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2.
Neurosurg Focus ; 53(6): E17, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36455270

RESUMO

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/genética
3.
Indian J Pathol Microbiol ; 65(4): 864-868, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36308195

RESUMO

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/patologia
4.
J Am Soc Cytopathol ; 11(4): 201-209, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35474265

RESUMO

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/complicações
5.
Cancer ; 128(13): 2493-2503, 2022 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-35383900

RESUMO

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/cirurgia
6.
Vet Comp Oncol ; 20(2): 509-520, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35066998

RESUMO

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 Testes
7.
Acta Neurochir (Wien) ; 164(8): 2035-2040, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35018531

RESUMO

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 Retrospectivos
8.
Pediatr Blood Cancer ; 69(2): e29401, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34693628

RESUMO

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/metabolismo
9.
Bull Exp Biol Med ; 172(1): 63-66, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34791557

RESUMO

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/genética
10.
Childs Nerv Syst ; 37(4): 1357-1362, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-32725466

RESUMO

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.


Assuntos
Astrocitoma , Neoplasias Encefálicas , Esclerose Tuberosa , Anaplasia , Astrocitoma/diagnóstico por imagem , Astrocitoma/genética , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/genética , Pré-Escolar , Feminino , Humanos , Mutação , Esclerose Tuberosa/genética
11.
Eur J Cancer ; 143: 127-133, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33302115

RESUMO

BACKGROUND: Established prognostic indicators in rhabdomyosarcoma (RMS), the most common childhood soft tissue sarcoma, include several clinicopathologic features. Among pathologic features, anaplasia has been suggested as a potential prognostic indicator, but the clinical significance of anaplasia remains unclear. METHODS: Patients enrolled on one of five recent Children's Oncology Group clinical trials for RMS (D9602, n = 357; D9802, n = 80; D9803, n = 462; ARST0331, n = 335; and ARST0531, n = 414) with prospective central pathology review were included in this study. Clinicopathologic variables including demographic information, risk group, histologic subtype, and anaplasia were recorded along with overall survival (OS) and failure-free survival (FFS) with failure defined by recurrence, progression, or death. The log-rank test was used to compare OS and FFS. RESULTS: Anaplasia was more common in embryonal RMS (27% of all embryonal RMS) than other subtypes of RMS (11% for alveolar RMS, 7% for botryoid RMS, 11% for spindle cell RMS). On multivariate analyses, anaplasia was not an independent prognostic factor in RMS (OS:hazard ratio (HR) = 1.12, p = 0.43; FFS:HR = 1.07, p = 0.56) across all subtypes or within embryonal RMS only (OS:HR = 1.41, p = 0.078; FFS:HR = 1.25, p = 0.16). Among tumors with TP53 mutations, 69% had anaplasia, while only 24% of tumors with anaplasia had a tumoral TP53 mutation. CONCLUSIONS: Anaplasia is not an independent indicator of adverse outcomes in RMS. Emerging information on the prognostic significance of TP53 mutations raises the possibility that anaplasia may be a surrogate marker of TP53 mutations in some cases. Tumoral TP53 mutation status may be investigated as a prognostic indicator in future studies.


Assuntos
Anaplasia/etiologia , Rabdomiossarcoma/complicações , Anaplasia/patologia , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Prognóstico , Rabdomiossarcoma/mortalidade , Fatores de Risco , Análise de Sobrevida
12.
Cancer ; 127(4): 628-638, 2021 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-33146894

RESUMO

BACKGROUND: WAGR syndrome (Wilms tumor, aniridia, genitourinary anomalies, and range of developmental delays) is a rare contiguous gene deletion syndrome with a 45% to 60% risk of developing Wilms tumor (WT). Currently, surveillance and treatment recommendations are based on limited evidence. METHODS: Clinical characteristics, treatments, and outcomes were analyzed for patients with WAGR and WT/nephroblastomatosis who were identified through International Society of Pediatric Oncology Renal Tumor Study Group (SIOP-RTSG) registries and the SIOP-RTSG network (1989-2019). Events were defined as relapse, metachronous tumors, or death. RESULTS: Forty-three patients were identified. The median age at WT/nephroblastomatosis diagnosis was 22 months (range, 6-44 months). The overall stage was available for 40 patients, including 15 (37.5%) with bilateral disease and none with metastatic disease. Histology was available for 42 patients; 6 nephroblastomatosis without further WT and 36 WT, including 19 stromal WT (52.8%), 12 mixed WT (33.3%), 1 regressive WT (2.8%) and 2 other/indeterminable WT (5.6%). Blastemal type WT occurred in 2 patients (5.6%) after prolonged treatment for nephroblastomatosis; anaplasia was not reported. Nephrogenic rests were present in 78.9%. Among patients with WT, the 5-year event-free survival rate was 84.3% (95% confidence interval, 72.4%-98.1%), and the overall survival rate was 91.2% (95% confidence interval, 82.1%-100%). Events (n = 6) did not include relapse, but contralateral tumor development (n = 3) occurred up to 7 years after the initial diagnosis, and 3 deaths were related to hepatotoxicity (n = 2) and obstructive ileus (n = 1). CONCLUSIONS: Patients with WAGR have a high rate of bilateral disease and no metastatic or anaplastic tumors. Although they can be treated according to existing WT protocols, intensive monitoring of toxicity and surveillance of the remaining kidney(s) are advised. LAY SUMMARY: WAGR syndrome (Wilms tumor, aniridia, genitourinary anomalies, and range of developmental delays) is a rare genetic condition with an increased risk of developing Wilms tumor. In this study, 43 patients with WAGR and Wilms tumor (or Wilms tumor precursor lesions/nephroblastomatosis) were identified through the international registry of the International Society of Pediatric Oncology Renal Tumor Study Group (SIOP-RTSG) and the SIOP-RTSG network. In many patients (37.5%), both kidneys were affected. Disease spread to other organs (metastases) did not occur. Overall, this study demonstrates that patients with WAGR syndrome and Wilms tumor can be treated according to existing protocols. However, intensive monitoring of treatment complications and surveillance of the remaining kidney(s) are advised.


Assuntos
Rim/efeitos dos fármacos , Fígado/efeitos dos fármacos , Síndrome WAGR/tratamento farmacológico , Tumor de Wilms/tratamento farmacológico , Anaplasia/induzido quimicamente , Anaplasia/patologia , Protocolos Antineoplásicos , Pré-Escolar , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Feminino , Deleção de Genes , Humanos , Lactente , Rim/patologia , Fígado/patologia , Masculino , Intervalo Livre de Progressão , Fatores de Risco , Síndrome WAGR/complicações , Síndrome WAGR/genética , Síndrome WAGR/patologia , Tumor de Wilms/complicações , Tumor de Wilms/genética , Tumor de Wilms/patologia
14.
World Neurosurg ; 142: e133-e139, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32599198

RESUMO

BACKGROUND: Atypical and anaplastic meningiomas (AAMs) are rare and comprise approximately 5% of all meningiomas. Extracranial metastases in meningioma patients occur in 0.1% of all cases, but these lesions are difficult to treat and may be a poor prognostic factor. METHODS: We conducted a retrospective chart review between 1990 and 2016 of patients who had surgical resection of AAM. In a cohort of 149 patients, 6 had metastatic lesions that were histologically confirmed to be meningioma. We compared baseline characteristics between patients with and without metastasis and performed a multivariate Cox regression analysis to assess risk factors for the development of systemic metastasis. RESULTS: Six patients had histologically confirmed meningioma metastasis. We hypothesized that the presence of scalp invasion in patients could be a potential risk factor for the development of systemic meningioma metastasis. Nine out of the 149 patients without metastasis had scalp invasion, whereas 4 out of the 6 patients with metastasis had scalp invasion. Patients with metastasis had a median age of 62 ± 20. Patients without metastasis had a median age of 59 ± 15 years. Gender distribution was similar; approximately 50% of patients in each group were female. Eighty-five percent of patients with metastatic disease were white, and 65% of patients without metastatic disease were white. Among patients without metastatic disease, 77% had World Health Organization II tumors, whereas 50% of patients with metastatic disease had World Health Organization II tumors. In multivariate analysis including age, tumor grade, size, location, extent of resection, sex, and scalp invasion, the only significant predictor of systemic metastasis was scalp invasion (odds ratio = 39.67; 95% confidence interval = 3.74-421.12; P = 0.0023). Median overall survival (OS) with metastasis was 126 months, and median OS without metastasis was 158 months. Having metastatic disease was not significantly associated with worse OS (P = 0.33). CONCLUSIONS: Metastasis development from AAM is a rare but serious event. Because scalp invasion is a strongly associated predictive factor for development of systemic metastasis in patients with AAM, it is necessary to consider strategies to prevent and to be vigilant of the development of scalp invasion.


Assuntos
Neoplasias Meníngeas/patologia , Meningioma/patologia , Meningioma/secundário , Recidiva Local de Neoplasia/patologia , Couro Cabeludo/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Anaplasia , Feminino , Humanos , Masculino , Margens de Excisão , Neoplasias Meníngeas/cirurgia , Meningioma/cirurgia , Pessoa de Meia-Idade , Gradação de Tumores , Invasividade Neoplásica , Metástase Neoplásica , Recidiva Local de Neoplasia/cirurgia , Procedimentos Neurocirúrgicos , Razão de Chances , Radioterapia Adjuvante , Fatores de Risco , Taxa de Sobrevida
15.
Mod Pathol ; 33(7): 1298-1306, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32047229

RESUMO

We describe a morphologically distinct pattern of tumor infarction and associated sarcoma-like changes, mimicking focal anaplasia, in otherwise WHO grade I meningiomas. The described cases (n = 9) all demonstrated a discrete spindle-cell (pseudosarcomatous) component with brisk mitotic activity (12-14 mitoses/10 HPF), elevated Ki-67 (mean 75.5 ± 25.0%, quantified), absence of PR, SSTR2A, or EMA expression, and potential SMA expression (50%). Despite these high-grade features, all nine patients remained free of progression or recurrence post resection (follow-up mean: 49.8 months). In contrast, among a comparison (control) cohort of consecutive WHO grade II and III meningiomas (n = 16), as expected, progression rate was high (68.8%, P = 0.002, Fisher's exact, average time to progression = 25 months, follow-up mean: 39.8 months). While necrosis was a frequent feature among atypical/anaplastic meningiomas (12/16, 75%), and elevated mitoses and proliferative index were present consistent with histologic grade, a well-defined zonal pattern with pseudosarcomatous component was not present among these tumors. DNA methylation-based analysis readily distinguished meningiomas by copy number profiles and DNA-based methylation meningioma random forest classification analysis (meningioma v2.4 classifier developed at University of Heidelberg); all pseudosarcomatous cases analyzed (4/9) matched with high level calibrated classifier score to "MC benign-1", with isolated loss of chromosome 22q identified as the sole copy number alteration. In contrast, multiple chromosomal losses were detected among the comparison cohort and classifier results demonstrated good concordance with histologic grade. Our findings suggest that pseudosarcomatous alterations represent reactive changes to central meningioma infarction, rather than focal anaplasia, and further support the use of DNA methylation-based analysis as a useful adjunct for predicting meningioma behavior. These indolent tumors should be distinguished from their atypical and anaplastic counterparts.


Assuntos
Infarto/patologia , Neoplasias Meníngeas/patologia , Meningioma/patologia , Idoso , Anaplasia/patologia , Biomarcadores Tumorais/genética , Metilação de DNA , Feminino , Humanos , Masculino , Neoplasias Meníngeas/genética , Meningioma/genética , Pessoa de Meia-Idade
16.
Clin Transl Oncol ; 22(7): 1138-1145, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31732915

RESUMO

PURPOSE: N-myc downstream-regulated gene 2 (NDRG2) is down-regulated in grade-III meningioma [anaplastic meningioma (AM)] and associated with clinically aggressive behavior. Current therapies in the treatment of high-grade meningioma are lacking with limited success. This study aims to validate the effect of NDRG2-targeted therapy using structurally related bioactive triterpene compounds derived from the edible mushroom Ganoderma lucidum (ganoderic acid A:GA-A/ganoderic acid DM:GA-DM) in human AM in relevant pre-clinical models. METHODS: Tissue samples from the AM tumor regions of three human patients and control non-tumor samples were used to analyze the expression pattern of NDRG2. In vitro cell culture and in vivo cell-line-derived orthotopic xenograft animal models of AM were utilized to assess efficacy of treatment with GA-A/DM. RESULTS: Downregulation of NDRG2 expression was observed in surgically resected high-grade meningiomas compared to normal brain. These results prompt us to use NDRG2-targeting agents GA-A/DM. In vitro results showed that 72-h treatments of 25 µM GA-A/DM induced AM cell death, upregulate NDRG2 protein expression, downregulate NDRG2 promoter methylation in meningioma cells as compared to azacitidine and decitabine, the most commonly used demethylating agents. Our results also demonstrated that GA-A/DM does not have any detrimental effect on normal human neurons and arachnoid cells. GA-A/DM promoted apoptotic factors (Bax) while suppressing MMP-9, p-P13K, p-AKT, p-mTOR, and Wnt-2 protein expression. RNAi-mediated knockdown of NDRG2 protein expression increased tumor proliferation, while forced expression of wt-NDRG2 decreased proliferation in an in vitro model. Magnetic resonance (MR) imaging and Hematoxylin (H&E) staining demonstrated gross reduction of tumor volume in GA-A/DM treated mice at 5 weeks when compared with saline-treated orthotopic AM xenografted controls. There was an overall decrease in tumor cell proliferation with increased survival in GA-A/DM-treated animals. Enzyme assays showed that GA-A/DM did not negatively impact hepatic function. CONCLUSION: GA-A/DM may be a promising natural therapeutic reagent in the treatment of AM by suppressing growth via NDRG2 modulation and altering of intracellular signal pathways. We have shown it could potentially be an effective treatment for AM with decreased cellular proliferation in vitro, decreased tumor volume and increased survival in vivo.


Assuntos
Ácidos Heptanoicos/farmacologia , Lanosterol/análogos & derivados , Neoplasias Meníngeas/metabolismo , Meningioma/metabolismo , Triterpenos/farmacologia , Proteínas Supressoras de Tumor/efeitos dos fármacos , Idoso , Anaplasia , Animais , Antimetabólitos Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Azacitidina/farmacologia , Morte Celular/efeitos dos fármacos , Metilação de DNA/efeitos dos fármacos , Decitabina/farmacologia , Regulação para Baixo , Técnicas de Silenciamento de Genes , Humanos , Técnicas In Vitro , Lanosterol/farmacologia , Metaloproteinase 9 da Matriz/efeitos dos fármacos , Metaloproteinase 9 da Matriz/metabolismo , Neoplasias Meníngeas/patologia , Meningioma/patologia , Camundongos , Camundongos SCID , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Gradação de Tumores , Fosfatidilinositol 3-Quinases/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação , Regiões Promotoras Genéticas , Proteínas Proto-Oncogênicas c-akt/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Serina-Treonina Quinases TOR/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Proteína Wnt2/efeitos dos fármacos , Proteína Wnt2/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto , Proteína X Associada a bcl-2/efeitos dos fármacos , Proteína X Associada a bcl-2/metabolismo
17.
J Comp Pathol ; 172: 48-52, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31690414

RESUMO

We describe the clinical and histological characteristics of stromal-type nephroblastomas that developed in two hedgehogs (Atelerix albiventris). In case 1, the tumour was composed of a proliferation of anaplastic stromal cells with ductal structures resembling the epithelium of nephroblastoma. In case 2, spindle-shaped cells that were somewhat larger than nephroblasts were frequently seen surrounding the cell cluster, and there was proliferation of stromal cells with collagen fibres at the periphery. Immunohistochemically, the tumour cells labelled weakly to strongly for the nephroblast marker Wilms' tumour-1 and were positive for Ki67 with rates of 5% and 10% for cases 1 and 2, respectively. Based on the above, the diagnosis was of stromal-type nephroblastoma with anaplasia in case 1 and without anaplasia in case 2. Our findings suggest that stromal-type nephroblastomas arise in adult hedgehogs and are clinically benign, and that histological anaplasia does not affect the prognosis.


Assuntos
Ouriços , Neoplasias Renais/veterinária , Tumor de Wilms/veterinária , Anaplasia , Animais , Biomarcadores Tumorais/metabolismo , Feminino , Imuno-Histoquímica , Antígeno Ki-67/metabolismo , Rim/patologia , Neoplasias Renais/patologia , Masculino , Proteínas WT1/metabolismo , Tumor de Wilms/patologia
18.
World Neurosurg ; 132: 282-291, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31476452

RESUMO

OBJECTIVE: Atypical and anaplastic meningiomas, unlike their benign counterparts, are highly aggressive, locally destructive, and likely to recur after treatment. These diseases are difficult to definitively treat with traditional radiotherapy without injuring adjacent brain parenchyma. The physical properties of ion radiotherapy allows for treatment plans that avoid damaging critical neural structures. The objectives of this systematic review were to evaluate the use and efficacy of ion radiotherapy in the treatment of atypical and anaplastic meningiomas. METHODS: We performed a systematic review of the literature by querying the PubMed and Ovid databases to identify and examine literature addressing the efficacy of ion radiotherapy in maintaining long-term local tumor control for patients with atypical or anaplastic meningiomas. The outcome of interest was rate of local tumor control at 5 years after ion radiotherapy. RESULTS: Across the included studies, proton therapy delivered a mean local control rate of 59.62% after 5 years. Carbon ion radiotherapy studies showed local control rates of 95% and 63% at 2 years for grade II and III meningiomas, respectively. In contrast, carbon ion radiotherapy studies that failed to differentiate between atypical and anaplastic meningiomas produced a local control rate of 33% at 2 years. CONCLUSIONS: Proton and carbon ion radiotherapy maintain comparable rates of local control to conventional photon therapy and allow for more targeted treatment plans that may limit excess radiation damage. Although additional prospective trials are needed, ion therapy represents a burgeoning field in the treatment of atypical and anaplastic meningiomas.


Assuntos
Neoplasias Meníngeas/radioterapia , Meningioma/radioterapia , Terapia com Prótons , Anaplasia , Radioterapia com Íons Pesados , Humanos , Neoplasias Meníngeas/patologia , Meningioma/patologia
19.
Breast Cancer Res Treat ; 178(1): 207-219, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31364002

RESUMO

PURPOSE: Transforming growth factor beta (TGFß) has paradoxical effects in breast cancer (BC), inhibiting initial tumors while promoting aggressive ones. A polymorphism on TGFBR2 promoter region (G-875A, rs3087465) increases TGFß type II receptor expression and is protective against cancer. Previously, we have shown that TGFB1 variants have subtype-specific roles in BC. This work sought to investigate the association between TGFBR2 and susceptibility and clinicopathological features in BC subgroups. METHODS: TGFBR2 G-875A was analyzed through PCR-RFLP in 388 BC patients and 405 neoplasia-free women. Case-control analyses as well as interaction with TGFB1 haplotypes previously associated with BC were tested through age-adjusted logistic regression. Correlations between G-875A and clinicopathological parameters were assessed through Kendall's Tau-b test. All statistical tests were two-tailed (α = 0.05). RESULTS: TGFBR2 G-875A was protective against BC in additive, genotypic, and dominant models. In subgroup-stratified analyses, these effects were greater in hormonal receptor-positive and luminal-A tumors, but were not significant in other subgroups. Logistic models including TGFB1 variants showed that in luminal-A tumors, G-875A retained its significance while TGFB1 haplotype showed a trend towards significance; otherwise, in HER2+ tumors TGFB1 variants remained significant while TGFBR2 showed a trend for association. There was no interaction between these genes. In correlation analyses, G-875A positively correlated with histopathological grade in total sample, and a trend towards significance was observed in triple-negative BCs. CONCLUSION: These results indicate that G-875A is a protective factor against BC, especially from luminal-A subtype, but may promote anaplasia in established tumors, consistent with TGFß signaling roles in BC.


Assuntos
Neoplasias da Mama/genética , Polimorfismo de Nucleotídeo Único , Receptor do Fator de Crescimento Transformador beta Tipo II/genética , Fator de Crescimento Transformador beta1/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Anaplasia , Brasil , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Estudos de Casos e Controles , Feminino , Predisposição Genética para Doença , Haplótipos , Humanos , Modelos Logísticos , Pessoa de Meia-Idade , Regiões Promotoras Genéticas
20.
World Neurosurg ; 131: e321-e328, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31356972

RESUMO

BACKGROUND: Anaplastic meningiomas are rare tumors with a poor prognosis, even after complete surgical resection and radiotherapy. There has been limited evidence with respect to the clinical factors and their effects on the course of the disease. Various retrospective studies have not been able to provide clear evidence of standardized treatment, usually presenting contradictory results. The aim of this study was to evaluate the prognostic factors influencing the progression-free survival (PFS) and overall survival (OS) of anaplastic meningiomas, with a particular focus on the roles of the extent of resection and postoperative adjuvant radiotherapy. METHODS: Between October 2001 and March 2016, 36 patients with anaplastic meningiomas were treated in our Department of Neurosurgery, of whom 11 underwent gross total resection (GTR) and 18 subtotal resection. Twenty-one patients received postoperative adjuvant radiotherapy, and 8 were treated with surgery alone. GTR (Simpson grades I and II) was associated with significantly improved PFS (P = 0.01) and OS (P = 0.004). Furthermore, adjuvant radiotherapy showed an improvement in PFS (P = 0.01) but not in OS (P = 0.16). CONCLUSIONS: The extent of resection in anaplastic meningiomas is correlated with a better outcome. However, resection alone is not sufficient for the long-term control of anaplastic meningiomas. Adjuvant radiotherapy is an essential component in the adjuvant treatment of anaplastic meningiomas, including for patients undergoing GTR. Further investigations through which to improve adjuvant therapy options are necessary to improve meningioma therapy.


Assuntos
Neoplasias Meníngeas/terapia , Meningioma/terapia , Recidiva Local de Neoplasia/epidemiologia , Procedimentos Neurocirúrgicos , Idoso , Anaplasia , Terapia Combinada , Feminino , Humanos , Masculino , Neoplasias Meníngeas/patologia , Meningioma/patologia , Pessoa de Meia-Idade , Gradação de Tumores , Prognóstico , Intervalo Livre de Progressão , Modelos de Riscos Proporcionais , Radioterapia Adjuvante , Estudos Retrospectivos , Taxa de Sobrevida
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