândula Tireoide/diagnóstico , Carcinoma Papilar/genética , Humanos , Mutação , Prognóstico , Regiões Promotoras Genéticas/genética , Medição de Risco/métodos , Câncer Papilífero da Tireoide , Neoplasias da Glândula Tireoide/genéticaRESUMO
AIMS: Paediatric follicular thyroid carcinomas are uncommon, and their clinicopathological features and molecular profiles are still unknown. In the present study, we aimed to investigate the clinicopathological aspects of a large series of follicular thyroid carcinomas (FTCs) in paediatric patients and to analyse the point mutations in codons 12, 13 and 61 of NRAS, HRAS and KRAS genes and the rearrangements of PAX8-PPARG. METHODS AND RESULTS: A total of 41 paediatric FTCs less than 21 years of age were enrolled into the present study. We used direct sequencing and reverse transcription-polymerase chain reaction (RT-PCR) to detect RAS mutations and PAX8-PPARG fusions, respectively. The paediatric FTCs were 6:1 in a female to male ratio, with a mean tumour size of 52.7 mm. Distant metastasis was found in one case at the time of presentation. During a median follow-up time of 69 months, two cases had lung metastasis and all patients were alive. Histologically, all cases were minimally invasive FTCs and varied in growth patterns: microfollicular (39%), follicular (14.6%), solid/trabecular (6%), oncocytic (4.9%) and mixed patterns (26.8%). The mean Ki67 index was 5.7% and it was not statistically different among the growth patterns. NRAS mutations were found in five cases (12.2%) and associated significantly with small tumour size (P = 0.014). PAX8-PPARG fusion was not detected in our series. CONCLUSION: Paediatric FTCs are indolent in clinical course in spite of their large tumour size and have a distinct genetic background. RAS mutations and PAX8-PPARG fusions may not play major roles in the tumorigenesis of paediatric FTCs.
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Adenocarcinoma Folicular/genética , Adenocarcinoma Folicular/patologia , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/patologia , Adolescente , Povo Asiático/genética , Criança , Feminino , Humanos , Masculino , Mutação , Proteínas de Fusão Oncogênica/genética , Prevalência , Adulto Jovem , Proteínas ras/genéticaRESUMO
The presence of distant metastasis is associated with an adverse outcome in papillary thyroid cancer. We performed a meta-analysis to investigate the role of molecular markers as predictors for distant metastasis in papillary thyroid cancer. Four electronic databases including PubMed, Web of Science, Scopus, and Virtual Health Library were searched, and odds ratio and its 95% confidence interval concerning the association of BRAF, RAS, and TERT promoter mutations and RET/PTC rearrangements with distant metastasis were calculated using random-effects model. In total, 42 studies with 11,109 papillary thyroid cancers were included for meta-analyses. Overall, the presence of TERT promoter (odds ratio = 5.95; 95% confidence interval = 2.95-11.99), RAS mutations (odds ratio = 2.5; 95% confidence interval = 1.00-6.22), and RET/PTC rearrangements (odds ratio = 1.92; 95% confidence interval = 1.03-3.56) were found to be associated with a significantly increased risk for distant metastasis. BRAF mutations were not associated with an elevated risk for distant metastasis (odds ratio = 0.79; 95% confidence interval = 0.54-1.16). In conclusion, our study demonstrated the promising value of few molecular biomarkers, especially TERT promoter mutations in predicting distant metastasis in papillary thyroid cancers, while BRAF mutations showed no association with distant metastasis. Our study affirms the value of selected mutations for tumor risk stratification and assessment of patients' prognosis.
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Biomarcadores Tumorais/genética , Carcinoma/genética , Carcinoma/patologia , Mutação/genética , Regiões Promotoras Genéticas/genética , Proteínas Proto-Oncogênicas B-raf/genética , Telomerase/genética , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/patologia , Adolescente , Adulto , Idoso , Carcinoma Papilar , Bases de Dados Factuais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica/genética , Metástase Neoplásica/patologia , Câncer Papilífero da Tireoide , Proteínas ras/genéticaRESUMO
We report three cases of chromophobe renal cell carcinoma-like thyroid carcinoma as a novel clinicopathologic entity possibly associated with tuberous sclerosis complex. A 15-year-old female, a 19-year-old male, and a 21-year-old male presented with primary thyroid carcinoma. Two of the patients had associated tuberous sclerosis complex. Macroscopically, the carcinomas showed invasive growth. Histologically, the carcinoma cells showed a trabecular pattern with thin vascular stroma, and were characterized by abundant eosinophilic cytoplasm with perinuclear clearing, a prominent cell border, a wrinkled nuclear membrane, and binucleation, which are all features of chromophobe renal cell carcinoma. Immunohistochemically, the carcinoma cells were positive for thyroglobulin, TTF1, and PAX8, and negative for CD10, calcitonin, and carcinoembryonic antigen. Vascular invasion was visible in all cases, but distant metastasis was not detected during follow-up. The original pathological diagnoses of the three cases were widely invasive follicular thyroid carcinoma, poorly differentiated thyroid carcinoma, and oxyphilic variant of papillary thyroid carcinoma. Thus, the cases were similar to chromophobe renal cell carcinoma associated with tuberous sclerosis complex as they were characterized by histologic findings consistent with chromophobe renal cell carcinoma, occurrence in an adolescent or young adult, and favorable prognosis regardless of the presence of vascular invasion and an infiltrating growth pattern resembling poorly differentiated carcinoma. The etiopathogenesis also seemed to suggest the presence of the tuberous sclerosis complex genetic abnormality.
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Carcinoma de Células Renais/diagnóstico , Neoplasias da Glândula Tireoide/diagnóstico , Esclerose Tuberosa/diagnóstico , Adolescente , Biomarcadores Tumorais/metabolismo , Carcinoma de Células Renais/complicações , Carcinoma de Células Renais/metabolismo , Carcinoma de Células Renais/patologia , Proteínas de Ligação a DNA/metabolismo , Diagnóstico Diferencial , Feminino , Humanos , Masculino , Fator de Transcrição PAX8/metabolismo , Tireoglobulina/metabolismo , Neoplasias da Glândula Tireoide/complicações , Neoplasias da Glândula Tireoide/metabolismo , Neoplasias da Glândula Tireoide/patologia , Fatores de Transcrição/metabolismo , Esclerose Tuberosa/complicações , Esclerose Tuberosa/metabolismo , Esclerose Tuberosa/patologia , Adulto JovemRESUMO
Whole exome sequencing (WES) and RNA sequencing (RNA-Seq) are two main platforms used for next-generation sequencing (NGS). While WES is primarily for DNA variant discovery and RNA-Seq is mainly for measurement of gene expression, both can be used for detection of genetic variants, especially single nucleotide variants (SNVs). How consistently variants can be detected from WES and RNA-Seq has not been systematically evaluated. In this study, we examined the technical and biological inconsistencies in SNV detection using WES and RNA-Seq data from 27 pairs of tumor and matched normal samples. We analyzed SNVs in three categories: WES unique - those only detected in WES, RNA-Seq unique - those only detected in RNA-Seq, and shared - those detected in both. We found a small overlap (average â¼14%) between the SNVs called in WES and RNA-Seq. The WES unique SNVs were mainly due to low coverage, low expression, or their location on the non-transcribed strand in RNA-Seq data, while the RNA-Seq unique SNVs were primarily due to their location out of the WES-capture boundary regions (accounting â¼71%), as well as low coverage of the regions, low coverage of the mutant alleles or RNA-editing. The shared SNVs had high locus-specific coverage in both WES and RNA-Seq and high gene expression levels. Additionally, WES unique and RNA-Seq unique SNVs showed different nucleotide substitution patterns, e.g., â¼55% of RNA-Seq unique variants were A:TâG:C, a hallmark of RNA editing. This study provides an important evaluation on the inconsistencies of somatic SNVs called in WES and RNA-Seq data.
Assuntos
Exoma/genética , Neoplasias Pulmonares/genética , Transcriptoma/genética , Genoma Humano , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Polimorfismo de Nucleotídeo Único/genéticaRESUMO
Acquired cystic disease-associated renal cell carcinoma (ACD-RCC) is a common subtype of renal cell carcinoma (RCC) in end-stage renal disease (ESRD) patients. The current systematic review and meta-analysis was performed to evaluate the clinicopathological, and genetic characteristics of patients with ACD-RCC. A systematic search on three electronic databases including the Pubmed, Scopus, and Web of Science databases were performed until December 31, 2022. A meta-analysis was performed following the PRISMA 2020 Guidelines. Of 888 identified articles, full-text screening in 69 articles, there were 26 articles analyzed, with a total of 2314 tumors in 2199 patients, including 418 ACD-RCC tumors in 363 patients, 1340 clear cell RCC (ccRCC) tumors, 308 papillary RCC (pRCC) tumors. Most ACD-RCC patients were male (80.2%). All the ACD-RCC patients underwent prior dialysis with 148.2 months of mean dialysis duration. There were 8.7%, 3.4%, and 5.8% tumors at the T3-4 stage, N1 stage, and M1 stage, respectively. The mean overall survival of ACD-RCC patients was 39.6 months (95% CI, 26.6-52.5). Compared to ccRCC and pRCC, ACD-RCC patients had a longer duration of dialysis (MD: 103.5 and 31.77 months, respectively; 95% CI: [75.48; 131.53] and [0.95; 62.58], respectively), and a higher rate of multifocal tumors (MD: 3.46 and 2.45 tumors, respectively; 95% CI [1.71; 6.98] and [1.26; 4.79], respectively). Regarding genetic characteristics, chromosomes 3 and 16 were the 2 most frequent chromosomal aberrations. The missense mutation in KMT2C (25%) and TSC2 (18.75%) were the 2 most common gene mutations in ACD-RCC. In conclusion, the ACD-RCC subtype exhibited several distinct clinicopathological and genetic characteristics compared to others RCC subtypes. Further researchs are needed to assess the survival outcome and the genetic characteristics of this subtype.