RESUMO
Uterine inflammatory myofibroblastic tumors (IMTs) are rare mesenchymal neoplasms of uncertain malignant potential. Aside from the recently described risk stratification score, which has not been validated by other studies, and rare reports of aberrant p16 expression in malignant tumors, there are no criteria to reliably predict behavior. Herein, we evaluated the clinicopathologic features and p16 expression patterns in 30 IMTs, with genomic profiling performed in a subset (13 malignant, 3 benign). Fifteen patients had malignant IMTs, defined by extrauterine disease at diagnosis (n=5) or recurrence (n=10; median: 24 mo). Patients ranged from 8 to 65 (median: 51) years and tumors from 6 to 22 (median: 12.5) cm. In primary tumors (n=13), infiltrative borders were noted in 10, moderate/severe cytologic atypia in 9, tumor cell necrosis in 7, and lymphovascular invasion in 6, while mitoses ranged from 0 to 21 (median: 7) per 10 high-power fields. In contrast, 15 patients with benign IMTs ranged from 28 to 65 (median: 44) years, with follow-up of 18 to 114 (median: 41) months. Tumors ranged from 1.9 to 8.5 (median: 5.5) cm, 2 demonstrated infiltrative borders, and 1 had moderate cytologic atypia. No other high-risk histologic features were observed. Application of the previously described clinicopathologic risk stratification score in all primary IMTs with complete data (n=18) classified 8 as high-risk (all malignant), 8 as intermediate-risk (3 malignant, 5 benign), and 2 as low-risk (benign). p16 was aberrant in all malignant IMTs, with <1% expression noted in 10, overexpression (>90%) in 4, and subclonal loss in 1; all benign tumors had patchy staining (20% to 80%; median 50%). Molecular analysis detected CDKN2A deletions in 8 of 9 tumors with <1% p16 expression, while the other harbored a TERT promoter mutation. TERT promoter mutations were also identified in 2 of 3 IMTs with p16 overexpression. Neither of these alterations was detected in the 3 sequenced benign IMTs. Thus, we recommend performing p16 on all uterine IMTs, which, combined with the risk stratification score, is a promising and cost-effective tool for predicting CDKN2A status and outcome in these patients. It may be particularly useful for tumors with incomplete information for risk stratification (ie, morcellated tumors) and for further stratifying intermediate-risk IMTs when sequencing is unavailable.
Assuntos
Biomarcadores Tumorais , Inibidor p16 de Quinase Dependente de Ciclina , Neoplasias Uterinas , Humanos , Feminino , Neoplasias Uterinas/genética , Neoplasias Uterinas/patologia , Neoplasias Uterinas/química , Inibidor p16 de Quinase Dependente de Ciclina/análise , Inibidor p16 de Quinase Dependente de Ciclina/genética , Pessoa de Meia-Idade , Adulto , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/análise , Idoso , Adolescente , Adulto Jovem , Criança , Deleção de Genes , Neoplasias de Tecido Muscular/genética , Neoplasias de Tecido Muscular/patologia , Neoplasias de Tecido Muscular/química , Imuno-Histoquímica , Valor Preditivo dos Testes , Recidiva Local de Neoplasia , Carga Tumoral , Fatores de RiscoRESUMO
Ovarian steroid and Leydig cell tumors (SCT and LCT, respectively) are rare stromal tumors, with aggressive behavior described in approximately one third of SCTs. Previously reported features potentially predictive of malignancy include size ≥7 cm, gross hemorrhage, necrosis, grade 2 or 3 nuclear atypia, and mitoses ≥2/10 HPFs; however, no subsequent studies have corroborated these findings. Herein, we evaluated a series of 25 tumors (21 SCT, 4 LCT) to explore their clinicopathologic and molecular features. Patients ranged from 16 to 79 years (median: 53 y) and all tumors were FIGO stage I. Recurrences occurred in 3 patients, all of whom died from disease. At least 1 atypical feature was identified in 63% of SCT/LCT and included hemorrhage (n=9), grade 2 or 3 atypia (n=7), mitoses≥2/10 HPFs (n=7), size≥7.0 cm (n=6), and necrosis (n=2); only malignant SCTs demonstrated 4 or 5 atypical features. Next-generation sequencing revealed malignant SCTs were genomically unstable, with uncommon and nonrecurring gene-level alterations ( MDM2/CDK4 coamplification, ATRX rearrangement, BAP1 mutation). One SCT with limited follow-up harbored FH and TP53 mutations and occasional arm-level copy number alterations, while all other sequenced tumors (n=7) were genomically stable; 1 had a CTNNB1 mutation and another a CASP10 mutation. In summary, the presence of at least 1 atypical feature is common in SCT/LCT, but most patients demonstrate a benign clinical course. Genomic alterations are infrequent but occur in malignant SCTs as well as a subset of benign SCTs. Molecular analysis of additional malignant SCTs is necessary to identify recurring and/or potentially actionable targets.
Assuntos
Neoplasias Ovarianas , Tumores do Estroma Gonadal e dos Cordões Sexuais , Feminino , Humanos , Recidiva Local de Neoplasia , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Necrose , HemorragiaRESUMO
Subclonal loss of mismatch repair (MMR) proteins has been described in a small subset of endometrial carcinomas (ECs), but the genomic basis for this phenomenon has received limited attention. Herein, we retrospectively evaluated all ECs with MMR immunohistochemistry (n=285) for subclonal loss, and in those (n=6), performed a detailed clinicopathologic and genomic comparison of the MMR-deficient and MMR-proficient components. Three tumors were FIGO stage IA, and one each stage IB, II, and IIIC2. Patterns of subclonal loss were as follows: (1) 3 FIGO grade 1 endometrioid carcinomas with subclonal MLH1/PMS2, MLH1 promoter hypermethylation, and no MMR gene mutations; (2) POLE -mutated FIGO grade 3 endometrioid carcinoma with subclonal PMS2, and PMS2 and MSH6 mutations limited to the MMR-deficient component; (3) dedifferentiated carcinoma with subclonal MSH2/MSH6, as well as complete loss of MLH1/PMS2, MLH1 promoter hypermethylation, and PMS2 and MSH6 mutations in both components; (4) dedifferentiated carcinoma with subclonal MSH6, and somatic and germline MSH6 mutations in both components, but with a higher allele frequency in MMR-deficient foci. Recurrences occurred in 2 patients, one consisted of the MMR-proficient component from a FIGO 1 endometrioid carcinoma, while the other was from the MSH6 -mutated dedifferentiated endometrioid carcinoma. At the last follow-up (median: 44 mo), 4 patients were alive and disease-free and 2 were alive with disease. In summary, subclonal MMR loss reflects subclonal and often complex genomic and epigenetic alterations, which may have therapeutic implications and therefore must be reported when present. In addition, subclonal loss can occur in both POLE -mutated and Lynch syndrome-associated ECs.
Assuntos
Carcinoma Endometrioide , Neoplasias do Endométrio , Feminino , Humanos , Carcinoma Endometrioide/genética , Carcinoma Endometrioide/patologia , Endonuclease PMS2 de Reparo de Erro de Pareamento/genética , Endonuclease PMS2 de Reparo de Erro de Pareamento/metabolismo , Reparo de Erro de Pareamento de DNA/genética , Estudos Retrospectivos , Proteína 1 Homóloga a MutL/genética , Proteína 1 Homóloga a MutL/metabolismo , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/patologia , GenômicaRESUMO
A subset of renal cell carcinomas harbor gene fusions, and we report the first case of an EZR-ROS1 fusion in renal cell carcinoma. A 47-year-old female presented with hematuria and a mass involving the renal pelvis. Renal biopsy revealed a tumor with solid and tubular architecture that was diffusely positive for PAX8, CK7, and vimentin; retained expression of INI1; focally positive for P504S; and negative for GATA3 and TFE3. Partial nephrectomy was performed, and histologically, the tumor had solid and tubular architecture with mucin-like content within tubules. The nuclei corresponded to WHO/ISUP grade 2 and 3. The morphology was neither specific nor diagnostic, and a final diagnosis of unclassified renal cell carcinoma with solid and tubular architecture was rendered. Molecular sequencing revealed an EZR-ROS1 fusion: a fusion that has never been reported in renal cell carcinoma. Recognition of this fusion is of significance if the tumor becomes metastatic as treatment with crizotinib may be considered.
Assuntos
Carcinoma de Células Renais , Carcinoma de Células de Transição , Neoplasias Renais , Neoplasias da Bexiga Urinária , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/genética , Biomarcadores Tumorais/genética , Carcinoma de Células Renais/diagnóstico , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/metabolismo , Feminino , Fusão Gênica , Humanos , Neoplasias Renais/diagnóstico , Neoplasias Renais/genética , Neoplasias Renais/metabolismo , Pessoa de Meia-Idade , Proteínas Tirosina Quinases/genética , Proteínas Proto-Oncogênicas/genéticaRESUMO
BACKGROUND: Nucleophosmin 1 (NPM1) is one of the most commonly mutated genes in acute myeloid leukemia, with mutations observed in approximately 30% of all adult cases. The persistence of NPM1 mutations following chemotherapy is associated with a greater risk of relapse as well as a lower rate of survival, making NPM1 measurable residual disease (MRD) an informative clinical target. METHODS: Herein, we have developed a straightforward unique molecular identifier (UMI)-based amplicon next-generation sequencing method for the detection of NPM1-mutated MRD that addresses some of the limitations present in other assays. RESULTS: The NPM1 assay allowed for accurate counting of individual mutant and wild-type molecules down to 0.01% variant allelic frequency. In silico contamination experiments highlighted the ability of this UMI methodology to maximize specificity through dramatic reductions in sequencing/demultiplexing bleed-through error. CONCLUSION: Performance and clinical utility of the NPM1 MRD assay are established via both validation experiments and analyses of live performance over 1.5 years of routine clinical service.
Assuntos
Sequenciamento de Nucleotídeos em Larga Escala/métodos , Leucemia Mieloide Aguda/genética , Neoplasia Residual/diagnóstico , Proteínas Nucleares/genética , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/genética , Humanos , Leucemia Mieloide Aguda/diagnóstico , Limite de Detecção , Mutação , Neoplasia Residual/genética , Proteínas Nucleares/sangue , Nucleofosmina , Recidiva , Sensibilidade e Especificidade , Análise de Sequência de DNARESUMO
OBJECTIVE Renin-angiotensin system (RAS) genetic polymorphisms are thought to play a role in cerebral aneurysm formation and rupture. The Cerebral Aneurysm Renin-Angiotensin System (CARAS) study prospectively evaluated common RAS polymorphisms and their relation to aneurysmal subarachnoid hemorrhage (aSAH). METHODS The CARAS study prospectively enrolled aSAH patients and controls at 2 academic centers in the United States. A blood sample was obtained from all patients for genetic evaluation and measurement of plasma angiotensin-converting enzyme (ACE) concentration. Common RAS polymorphisms were detected using 5' exonuclease (TaqMan) genotyping assays and restriction fragment length polymorphism analysis. RESULTS Two hundred forty-eight patients were screened, and 149 aSAH patients and 50 controls were available for analysis. There was a recessive effect of the C allele of the angiotensinogen ( AGT) C/T single-nucleotide polymorphism (SNP) (OR 1.94, 95% CI 0.912-4.12, p = 0.0853) and a dominant effect of the G allele of the angiotensin II receptor Type 2 ( AT2) G/A SNP (OR 2.11, 95% CI 0.972-4.57, p = 0.0590) on aSAH that did not reach statistical significance after adjustment for potential confounders. The ACE level was significantly lower in aSAH patients with the II genotype (17.6 ± 8.0 U/L) as compared with the ID (22.5 ± 12.1 U/L) and DD genotypes (26.6 ± 14.2 U/L) (p = 0.0195). CONCLUSIONS The AGT C/T and AT2 G/A polymorphisms were not significantly associated with aSAH after controlling for potential confounders. However, a strong trend was identified for a dominant effect of the G allele of the AT2 G/A SNP. Downregulation of the local RAS may contribute to the formation of cerebral aneurysms and subsequent presentation with aSAH. Further studies are required to elucidate the relevant pathophysiology and its potential implication in treatment of patients with aSAH.
Assuntos
Angiotensinogênio/genética , Aneurisma Intracraniano/genética , Polimorfismo de Nucleotídeo Único , Receptor Tipo 2 de Angiotensina/genética , Sistema Renina-Angiotensina/genética , Hemorragia Subaracnóidea/genética , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Aneurisma Intracraniano/enzimologia , Aneurisma Intracraniano/etiologia , Masculino , Pessoa de Meia-Idade , Peptidil Dipeptidase A/genética , Peptidil Dipeptidase A/metabolismo , Estudos Prospectivos , Receptor Tipo 1 de Angiotensina/genética , Hemorragia Subaracnóidea/complicações , Hemorragia Subaracnóidea/enzimologiaRESUMO
OBJECTIVE Renin-angiotensin system (RAS) genetic polymorphisms are thought to play a role in cerebral aneurysm formation and rupture. The Cerebral Aneurysm Renin Angiotensin System (CARAS) study prospectively evaluated associations of common RAS polymorphisms and clinical course after aneurysmal subarachnoid hemorrhage (aSAH). METHODS The CARAS study prospectively enrolled aSAH patients at 2 academic centers in the United States. A blood sample was obtained from all patients for genetic evaluation and measurement of plasma angiotensin converting enzyme (ACE) concentration. Common RAS polymorphisms were detected using 5'exonuclease genotyping assays and pyrosequencing. Analysis of associations of RAS polymorphisms and clinical course after aSAH were performed. RESULTS A total of 166 patients were screened, and 149 aSAH patients were included for analysis. A recessive effect of allele I (insertion) of the ACE I/D (insertion/deletion) polymorphism was identified for Hunt and Hess grade in all patients (OR 2.76, 95% CI 1.17-6.50; p = 0.0206) with subsequent poor functional outcome. There was a similar effect on delayed cerebral ischemia (DCI) in patients 55 years or younger (OR 3.63, 95% CI 1.04-12.7; p = 0.0439). In patients older than 55 years, there was a recessive effect of allele A of the angiotensin II receptor Type 2 (AT2) A/C single nucleotide polymorphism (SNP) on DCI (OR 4.70, 95% CI 1.43-15.4; p = 0.0111). CONCLUSIONS Both the ACE I/D polymorphism and the AT2 A/C single nucleotide polymorphism were associated with an age-dependent risk of delayed cerebral ischemia, whereas only the ACE I/D polymorphism was associated with poor clinical grade at presentation. Further studies are required to elucidate the relevant pathophysiology and its potential implication in the treatment of patients with aSAH.