RESUMO
INTRODUCTION: The purpose of this study is to examine the outcomes in children with anaplastic bilateral Wilms tumor (BWT) from study AREN0534 in order to define potential prognostic factors and areas to target in future clinical trials. METHODS: Demographic and clinical data from AREN0534 study patients with anaplasia (focal anaplasia [FA], or diffuse anaplasia [DA]) were compared. Event-free survival (EFS) and overall survival (OS) were reported using Kaplan-Meier estimation with 95% confidence bands, and differences in outcomes between FA and DA compared using log-rank tests. The impact of margin status was analyzed. RESULTS: Twenty-seven children who enrolled on AREN0534 had evidence of anaplasia (17 DA, 10 FA) in at least one kidney and were included in this analysis. Twenty-six (96%) had BWT. Nineteen percent had anaplastic histology in both kidneys (four of 17 DA, and one of 10 FA). Forty-six percent with BWT had bilateral nephron-sparing surgery (NSS); one child who went off protocol therapy, eventually required bilateral completion nephrectomies. Median follow-up for EFS and OS was 8.6 and 8.7 years from enrollment. Four- and 8-year EFS was 53% [95% confidence interval (CI): 34%-83%] for DA; 4-year EFS was 80% [95% CI: 59%-100%], and 8-year EFS 70% [95% CI: 47%-100%] for FA. Three out of 10 children with FA and eight out of 17 children with DA had events. EFS did not differ statistically by margin status (p = .79; HR = 0.88). Among the six children who died (five DA, one FA), all experienced prior relapse or progression within 18 months. CONCLUSION: Events in children with DA/FA in the setting of BWT occurred early. Caution should be taken about interpreting the impact of margin status outcomes in the context of contemporary multimodal therapy. Future targeted investigations in children with BWT and DA/FA are needed.
Assuntos
Neoplasias Renais , Tumor de Wilms , Humanos , Tumor de Wilms/patologia , Tumor de Wilms/mortalidade , Tumor de Wilms/terapia , Tumor de Wilms/cirurgia , Masculino , Feminino , Neoplasias Renais/patologia , Neoplasias Renais/mortalidade , Neoplasias Renais/terapia , Neoplasias Renais/cirurgia , Pré-Escolar , Lactente , Anaplasia/patologia , Criança , Prognóstico , Taxa de Sobrevida , Seguimentos , NefrectomiaRESUMO
Anaplasia in Wilms tumor is recognized as the most important prognostically unfavorable histological feature. It is subtyped as focal anaplastic Wilms tumor (FAWT) and diffuse anaplastic Wilms tumor (DAWT). Outcomes of patients with DAWT remain poor in patients with stage III and IV tumors. Important issues relevant to anaplasia in Wilms tumor, including prevalence, treatment, outcomes, biomarkers, anaplasia, and chemotherapy, and the concept of tumor aggressiveness, are reviewed and discussed here. We also consider the differences in clinical approaches to anaplasia in Wilms tumor between the two major renal tumor clinical research groups: the International Society of Paediatric Oncology (SIOP) Renal Tumour Study Group and the Children's Oncology Group (COG) Renal Tumor Group. We emphasize the importance and implications of recognizing FAWT and DAWT as separate clinico-pathological entities.
Assuntos
Neoplasias Renais , Tumor de Wilms , Tumor de Wilms/patologia , Tumor de Wilms/terapia , Tumor de Wilms/complicações , Humanos , Neoplasias Renais/patologia , Neoplasias Renais/terapia , Anaplasia/patologia , PrognósticoRESUMO
BACKGROUND: To review race and ethnic group enrollment and outcomes for Wilms tumor (WT) across all 4 risk-assigned therapeutic trials from the current era Children's Oncology Group Renal Tumor Biology and Risk Stratification Protocol, AREN03B2. STUDY DESIGN: For patients with WT enrolled in AREN03B2 (2006 to 2019), disease and biologic features, therapeutic study-specific enrollment, and event-free (EFS) and overall (OS) 4-year survival were compared between institutionally reported race and ethnic groups. RESULTS: Among 5,146 patients with WT, no statistically significant differences were detected between race and ethnic groups regarding subsequent risk-assigned therapeutic study enrollment, disease stage, histology, biologic factors, or overall EFS or OS, except the following variables: Black children were older and had larger tumors at enrollment, whereas Hispanic children had lower rates of diffuse anaplasia WT and loss of heterozygosity at 1p. The only significant difference in EFS or OS between race and ethnic groups was observed among the few children treated for diffuse anaplasia WT with regimen UH-1 and -2 on high-risk protocol, AREN0321. On this therapeutic arm only, Black children showed worse EFS (hazard ratio = 3.18) and OS (hazard ratio = 3.42). However, this finding was not replicated for patients treated with regimen UH-1 and -2 under AREN03B2 but not on AREN0321. CONCLUSIONS: Race and ethnic group enrollment appeared constant across AREN03B2 risk-assigned therapeutic trials. EFS and OS on these therapeutic trials when analyzed together were comparable regarding race and ethnicity. Black children may have experienced worse stage-specific survival when treated with regimen UH-1 and -2 on AREN0321, but this survival gap was not confirmed when analyzing additional high-risk AREN03B2 patients.
Assuntos
Neoplasias Renais , Tumor de Wilms , Criança , Humanos , Anaplasia , Etnicidade , Hispânico ou Latino , Neoplasias Renais/terapia , Neoplasias Renais/patologia , Tumor de Wilms/genética , Tumor de Wilms/terapia , Negro ou Afro-Americano , Grupos Raciais , Taxa de SobrevidaRESUMO
We report a case of pediatric glioma with uncommon imaging, morphological, and genetic features. A one-year-old boy incidentally presented with a tumor in the fourth ventricle. The tumor was completely resected surgically and investigated pathologically. The mostly circumscribed tumor had piloid features but primitive and anaplastic histology, such as increasing cellularity and mitosis. The Ki-67 staining index was 25% at the hotspot. KIAA1549::BRAF fusion and KIAA1549 partial deletions were detected by direct PCR, supported by Sanger sequencing. To the best of our knowledge, this is the first report of a glioma with both deletion of KIAA1549 p.P1771_P1899 and fusion of KIAA1549::BRAF. The tumor could not be classified using DNA methylome analysis. The present tumor fell into the category of pilocytic astrocytoma with histological features of anaplasia (aPA). Further studies are needed to establish pediatric aPA.
Assuntos
Astrocitoma , Neoplasias Encefálicas , Glioma , Masculino , Humanos , Criança , Lactente , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Anaplasia , Proteínas Proto-Oncogênicas B-raf/genética , Astrocitoma/genética , Astrocitoma/patologia , Glioma/patologiaRESUMO
Patients with Wilms tumor (WT) in general have excellent survival, but the prognosis of patients belonging to the subgroup of WT with diffuse anaplasia (DA) is poor due to frequent resistance to chemotherapy. We hypothesized that DA WT cells might undergo changes, such as acquiring a persistent tolerance to DNA damage and copy number aberrations (CNAs), which could eventually lead to their resistance to chemotherapy treatment. Tissue sections from chemotherapy-treated DA WTs (n = 12) were compared with chemotherapy-treated nonanaplastic WTs (n = 15) in a tissue microarray system, enabling analysis of 769 tumor regions. All regions were scored for anaplastic features and immunohistochemistry was used to quantify p53 expression, proliferation index (Ki67), and DNA double-strand breaks (γH2AX). CNAs were assessed by array-based genotyping and TP53 mutations using targeted sequencing. Proliferation index and the frequency of DNA double-strand breaks (γH2AX dot expression) increased with higher anaplasia scores. Almost all (95.6%) areas with full-scale anaplasia had TP53 mutations or loss of heterozygosity, along with an increased amount of CNAs. Interestingly, areas with wild-type TP53 with loss of heterozygosity and only one feature of anaplasia (anaplasia score 1) also had significantly higher proliferation indices, more DNA double-strand breaks, and more CNAs than regions without any anaplastic features (score 0); such areas may be preanaplastic cell populations under selective pressure for TP53 mutations. In conclusion, we suggest that chemoresistance of DA WTs may be partly explained by a high proliferative capability of anaplastic cells, which also have a high burden of double-stranded DNA breaks and CNAs, and that there is a gradual emergence of anaplasia in WT.
Assuntos
Neoplasias Renais , Tumor de Wilms , Humanos , Neoplasias Renais/genética , Neoplasias Renais/patologia , Anaplasia/genética , Tumor de Wilms/genética , Tumor de Wilms/tratamento farmacológico , Tumor de Wilms/patologia , Mutação , Prognóstico , DNARESUMO
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.
Assuntos
Doenças do Cão , Neoplasias Meníngeas , Meningioma , Humanos , Cães , Animais , Meningioma/diagnóstico , Meningioma/veterinária , Meningioma/patologia , Anaplasia/veterinária , Doenças do Cão/diagnóstico , Neoplasias Meníngeas/diagnóstico , Neoplasias Meníngeas/veterinária , Neoplasias Meníngeas/patologia , Necrose/veterinária , Padrões de Referência , Gradação de TumoresRESUMO
PURPOSE: Chemotherapy is commonly used for treatment in children over three years old with high-risk medulloblastoma(MB). However, little is currently known about the therapeutic benefits and side effects of intrathecal methotrexate(MTX), warranting further research. METHODS: In this retrospective study, patients who received intrathecal MTX during chemotherapy were included in the MTX group (n = 32), and patients that only underwent cerebrospinal fluid (CSF) cytology analysis were assigned to the control group (n = 14). RESULTS: In the MTX group, 27(84.38%) patients had metastatic disease, 3(9.38%) had diffuse anaplasia, and 3(9.38%) had residual disease greater than 1.5 cm2. Molecular subgroup classification was available for 28(87.5%) patients. In the control group, 8(57.14%) patients had metastatic disease, 3(27.27%) had diffuse anaplasia, and 6(42.86%) had residual disease greater than 1.5 cm2. Molecular subgroup classification was available for 6(42.86%) patients. The 5-year progression-free survival was 70.99% and the 5-year overall survival was 72.99% for the MTX group, and the corresponding values were 41.67% and 50% for the control group, respectively. 6 (18.75%) patients in the MTX group with group 4 disease developed MTX-related acute leukoencephalopathy and one of them died. CONCLUSIONS: Our findings support the addition of intrathecal MTX during chemotherapy as the optimal management for children with group 3 and SHH high-risk MB. However, it is not recommended for group 4 MB patients, especially in resource-limited regions. TRIAL REGISTRATION NUMBER: Retrospective registered No.(2020 - 117).
Assuntos
Neoplasias Cerebelares , Meduloblastoma , Criança , Humanos , Pré-Escolar , Metotrexato/efeitos adversos , Meduloblastoma/patologia , Estudos Retrospectivos , Anaplasia/induzido quimicamente , Anaplasia/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias Cerebelares/patologiaRESUMO
OBJECTIVE: Immunohistochemical expression of P53 protein is so closely related to status of mutation of P53 gene which is tightly linked with pathogenesis of nephroblastoma or Wilms tumor. This study aims to determine the immunohistochemical expression of P53 protein and its predictors in formalin-fixed paraffin-embedded tissue blocks of patients with nephroblastoma. MATERIALS AND METHODS: A series of 83 histologically diagnosed cases of nephroblastoma from formalin-fixed paraffin-embedded tissue blocks archived at the Department of Pathology, Makerere University, in Kampala, Uganda, were analyzed. Monoclonal anti-p53 antibody (DO-7, DAKO) was used to assess the expression of P53 protein expression. Multivariable logistic regression analysis was performed to determine the predictors of P53 protein immunohistochemical expression, and statistical significance was considered when p-value was less than 0.05. RESULTS: Most (42.2%, n = 35) of the cases were in advanced tumor stages (III-V), and almost one-quarter (21.7%, n = 18) of the cases were in high-risk group. The immunohistochemical expression of P53 protein was (8.4%, n = 7), and there were more (83.3%, n = 5) positive anaplastic cases for P53 protein compared with (2.6%, n = 2) of P53 expression for non-anaplastic cases. High risk (AOR = 3.42, 95% CI = 7.91-12.55, p = 0.037) and anaplasia (AOR = 1.41, 95% CI = 13.85-4.46, p = 0.001) were potential predictors of immunohistochemical expression of P53 protein. CONCLUSION: Most of patients with nephroblastoma in resources-limited settings are diagnosed with advanced clinical stages. Association of P53 protein with anaplasia found in this study indicates the possibility of having novel target therapy for treatment of patients with anaplastic form of nephroblastoma with a focus of identifying molecules that lead to its suppression in such subpopulations of patients with nephroblastoma.
Assuntos
Neoplasias Renais , Tumor de Wilms , Humanos , Anaplasia , Formaldeído , Imuno-Histoquímica , Neoplasias Renais/diagnóstico , Neoplasias Renais/genética , Prognóstico , Proteína Supressora de Tumor p53/genética , Uganda , Tumor de Wilms/diagnóstico , Tumor de Wilms/genética , Tumor de Wilms/patologiaRESUMO
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.
Assuntos
Neoplasias Renais , Tumor de Wilms , Humanos , Neoplasias Renais/patologia , Anaplasia/genética , Estudos Retrospectivos , Filogenia , Tumor de Wilms/genética , Tumor de Wilms/patologiaRESUMO
Distant intercellular communication in gliomas is based on the expansion of tumor microtubuli, where actin forms cytoskeleton and GAP-43 mediates the axonal conus growth. We aimed to investigate the impact of GAP-43 and actin expression on overall survival (OS) as well as crucial prognostic factors. FFPE tissue of adult patients with diffuse and anaplastic gliomas, who underwent first surgery in our center between 2010 and 2019, were selected. GAP-43, Cx43 and actin expression was analyzed using immunohistochemistry and semi-quantitatively ranked. 118 patients with a median age of 46 years (IqR: 35-57) were evaluated. 48 (41%) presented with a diffuse glioma and 70 (59%) revealed anaplasia. Tumors with higher expression of GAP-43 (p = 0.024, HR = 1.71/rank) and actin (p < 0.001, HR = 2.28/rank) showed significantly reduced OS. IDH1 wildtype glioma demonstrated significantly more expression of all proteins: GAP-43 (p = 0.009), Cx43 (p = 0.003) and actin (p < 0.001). The same was confirmed for anaplasia (GAP-43 p = 0.028, actin p = 0.029), higher proliferation rate (GAP-43 p = 0.016, actin p = 0.038), contrast-enhancement in MRI (GAP-43 p = 0.023, actin p = 0.037) and age (GAP-43 p = 0.004, actin p < 0.001; Cx43 n.s. in all groups). The intercellular distant communication network in diffuse and anaplastic gliomas formed by actin and GAP-43 is associated with a negative impact on overall survival and with unfavorable prognostic features. Cx43 did not show relevant impact on OS.
Assuntos
Neoplasias Encefálicas , Glioma , Adulto , Humanos , Pessoa de Meia-Idade , Actinas/genética , Anaplasia , Neoplasias Encefálicas/patologia , Conexina 43/genética , Conexina 43/metabolismo , Proteína GAP-43 , Glioma/patologia , PrognósticoRESUMO
OBJECTIVE: The authors aimed to assess the frequency of homozygous CDKN2A deletion in isocitrate dehydrogenase (IDH)-mutant diffuse astrocytomas (grade 2/3) and to narrow down the clinicopathological indications in which the CDKN2A fluorescence in situ hybridization (FISH) assay is cost-effective in resource-constrained settings. METHODS: IDH-mutant astrocytomas were analyzed for ATRX, p53, MIB1-LI, and p16 expression using immunohistochemistry. The FISH assay was used to evaluate CDKN2A deletion and 1p/19q codeletion. Survival outcomes were assessed according to the different molecular markers. RESULTS: A total of 150 adult patients with IDH-mutant grade 2 (n = 95) and grade 3 (n = 55) astrocytomas (145 primary and 5 recurrent) were analyzed. Using a cutoff value of 30% for defining significant homozygous CDKN2A deletion, none of the grade 2 and 10.9% (6/55) of grade 3 astrocytomas showed this deletion (4 primary and 2 recurrent grade 3 tumors) and were reclassified as grade 4. This mutation was more frequent in recurrent (40%, 2/5) than primary (2.76%, 4/145) gliomas. Half (3/6, 50%) of the CDKN2A-deleted cases demonstrated poor outcomes; 2 of these cases experienced recurrence at 12 and 36 months after surgery, and 1 died at 5 months. The majority of CDKN2A-deleted cases showed marked cellularity (100%), pleomorphism (100%), brisk mitosis (83.3%), and tumor giant cell formation (83.4%). None of the cases with retained p16 expression harbored this deletion. Both overall survival (p = 0.039) and progression-free survival (p = 0.0045) were found to be worse in cases with p16 loss. Selectively performing CDKN2A FISH only in high-risk cases with histomorphological features of anaplasia, p16 loss, or recurrent tumors achieved a sensitivity and negative predictive value of 100%. This approach would have resulted in saving 41.1% of the original expenditure ($6900 US per 150 samples) and 27.6 person-minutes per sample without compromising the identification of deleted cases. CONCLUSIONS: Homozygous CDKN2A deletion is conspicuously absent in grade 2 and rare in primary grade 3 IDH-mutant astrocytomas. The authors propose that restricting use of the FISH assay to cases showing histomorphological features of anaplasia, p16 loss, or recurrent tumors will help this platform to be utilized in the most cost-effective manner in resource-constrained settings.
Assuntos
Astrocitoma , Glioma , Humanos , Anaplasia , Hibridização in Situ Fluorescente , Astrocitoma/genética , Intervalo Livre de Progressão , Inibidor p16 de Quinase Dependente de Ciclina/genéticaRESUMO
Background: Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children. Anaplasia is a rare phenomenon seen in childhood RMS. The most common histologic subtype was Embryonal followed by Alveolar and spindle subtype. Design: A total of 11 cases of pediatric RMS were selected from January 2017 to June 2019 presenting at various sites. Out of 11 cases, 2 were further diagnosed as Embryonal, 2 as Alveolar, 2 as Pleomorphic, 1 as Spindle subtype and rest 4 as RMS-NOS based on morphology. All cases were positive for Desmin. The presence of cells with lobated, hyperchromatic nuclei at least three times larger than the tumor cell (anaplastic cells) was selected as the main criterion to diagnose Anaplasia. Results: Out of the total 11 cases, anaplasia was seen in 7 cases. Out of these seven, five cases showed Focal Anaplasia (FA) (71.4%) and 2 cases showed Diffuse Anaplasia (DA) (28.6%). Out of 2 cases of Embryonal RMS one exhibited focal anaplasia (50%). One case of Spindle RMS showed diffuse anaplasia, 2 cases of pleomorphic RMS showed focal anaplasia. Out of 3 cases of RMS- NOS, 2 exhibited focal anaplaisa and one displayed Diffuse anaplasia. Both Alveolar RMS had no features of anaplasia. Conclusion: Presence of Anaplasia is a frequent observation in pediatric RMS. Anaplasia is often under reported in pediatric RMS. Pathologist should be more aware of this rare phenomenon.
Assuntos
Rabdomiossarcoma Alveolar , Rabdomiossarcoma , Sarcoma , Neoplasias de Tecidos Moles , Criança , Humanos , Anaplasia , Rabdomiossarcoma/diagnóstico , Rabdomiossarcoma/patologia , Sarcoma/patologia , Neoplasias de Tecidos Moles/patologia , Rabdomiossarcoma Alveolar/diagnóstico , Rabdomiossarcoma Alveolar/patologiaRESUMO
BACKGROUND: An objective of the Children's Oncology Group AREN0534 Study was to improve the survival of patients with bilateral Wilms tumors (BWT) by using preoperative chemotherapy of limited duration and tailoring postoperative therapy based on histopathologic response. The authors report outcomes based on postoperative histopathologic responses. METHODS: Patients with BWT received treatment with vincristine, dactinomycin, and doxorubicin for 6 or 12 weeks followed by surgery. Postoperative therapy was prescribed based on the highest risk tumor according to the International Society of Pediatric Oncology classification and the Children's Oncology Group staging system. RESULTS: Analyses were performed on data from 180 evaluable children. The 4-year event-free survival (EFS) and overall survival (OS) rates were 81% (95% CI, 74%-87%) and 95% (95% CI, 91%-99%), respectively. Seven patients who had completely necrotic tumors had a 4-year EFS rate of 100%. Of 118 patients who had tumors with intermediate-risk histopathology, the 4-year EFS and OS rates were 82% (95% CI, 74%-90%) and 97% (95% CI, 94%-100%), respectively. Fourteen patients who had blastemal-type tumors had 4-year EFS and OS rates of 79% (95% CI, 56%-100%) and 93% (95% CI, 79%-100%), respectively. Eighteen patients who had diffuse anaplasia had 4-year EFS and OS rates of 61% (95% CI, 35%-88%) and 72% (95% CI, 47%-97%), respectively; and the 4-year EFS and OS rates of 7 patients who had focal anaplasia were 71% (95% CI, 38%-100%) and 100%, respectively. There was no difference in the outcomes of patients who had different histopathologic subtypes within the intermediate-risk group (P = .54). CONCLUSIONS: A risk-adapted treatment approach for BWT results in excellent outcomes. This approach was not successful in improving the outcome of patients who had diffuse anaplasia.
Assuntos
Neoplasias Renais , Tumor de Wilms , Anaplasia/patologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Criança , Humanos , Lactente , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/patologia , Neoplasias Renais/cirurgia , Estadiamento de Neoplasias , Nefrectomia , Estudos Prospectivos , Vincristina , Tumor de Wilms/tratamento farmacológico , Tumor de Wilms/patologia , Tumor de Wilms/cirurgiaRESUMO
INTRODUCTION: The presence of tumor cell anaplasia and multinucleation (A/M) in oropharyngeal squamous cell carcinoma (OPSCC) has recently been found to be associated with increased disease recurrence and poorer disease-specific survival, regardless of human papillomavirus status. We studied the detection of A/M in cytology specimens. MATERIALS AND METHODS: We performed a comprehensive data search for all patients with OPSCC diagnosed and treated at Northwestern Memorial Hospital between January 2013 and April 2020. All cytology and histopathologic slides were reviewed for the presence of A/M in patients with both surgical resection or biopsy specimens and fine needle aspiration cytology of a metastatic site. RESULTS: A total of 87 patients were identified with both surgical and cytology specimens available for review. A/M was identified in 21 cytology specimens and 14 surgical specimens. Cytologic A/M was seen in 11 of the 14 patients (78.5%) with corresponding histologic A/M and in 10 of the 73 patients (13.7%) without histologic A/M. Disease-specific survival was significantly worse for the patients with cytologic A/M regardless of the presence of histologic A/M (P = 0.0064) and for the patients with cytologic A/M only (P = 0.0271). In patients with p16-positive/human papillomavirus-associated carcinoma, disease-specific survival was significantly worse for the patients with both histologic and cytologic A/M (P = 0.0305). CONCLUSIONS: A/M can be reliably identified in cytology specimens among all the various stains and preparations, irrespective of the primary tumor histologic type. Identification of A/M on cytology specimens could indicate more aggressive clinical behavior and help guide patient management.
Assuntos
Alphapapillomavirus , Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , Neoplasias Orofaríngeas , Infecções por Papillomavirus , Anaplasia/complicações , Carcinoma de Células Escamosas/patologia , Neoplasias de Cabeça e Pescoço/complicações , Humanos , Neoplasias Orofaríngeas/patologia , Papillomaviridae , Infecções por Papillomavirus/diagnóstico , Carcinoma de Células Escamosas de Cabeça e Pescoço/complicaçõesRESUMO
PURPOSE: We evaluated differentiations in gadolinium contrast enhancement (CE) between low-grade WHO °II and high-grade WHO °III gliomas in conventional MRI, which have been repeatedly questioned. METHODS: Ninety-nine patients, who underwent first resection of WHO°II and °III gliomas, were retrospectively retrieved from a prospective database. The quantitative metric volume of Gd-CE in T1-weighted pre-operative MRI was measured using volumetric segmentation. RESULTS: The OR to detect CE in anaplastic gliomas was seven times higher than that in diffuse gliomas (CI95% 2.8-17.2, p<0.0001). No CE was seen in 50% (8/16) of focal anaplastic and in 28% (10/36) of entirely anaplastic gliomas. CE was present in 21% (10/47) of diffuse gliomas. Anaplasia correlated with a larger CE volume (r=0.49, p<0.0001) and provided additional 4 cm3 of CE volume compared to entirely diffuse tumors. The OR to have CE was 3.6 times for IDH1 wild-type tumors (CI95% 1.3-10.2, p=0.05) and 4.8 for tumors with ATRX expression (CI95% 1.3-17.2, p=0.05). In all sub-groups, at least a quarter of cases showed no CE at all and there were cases with present CE. CONCLUSION: CE is associated with higher odds of unfavorable prognostic features like anaplasia, wild-type IDH1 and retained ATRX. There was no CE in one-fourth of anaplastic gliomas and half of gliomas with focal anaplasia.
Assuntos
Neoplasias Encefálicas , Glioma , Anaplasia , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/cirurgia , Glioma/patologia , Humanos , Isocitrato Desidrogenase/genética , Imageamento por Ressonância Magnética , Mutação , Estudos RetrospectivosRESUMO
The human grading system is currently applied to canine meningioma, although it has not been validated in dogs. The present study focused on standardising the human grading system applied to canine meningioma. Four veterinary neuropathologists graded 186 canine meningiomas as follows: Grade I tumour, with <4 mitoses/2.37 mm2 ; Grade II tumour, with ≥4 mitoses/2.37 mm2 , brain invasion or at least three of the following criteria: sheeting architecture, hypercellularity, small cells, macronucleoli, necrosis; Grade III tumour, with ≥20 mitoses/2.37 mm2 or anaplasia. Slides with grading disagreement were reviewed to define a consensus diagnosis and to assess reproducible criteria. Concordance between histologic grade and the consensus diagnosis, as well as intra- and inter-observer agreements for each criterion, were statistically analysed. Concordance between histologic grade and consensus diagnosis ranged from 59% to 100%, with lower concordance for Grade I and II tumours. The lowest inter-observer agreement was recorded for macronucleoli, small cells, hypercellularity and sheeting architecture. Tumour invasion and necrosis displayed fair agreement, while moderate agreement was reached for mitotic grade and anaplasia. The following recommendations were issued to improve the reproducibility of canine meningioma grading: (1) Assess mitotic grade in consecutive HPFs within the most mitotically active area; (2) Define invasion as neoplastic protrusions within central nervous tissue without pial lining; (3) Report spontaneous necrosis; (4) Report prominent nucleoli when visible at ×100; (5) Report pattern loss when visible at ×100 in >50% of the tumour; (6) Report necrosis, small cells, hypercellularity and macronucleoli, even when focal; (7) Report anaplasia if multifocal.
Assuntos
Doenças do Cão , Neoplasias Meníngeas , Meningioma , Anaplasia/veterinária , Animais , Doenças do Cão/diagnóstico , Doenças do Cão/patologia , Cães , Humanos , Neoplasias Meníngeas/diagnóstico , Neoplasias Meníngeas/patologia , Neoplasias Meníngeas/veterinária , Meningioma/diagnóstico , Meningioma/patologia , Meningioma/veterinária , Necrose/veterinária , Gradação de Tumores , Variações Dependentes do Observador , Reprodutibilidade dos TestesRESUMO
BACKGROUND: Wilms tumor is the most common childhood kidney cancer. Two distinct histological subtypes of Wilms tumor have been described: tumors lacking anaplasia (the favorable subtype) and tumors displaying anaplastic features (the unfavorable subtype). Children with favorable disease generally have a very good prognosis, whereas those with anaplasia are oftentimes refractory to standard treatments and suffer poor outcomes, leading to an unmet clinical need. MYCN dysregulation has been associated with a number of pediatric cancers including Wilms tumor. PROCEDURES: In this context, we undertook a functional genomics approach to uncover novel therapeutic strategies for those patients with anaplastic Wilms tumor. Genomic analysis and in vitro experimentation demonstrate that cell growth can be reduced by modulating MYCN overexpression via bromodomain 4 (BRD4) inhibition in both anaplastic and nonanaplastic Wilms tumor models. RESULTS: We observed a time-dependent reduction of MYCN and MYCC protein levels upon BRD4 inhibition in Wilms tumor cell lines, which led to cell death and proliferation suppression. BRD4 inhibition significantly reduced tumor volumes in Wilms tumor patient-derived xenograft (PDX) mouse models. CONCLUSIONS: We suggest that AZD5153, a novel dual-BRD4 inhibitor, can reduce MYCN levels in both anaplastic and nonanaplastic Wilms tumor cell lines, reduces tumor volume in Wilms tumor PDXs, and should be further explored for its therapeutic potential.
Assuntos
Neoplasias Renais , Tumor de Wilms , Anaplasia/genética , Animais , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Criança , Regulação para Baixo , Feminino , Humanos , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/genética , Neoplasias Renais/metabolismo , Masculino , Camundongos , Proteína Proto-Oncogênica N-Myc/genética , Proteínas Nucleares/genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Tumor de Wilms/tratamento farmacológico , Tumor de Wilms/genética , Tumor de Wilms/metabolismoRESUMO
We examined postoperative material from 28 patients aged 39-61 years with gliomas of different degrees of anaplasia (the diagnosis was histologically verified according to the WHO classification of CNS tumors) who had not previously received antitumor treatment. In glioma tissue, the glucose concentration was significantly higher than in the brain tissue of subjects dead from traumas (control), while lactate concentration did not differ from that in the control group or was lower. Hexokinase activity demonstrated a tendency to an increase in grade I and significant elevation in grades II and III, while in grade IV gliomas, this parameter did not differ from the control. Activities of the pentose-phosphate pathway enzymes glucose-6-phosphate dehydrogenase and transketolase increased with increasing of tumor anaplasia. Activity of glycogen synthase 3ß kinase was significantly higher than in the control group. IDH1 mutation was discovered in 40% cases, the MGMT promoter methylation was detected in more than 50%, the Ki-67 level increased with increasing tumor anaplasia. The most significant correlations with glioma markers were detected for glucose-6-phosphate dehydrogenase and glycogen synthase 3ß kinase. Activities of the studied enzymes of carbohydrate metabolism significantly correlated with Ki-67 marker.
Assuntos
Química Encefálica/fisiologia , Neoplasias Encefálicas/patologia , Glioma/genética , Glioma/patologia , Glucosefosfato Desidrogenase/metabolismo , Glicogênio Sintase Quinase 3 beta/metabolismo , Adulto , Anaplasia/patologia , Biomarcadores Tumorais/genética , Neoplasias Encefálicas/genética , Metabolismo dos Carboidratos/genética , Metabolismo dos Carboidratos/fisiologia , Metilação de DNA/genética , Metilases de Modificação do DNA/genética , Enzimas Reparadoras do DNA/genética , Glucose/análise , Hexoquinase/metabolismo , Humanos , Isocitrato Desidrogenase/genética , Ácido Láctico/análise , Pessoa de Meia-Idade , Regiões Promotoras Genéticas/genética , Transcetolase/metabolismo , Proteínas Supressoras de Tumor/genéticaRESUMO
We report a case of subependymal giant cell astrocytoma (SEGA) with anaplastic histological features in a 3-year-old girl. She had no clinical manifestations of tuberous sclerosis complex (TSC) and no relevant family history. A few cases have been reported in which patients with SEGA had no other clinical manifestations of TSC (solitary SEGA). Genetic analysis using a blood sample from the patient showed no germline alterations in TSC1 or TSC2 genes, while the tumor tissue exhibited loss of heterozygosity (LOH) in TSC2. SEGAs are benign, slowly growing tumors that rarely have significant mitotic activity. However, histopathological examination in the present case revealed high mitotic activity and necrosis besides the typical large plump cells arranged in sheets. This may be the first genetically proven case of a solitary SEGA with histopathological anaplastic features. In this report, we reviewed solitary SEGAs and histopathological malignancy in SEGA.