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Clinical Cancer Research : An Official... Jul 2023While patients with intermediate-risk (IR) Wilms tumors now have an overall survival (OS) rate of almost 90%, those affected by high-stage tumors with diffuse anaplasia...
PURPOSE
While patients with intermediate-risk (IR) Wilms tumors now have an overall survival (OS) rate of almost 90%, those affected by high-stage tumors with diffuse anaplasia have an OS of only around 50%. We here identify key events in the pathogenesis of diffuse anaplasia by mapping cancer cell evolution over anatomic space in Wilms tumors.
EXPERIMENTAL DESIGN
We spatially mapped subclonal landscapes in a retrospective cohort of 20 Wilms tumors using high-resolution copy-number profiling and TP53 mutation analysis followed by clonal deconvolution and phylogenetic reconstruction. Tumor whole-mount sections (WMS) were utilized to characterize the distribution of subclones across anatomically distinct tumor compartments.
RESULTS
Compared with non-diffuse anaplasia Wilms tumors, tumors with diffuse anaplasia showed a significantly higher number of genetically distinct tumor cell subpopulations and more complex phylogenetic trees, including high levels of phylogenetic species richness, divergence, and irregularity. All regions with classical anaplasia showed TP53 alterations. TP53 mutations were frequently followed by saltatory evolution and parallel loss of the remaining wild-type (WT) allele in different regions. Morphologic features of anaplasia increased with copy-number aberration (CNA) burden and regressive features. Compartments demarcated by fibrous septae or necrosis/regression were frequently (73%) associated with the emergence of new clonal CNAs, although clonal sweeps were rare within these compartments.
CONCLUSIONS
Wilms tumors with diffuse anaplasia display significantly more complex phylogenies compared with non-diffuse anaplasia Wilms tumors, including features of saltatory and parallel evolution. The subclonal landscape of individual tumors was constrained by anatomic compartments, which should be considered when sampling tissue for precision diagnostics.
Topics: Humans; Kidney Neoplasms; Anaplasia; Retrospective Studies; Phylogeny; Wilms Tumor
PubMed: 37140929
DOI: 10.1158/1078-0432.CCR-23-0311 -
Journal of Hepatology Oct 2022Hepatoblastoma (HB) and hepatocellular carcinoma (HCC) are the predominant liver cancers in children, though their respective treatment options and associated outcomes...
BACKGROUND & AIMS
Hepatoblastoma (HB) and hepatocellular carcinoma (HCC) are the predominant liver cancers in children, though their respective treatment options and associated outcomes differ dramatically. Risk stratification using a combination of clinical, histological, and molecular parameters can improve treatment selection, but it is particularly challenging for tumors with mixed histological features, including those in the recently created hepatocellular neoplasm not otherwise specified (HCN NOS) provisional category. We aimed to perform the first molecular characterization of clinically annotated cases of HCN NOS.
METHODS
We tested whether these histological features are associated with genetic alterations, cancer gene dysregulation, and outcomes. Namely, we compared the molecular features of HCN NOS, including copy number alterations, mutations, and gene expression profiles, with those in other pediatric hepatocellular neoplasms, including HBs and HCCs, as well as HBs demonstrating focal atypia or pleomorphism (HB FPAs), and HBs diagnosed in older children (>8).
RESULTS
Molecular profiles of HCN NOS and HB FPAs revealed common underlying biological features that were previously observed in HCCs. Consequently, we designated these tumor types collectively as HBs with HCC features (HBCs). These tumors were associated with high mutation rates (∼3 somatic mutations/Mb) and were enriched with mutations and alterations in key cancer genes and pathways. In addition, recurrent large-scale chromosomal gains, including gains of chromosomal arms 2q (80%), 6p (70%), and 20p (70%), were observed. Overall, HBCs were associated with poor clinical outcomes.
CONCLUSIONS
Our study indicates that histological features seen in HBCs are associated with combined molecular features of HB and HCC, that HBCs are associated with poor outcomes irrespective of patient age, and that transplanted patients are more likely to have good outcomes than those treated with chemotherapy and surgery alone. These findings highlight the importance of molecular testing and early therapeutic intervention for aggressive childhood hepatocellular neoplasms.
LAY SUMMARY
We molecularly characterized a class of histologically aggressive childhood liver cancers and showed that these tumors are clinically aggressive and that their observed histological features are associated with underlying recurrent molecular features. We proposed a diagnostic algorithm to identify these cancers using a combination of histological and molecular features, and our analysis suggested that these cancers may benefit from specialized treatment strategies that may differ from treatment guidelines for other childhood liver cancers.
Topics: Carcinoma, Hepatocellular; Child; Chromosome Aberrations; Hepatoblastoma; Humans; Liver Neoplasms; Mutation; Young Adult
PubMed: 35577029
DOI: 10.1016/j.jhep.2022.04.035 -
Journal of the Egyptian National Cancer... Jun 2015The presence of anaplastic features has been known to correlate with poor clinical outcome in various pediatric malignancies, including Wilms tumor and medulloblastoma...
BACKGROUND
The presence of anaplastic features has been known to correlate with poor clinical outcome in various pediatric malignancies, including Wilms tumor and medulloblastoma but not in rhabdomyosarcoma.
AIM
Aim was to study the frequency of anaplasia at presentation in childhood rhabdomyosarcoma and its relationship to clinical and pathological characteristics as well as to outcome.
PATIENTS AND METHODS
Anaplasia was retrospectively assessed in 105 consecutive pediatric rhabdomyosarcoma patients who were registered at the Children's Cancer Hospital in Egypt (CCHE) during the period from July 2007 till the end of May 2010.
RESULTS
Anaplasia was diagnosed in 18 patients (17.1%), focal in 10 (9.5%) and diffuse in 8 (7.6%). The distribution of anaplasia was found to be more common in older patients having age⩾10 years. Also it was more likely to occur in the high risk group and in tumors with unfavorable histology (alveolar subtype), and stage IV. The 3-year failure free survival rates for patients with and without anaplasia were 27.8±10.6% and 53.4±5.8%, respectively (p=0.014) and the 3-year overall survival rates were 35.3±11.6% and 61±6%, respectively (p=0.019).
CONCLUSIONS
The frequency of anaplasia in pediatric patients with rhabdomyosarcoma in our study was 17.1%. The presence of anaplasia had statistically significant worse clinical outcome.
Topics: Adolescent; Age Factors; Anaplasia; Child; Child, Preschool; Disease Progression; Egypt; Female; Follow-Up Studies; Humans; Infant; Male; Neoplasm Grading; Neoplasm Metastasis; Neoplasm Staging; Prognosis; Registries; Retrospective Studies; Rhabdomyosarcoma; Survival Analysis; Treatment Outcome; Tumor Burden
PubMed: 25921241
DOI: 10.1016/j.jnci.2015.03.003 -
American Journal of Ophthalmology Apr 2015To determine whether the degree of tumor anaplasia has prognostic value by evaluating its correlation with high-risk histopathologic features and clinical outcomes in a...
PURPOSE
To determine whether the degree of tumor anaplasia has prognostic value by evaluating its correlation with high-risk histopathologic features and clinical outcomes in a series of retinoblastoma patients.
DESIGN
Retrospective clinicopathologic study.
METHODS
The clinical and pathologic findings in 266 patients who underwent primary enucleation for retinoblastoma were reviewed. The histologic degree of anaplasia was graded as retinocytoma, mild, moderate, or severe as defined by increasing cellular pleomorphism, number of mitoses, nuclear size, and nuclear hyperchromatism. Nuclear morphometric characteristics were measured. The clinical and pathologic data of 125 patients were compared using Kaplan-Meier estimates of survival. Fisher exact test and multivariate regression were used to analyze the association between anaplasia grade and high-risk histologic features.
RESULTS
Increasing grade of anaplasia was associated with decreased overall survival (P = .003) and increased risk of metastasis (P = .0007). Histopathologic features that were associated with anaplasia included optic nerve invasion (P < .0001), choroidal invasion (P < .0001), and anterior segment invasion (P = .04). Multivariate analysis considering high-risk histopathology and anaplasia grading as predictors of distant metastasis and death showed that high-risk histopathology was statistically significant as an independent predictor (P = .01 for metastasis, P = .03 for death) but anaplasia was not (P = .63 for metastasis, P = .30 for death). In the absence of high-risk features, however, severe anaplasia identified an additional risk for metastasis (P = .0004) and death (P = .01).
CONCLUSION
Grading of anaplasia may be a useful adjunct to standard histopathologic criteria in identifying retinoblastoma patients who do not have high-risk histologic features but still have an increased risk of metastasis and may need adjuvant therapy.
Topics: Anaplasia; Child; Child, Preschool; Eye Enucleation; Female; Humans; Infant; Male; Mitotic Index; Neoplasm Invasiveness; Retinal Neoplasms; Retinoblastoma; Retrospective Studies; Survival Rate
PubMed: 25528954
DOI: 10.1016/j.ajo.2014.12.014 -
Ophthalmology Science Mar 2022Gain of chromosome 6p has been associated with poor ocular survival in retinoblastoma and histopathologic grading of anaplasia with increased risk of metastatic spread...
PURPOSE
Gain of chromosome 6p has been associated with poor ocular survival in retinoblastoma and histopathologic grading of anaplasia with increased risk of metastatic spread and death. This study examined the correlation between these factors and other chromosomal abnormalities as well as results of whole genome sequencing, digital morphometry, and progression-free survival.
DESIGN
Retrospective cohort study from 2 United States tertiary referral centers.
PARTICIPANTS
Forty-two children who had undergone enucleation for retinoblastoma from January 2000 through December 2017.
METHODS
Status of chromosomes 6p, 1q, 9q, and 16q was evaluated with fluorescence in situ hybridization, the degree of anaplasia and presence of histologic high-risk features were assessed by ocular pathologists, digital morphometry was performed on scanned tumor slides, and whole genome sequencing was performed on a subset of tumors. Progression-free survival was defined as absence of distant or local metastases or tumor growth beyond the cut end of the optic nerve.
MAIN OUTCOME MEASURES
Correlation between each of chromosomal abnormalities, anaplasia, morphometry and sequencing results, and survival.
RESULTS
Forty-one of 42 included patients underwent primary enucleation and 1 was treated first with intra-arterial chemotherapy. Seven tumors showed mild anaplasia, 19 showed moderate anaplasia, and 16 showed severe anaplasia. All tumors had gain of 1q, 18 tumors had gain of 6p, 6 tumors had gain of 9q, and 36 tumors had loss of 16q. Tumors with severe anaplasia were significantly more likely to harbor 6p gains than tumors with nonsevere anaplasia ( < 0.001). Further, the hematoxylin staining intensity was significantly greater and that of eosin staining significantly lower in tumors with severe anaplasia ( < 0.05). Neither severe anaplasia ( = 0.10) nor gain of 6p ( = 0.21) correlated with histologic high-risk features, and severe anaplasia did not correlate to , , , or mutations in a subset of 14 tumors ( > 0.5). Patients with gain of 6p showed significantly shorter progression-free survival ( = 0.03, Wilcoxon test).
CONCLUSIONS
Gain of chromosome 6p emerges as a strong prognostic biomarker in retinoblastoma because it correlates with severe anaplasia, quantifiable changes in tumor cell staining characteristics, and extraocular spread.
PubMed: 36246172
DOI: 10.1016/j.xops.2021.100089 -
Veterinary and Comparative Oncology Dec 2023Canine meningiomas are currently graded using the human grading system. Recently published guidelines have adapted the human grading system for use in dogs. The goal of...
Canine meningiomas are currently graded using the human grading system. Recently published guidelines have adapted the human grading system for use in dogs. The goal of this study was to validate the new guidelines for canine meningiomas. To evaluate the inter-observer agreement, 5 veterinary surgical pathologists graded 158 canine meningiomas following the human grading system alone or with the new guidelines. The inter-observer agreement for histologic grade and each of the grading criteria (mitotic grade, invasion, spontaneous necrosis, macronucleoli, small cells, hypercellularity, pattern loss and anaplasia) was evaluated using the Fleiss kappa index. The diagnostic accuracy (sensitivity and specificity) was assessed by comparing the diagnoses obtained with the 2 grading systems with a consensus grade (considered the reference classification). The consensus histologic grade was obtained by agreement between 4 experienced veterinary neuropathologists following the guidelines. Compared with the human grading alone, the canine-specific guidelines increased the inter-observer agreement for: histologic grade (κ = 0.52); invasion (κ = 0.67); necrosis (κ = 0.62); small cells (κ = 0.36); pattern loss (κ = 0.49) and anaplasia (κ = 0.55). Mitotic grade agreement remained substantial (κ = 0.63). The guidelines improved the sensitivity in identifying grade 1 (95.6%) and the specificity in identifying grade 2 (96.2%) meningiomas. In conclusion, the new grading guidelines for canine meningiomas are associated with an overall improvement in the inter-observer agreement and higher diagnostic accuracy in diagnosing grade 1 and grade 2 meningiomas.
Topics: Humans; Dogs; Animals; Meningioma; Anaplasia; Dog Diseases; Meningeal Neoplasms; Necrosis; Reference Standards; Neoplasm Grading
PubMed: 37635372
DOI: 10.1111/vco.12932 -
Cancers Aug 2022(1) Background: Vena cava thrombus (VCT) is rare in Wilms tumor (WT) (4−10%). The aim of this study is to identify factors for an outcome to improve treatment for...
(1) Background: Vena cava thrombus (VCT) is rare in Wilms tumor (WT) (4−10%). The aim of this study is to identify factors for an outcome to improve treatment for better survival. (2) Methods: 148/3015 patients with WT (aged < 18 years) and VCT, prospectively enrolled over a period of 32 years (1989−2020) by the German Society for Pediatric Oncology and Hematology (SIOP-9/GPOH, SIOP-93-01/GPOH and SIOP-2001/GPOH), are retrospectively analyzed to describe clinical features, response to preoperative chemotherapy (PC) (142 patients) and surgical interventions and to evaluate risk factors for overall survival (OS). (3) Results: 14 VCT regressed completely with PC and another 12 in parts. The thrombus was completely removed in 111 (85.4%), incompletely in 16 (12.3%), and not removed in 3 (2.3%). The type of removal is unknown in four patients. Patients without VCT have a significantly (p < 0.001) better OS (97.8%) than those with VCT (90.1%). OS after complete resection is (89.9%), after incomplete (93.8%) and with no resection (100%). Patients with anaplasia or stage IV without complete remission (CR) after PC had a significantly worse OS compared to the remaining patients with VCT (77.1% vs. 94.4%; p = 0.002). (4) Conclusions: As a result of our study, two risk factors for poor outcomes in WT patients with VCT emerge: diffuse anaplasia and metastatic disease, especially those with non-CR after PC.
PubMed: 36010917
DOI: 10.3390/cancers14163924 -
Neurologia May 2023No formal indication currently exists for seizure prophylaxis in neurosurgical oncology patients. Neither have specific recommendations been made on the use of... (Meta-Analysis)
Meta-Analysis Review
INTRODUCTION
No formal indication currently exists for seizure prophylaxis in neurosurgical oncology patients. Neither have specific recommendations been made on the use of antiepileptic drugs (AED) in seizure-free patients with meningiomas scheduled for surgery. AEDs are generally prescribed on a discretionary basis, taking into consideration a range of clinical and radiological risk factors. We present a systematic review and meta-analysis exploring the effectiveness of antiepileptic prophylaxis in patients with meningioma and no history of seizures.
METHODS
We performed a systematic review of the PubMed/MEDLINE, Cochrane Central Register of Controlled Trials, Embase, and clinicaltrials.gov databases. Of a total of 4368 studies initially identified, 12 were selected for extraction of data and qualitative analysis. Based on the clinical data presented, we were only able to include 6 studies in the meta-analysis. We performed heterogeneity studies, calculated a combined odds ratio, evaluated publication bias, and conducted a sensitivity analysis.
RESULTS
AED prophylaxis in patients with meningioma and no history of seizures did not significantly reduce the incidence of post-operative seizures in comparison to controls (Mantel-Haenszel combined odds ratio, random effects model: 1.26 [95% confidence interval, 0.60-2.78]; 2041 patients). However, we are unable to establish a robust recommendation against this treatment due to the lack of prospective studies, the presence of selection bias in the studies reviewed, the likelihood of underestimation of seizure frequency during follow-up, and the strong influence of one study on the overall effect.
CONCLUSIONS
Despite the limitations of this review, the results of the meta-analysis do not support the routine use of seizure prophylaxis in patients with meningioma and no history of seizures.
Topics: Humans; Meningioma; Phenytoin; Anticonvulsants; Incidence; Meningeal Neoplasms
PubMed: 35781420
DOI: 10.1016/j.nrleng.2022.03.002 -
Radiologia 2023Meningiomas are tumors that originate in the arachnoid villi and are the most common non-glial neoplasm in the central nervous system. The clinical manifestations...
Meningiomas are tumors that originate in the arachnoid villi and are the most common non-glial neoplasm in the central nervous system. The clinical manifestations associated with meningioma depend, fundamentally, on its location. The location in the cerebral convexity is the most frequent, especially in the frontal lobes, manifesting with headache, motor disturbances, seizures and even neurocognitive disorders. There are 15 histologic subtypes of meningioma and three histologic grades. Within these, grades two and three have a worse prognosis and a higher rate of recurrence, as well as a radiological behavior that is generally more aggressive. Although there are some imaging features that can suggest a specific subtype, the definitive diagnosis will always require histological/molecular confirmation.
Topics: Humans; Meningioma; Diagnostic Imaging; Radiography; Prognosis; Meningeal Neoplasms
PubMed: 37758336
DOI: 10.1016/j.rxeng.2023.09.002