RESUMEN
BACKGROUND: Intracranial germ cell tumors (IGCTs) are a rare group of malignancies that are clinically classified as germinomas and nongerminomatous germ cell tumors (NGGCTs). Previous studies have found that somatic mutations involving the mitogen-activated protein kinase/mTOR signaling pathway are common early events. However, a comprehensive genomic understanding of IGCTs is still lacking. METHODS: We established a cohort including over 100 IGCTs and conducted genomic and transcriptomic sequencing. RESULTS: We identified novel recurrent driver genomic aberrations, including USP28 truncation mutations and high-level copy number amplification of KRAS and CRKL caused by replication of extrachromosomal DNA. Three distinct subtypes associated with unique genomic and clinical profiles were identified with transcriptome analysis: Immune-hot, MYC/E2F, and SHH. Both immune-hot and MYC/E2F were predominantly identified in germinomas and shared similar mutations involving the RAS/MAPK signaling pathway. However, the immune-hot group showed an older disease onset age and a significant immune response. MYC/E2F was characterized by a younger disease onset age and increased genomic instability, with a higher proportion of tumors showing whole-genome doubling. Additionally, the SHH subtype was mostly identified in NGGCTs. CONCLUSIONS: Novel genomic aberrations and molecular subtypes were identified in IGCTs. These findings provide molecular basis for the potential introduction of new treatment strategies in this setting.
Asunto(s)
Neoplasias Encefálicas , Neoplasias de Células Germinales y Embrionarias , Humanos , Neoplasias de Células Germinales y Embrionarias/genética , Neoplasias de Células Germinales y Embrionarias/clasificación , Neoplasias de Células Germinales y Embrionarias/patología , Masculino , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/clasificación , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/terapia , Adulto , Femenino , Adolescente , Adulto Joven , Niño , Mutación , Biomarcadores de Tumor/genética , Persona de Mediana Edad , Pronóstico , Perfilación de la Expresión Génica , PreescolarRESUMEN
INTRODUCTION: This is the first German evidence- and consensus-based clinical guideline on diagnosis, treatment, and follow-up on germ cell tumours (GCTs) of the testis in adult patients. We present the guideline content in two publications. Part I covers the topic's background, methods, epidemiology, classification systems, diagnostics, prognosis, and treatment recommendations for the localized stages. METHODS: An interdisciplinary panel of 42 experts including 1 patient representative developed the guideline content. Clinical recommendations and statements were based on scientific evidence and expert consensus. For this purpose, evidence tables for several review questions, which were based on systematic literature searches (last search was in March 2018) were provided. Thirty-one experts entitled to vote, rated the final clinical recommendations and statements. RESULTS: We provide 161 clinical recommendations and statements. We present information on the quality of cancer care and epidemiology and give recommendations for staging and classification as well as for diagnostic procedures. The diagnostic recommendations encompass measures for assessing the primary tumour as well as procedures for the detection of metastases. One chapter addresses prognostic factors. In part I, we separately present the treatment recommendations for germ cell neoplasia in situ, and the organ-confined stages (clinical stage I) of both seminoma and nonseminoma. CONCLUSION: Although GCT is a rare tumour entity with excellent survival rates for the localized stages, its management requires an interdisciplinary approach, including several clinical experts. Quality of care is highly related to institutional expertise and can be reassured by established online-based second-opinion boards. There are very few studies on diagnostics with good level of evidence. Treatment of metastatic GCTs must be tailored to the risk according to the International Germ Cell Cancer Collaboration Group classification after careful diagnostic evaluation. An interdisciplinary approach as well as the referral of selected patients to centres with proven experience can help achieve favourable clinical outcomes.
Asunto(s)
Neoplasias de Células Germinales y Embrionarias , Neoplasias Testiculares , Adulto , Preservación de la Fertilidad , Humanos , Masculino , Estadificación de Neoplasias , Neoplasias de Células Germinales y Embrionarias/clasificación , Neoplasias de Células Germinales y Embrionarias/diagnóstico , Neoplasias de Células Germinales y Embrionarias/epidemiología , Neoplasias de Células Germinales y Embrionarias/terapia , Guías de Práctica Clínica como Asunto , Pronóstico , Neoplasias Testiculares/clasificación , Neoplasias Testiculares/diagnóstico , Neoplasias Testiculares/epidemiología , Neoplasias Testiculares/terapiaRESUMEN
Central nervous system tumors comprise 26% of cancer in children, representing the most frequent solid neoplasms. Embryonal tumors comprise 15% of them, and they are defined as "small round blue cells" in which morphology is reminiscent of the developing embryonic nervous system. They are the most common high-grade central nervous system neoplasms. Over the years, molecular research has been improving our knowledge concerning these neoplasms, stressing the need for tumor reclassification. Indeed, the revised 2016 fourth edition of the World Health Organization classification introduced genetic parameters in the classification. Specific molecular signatures allow a more accurate risk assessment, leading to proper therapeutic approach and potentially improved prognosis. Holding this new approach, medulloblastoma is noteworthy. The present classification combines the previous histologic classification with a new genetic definition in WNT-activated, sonic hedgehog-activated and non-WNT/non-sonic hedgehog. Molecular data are also a defining feature in the diagnosis of atypical teratoid/rhabdoid tumors and embryonal tumors with multilayered rosettes. However, there are still embryonal tumors that challenge the present World Health Organization classification, and new molecular data have been underlining the need for novel tumor entities. Likewise, recent research has been highlighting heterogeneity in recognized entities. How to translate these molecular developments into routine clinical practice is still a major challenge.
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Neoplasias del Sistema Nervioso Central/clasificación , Neoplasias de Células Germinales y Embrionarias/clasificación , Neoplasias del Sistema Nervioso Central/genética , Neoplasias del Sistema Nervioso Central/patología , Niño , Cromosomas Humanos Par 19 , Predisposición Genética a la Enfermedad , Humanos , MicroARNs/genética , Mutación , Neoplasias de Células Germinales y Embrionarias/genética , Neoplasias de Células Germinales y Embrionarias/patología , Organización Mundial de la SaludRESUMEN
Embryonal tumors of the pediatric central nervous system are challenging clinically and diagnostically. These tumors are aggressive, and patients often have poor outcomes even with intense therapy. Proper tumor classification is essential to patient care, and this process has undergone significant changes with the World Health Organization recommending histopathologic and molecular features be integrated in diagnostic reporting. This has especially impacted the workup of embryonal tumors because molecular testing has resulted in the identification of clinically relevant tumor subgroups and new entities. This review summarizes recent developments and provides a framework to workup embryonal tumors in diagnostic practice.
Asunto(s)
Neoplasias del Sistema Nervioso Central/diagnóstico , Neoplasias del Sistema Nervioso Central/patología , Neoplasias de Células Germinales y Embrionarias/diagnóstico , Neoplasias de Células Germinales y Embrionarias/patología , Biomarcadores de Tumor , Neoplasias del Sistema Nervioso Central/clasificación , Niño , Humanos , Meduloblastoma/clasificación , Meduloblastoma/diagnóstico , Meduloblastoma/patología , Neoplasias de Células Germinales y Embrionarias/clasificación , Tumor Rabdoide/clasificación , Tumor Rabdoide/diagnóstico , Tumor Rabdoide/patologíaRESUMEN
Aim: Characterize DNA methyltransferases/demethylases expression in testicular germ cell tumors (TGCTs). Methods:In silico analysis of TCGA database, assessment of transcript levels of most relevant enzymes in four TGCT cell lines and validation in patient cohort (real-time quantitative polymerase chain reaction; immunohistochemistry). Results:DNMT3A, DNMT3B and TET2 were the most differentially expressed between seminomas (SEs) and nonseminomas (NSs). DNMT3B was significantly overexpressed in NS-related cell lines, and the opposite was found for TET2. Significantly higher DNMT3A/B mRNA expression was observed in NS, indicating a role for de novo methylation in reprogramming. Significantly higher TET2 protein expression was observed in SEs, suggesting active demethylation contributes for SE hypomethylated state. More differentiated histologies disclosed distinct expression patterns. Conclusion: DNA-modifying enzymes are differentially expressed between TGCT subtypes, influencing reprogramming and differentiation.
Asunto(s)
ADN (Citosina-5-)-Metiltransferasas/metabolismo , Proteínas de Unión al ADN/metabolismo , Neoplasias de Células Germinales y Embrionarias/enzimología , Proteínas Proto-Oncogénicas/metabolismo , Neoplasias Testiculares/enzimología , Adolescente , Adulto , Línea Celular Tumoral , Simulación por Computador , ADN (Citosina-5-)-Metiltransferasas/genética , ADN Metiltransferasa 3A , Proteínas de Unión al ADN/genética , Dioxigenasas , Humanos , Masculino , Persona de Mediana Edad , Neoplasias de Células Germinales y Embrionarias/clasificación , Neoplasias de Células Germinales y Embrionarias/genética , Proteínas Proto-Oncogénicas/genética , ARN Mensajero/metabolismo , Neoplasias Testiculares/clasificación , Neoplasias Testiculares/genética , Adulto Joven , ADN Metiltransferasa 3BRESUMEN
Recent studies have revealed that feed-forward loops (FFLs) as regulatory motifs have synergistic roles in cellular systems and their disruption may cause diseases including cancer. FFLs may include two regulators such as transcription factors (TFs) and microRNAs (miRNAs). In this study, we extensively investigated TF and miRNA regulation pairs, their FFLs, and TF-miRNA mediated regulatory networks in two major types of testicular germ cell tumors (TGCT): seminoma (SE) and non-seminoma (NSE). Specifically, we identified differentially expressed mRNA genes and miRNAs in 103 tumors using the transcriptomic data from The Cancer Genome Atlas. Next, we determined significantly correlated TF-gene/miRNA and miRNA-gene/TF pairs with regulation direction. Subsequently, we determined 288 and 664 dysregulated TF-miRNA-gene FFLs in SE and NSE, respectively. By constructing dysregulated FFL networks, we found that many hub nodes (12 out of 30 for SE and 8 out of 32 for NSE) in the top ranked FFLs could predict subtype-classification (Random Forest classifier, average accuracy ≥90%). These hub molecules were validated by an independent dataset. Our network analysis pinpointed several SE-specific dysregulated miRNAs (miR-200c-3p, miR-25-3p, and miR-302a-3p) and genes (EPHA2, JUN, KLF4, PLXDC2, RND3, SPI1, and TIMP3) and NSE-specific dysregulated miRNAs (miR-367-3p, miR-519d-3p, and miR-96-5p) and genes (NR2F1 and NR2F2). This study is the first systematic investigation of TF and miRNA regulation and their co-regulation in two major TGCT subtypes.
Asunto(s)
Regulación Neoplásica de la Expresión Génica/genética , Redes Reguladoras de Genes/genética , MicroARNs/genética , Neoplasias de Células Germinales y Embrionarias/clasificación , Neoplasias de Células Germinales y Embrionarias/genética , Seminoma/clasificación , Seminoma/genética , Neoplasias Testiculares/clasificación , Neoplasias Testiculares/genética , Factores de Transcripción/genética , Humanos , Factor 4 Similar a Kruppel , MasculinoRESUMEN
The classification of ovarian germ cell tumours has remained unchanged for many years, while there have been considerable changes in the testicular classification. In recent years there has been concern about the overtreatment of clinical stage 1 testicular germ cell tumours with increasing use of surveillance for low-risk disease. We outline here the current classification of germ cell tumours of the ovary with particular regard to treatment and outcome and highlight some areas which may cause confusion, particularly pertaining to immature teratomas and mixed germ cell tumours. We suggest that some minor changes to the classification, evidenced by a recent retrospective series by some of the authors, may lead to less adjuvant chemotherapy for immature teratomas and may obviate the need for the grading of immature teratomas, by aligning with testicular experience in pure post-pubertal teratomas. Adoption of this will require retrospective and prospective re-evaluation, but may avoid long-term patient morbidity.
Asunto(s)
Neoplasias de Células Germinales y Embrionarias/clasificación , Neoplasias Ováricas/clasificación , Ovario/patología , Neoplasias Testiculares/clasificación , Testículo/patología , Femenino , Humanos , Masculino , Neoplasias de Células Germinales y Embrionarias/patología , Neoplasias Ováricas/patología , Neoplasias Testiculares/patologíaRESUMEN
BACKGROUND: The International Germ Cell Consensus Classification (IGCCC) is the recommended stratification scheme for newly diagnosed metastatic seminoma (mSGCT) and non-seminoma germ cell tumor (mNSGCT) patients. However, a contemporary North-American population-based validation has never been completed and represented our focus. MATERIALS AND METHODS: We identified mSGCT and mNSGCT patients within the SEER database (2004-2015). The IGCCC criteria were used for stratification into prognostic groups. Kaplan-Meier (KM) derived actuarial 5-year overall survival (OS) rates were calculated. In addition, cumulative incidence plots tested cancer-specific (CSM) and other-cause mortality (OCM) rates. RESULTS: Of 321 mSGCT patients, 190 (59.2%) and 131 (40.8%), respectively, fulfilled good and intermediate prognosis criteria. Of 803 mNSGCT patients, 209 (26.1%), 100 (12.4%), and 494 (61.5%), respectively, fulfilled good, intermediate, and poor prognosis criteria. In mSGCT patients, actuarial KM derived 5-year OS was 87% and 78% for, respectively, good and intermediate prognosis groups (p = 0.02). In cumulative incidence analyses, statistically significant differences were recorded for CSM but not for OCM between good versus intermediate prognosis groups. In mNSGCT patients, actuarial KM derived 5-year OS was 89%, 75% and 60% for, respectively, good, intermediate, and poor prognosis groups (p < 0.001). In cumulative incidence analyses, statistically significant differences were recorded for both CSM and OCM between good, intermediate, and poor prognosis groups. CONCLUSIONS: Our findings represent the first population-based validation of the IGCCC in contemporary North-American mSGCT and mNSGCT patients. The recorded OM rates closely replicate those of the original publication, except for better survival of poor prognosis mNSGCT patients.
Asunto(s)
Neoplasias de Células Germinales y Embrionarias/clasificación , Neoplasias de Células Germinales y Embrionarias/secundario , Seminoma/clasificación , Seminoma/secundario , Neoplasias Testiculares/patología , Adulto , Conferencias de Consenso como Asunto , Humanos , Cooperación Internacional , Masculino , Persona de Mediana Edad , Neoplasias de Células Germinales y Embrionarias/mortalidad , Pronóstico , Estudios Retrospectivos , Seminoma/mortalidad , Tasa de Supervivencia , Neoplasias Testiculares/clasificación , Neoplasias Testiculares/mortalidad , Neoplasias Testiculares/secundarioRESUMEN
This review describes the germ cell neoplasms that are malignant and most commonly associated with several types of gonadal dysgenesis. The most common neoplasm is gonadoblastoma, while others including dysgerminomas, yolk-sac tumors and teratomas are rare but can occur. The purpose of this review is to evaluate the incidences of these abnormalities and the circumstances surrounding these specific tumors.According to well-established methods, a PubMed systematic review was performed, to obtain relevant studies published in English and select those with the highest-quality data.Initially, the first search was performed using gonadal dysgenesis as the search term, resulting in 12,887 PubMed papers, published, from 1945 to 2017. A second search using ovarian germ cell tumors as the search term resulted in 10,473 papers, published from 1960 to 2017. Another search was performed in Medline, using germ cell neoplasia as the search term, and this search resulted in 7,560 papers that were published between 2003 to 2016, with 245 new papers assessing gonadoblastomas.The higher incidence of germ cell tumors in gonadal dysgenesis is associated with a chromosomal anomaly that leads to the absence of germ cells in these gonads and, consequently, a higher incidence of neoplasms when these tumors are located inside the abdomen. Several hypotheses suggest that increased incidence of germ cell tumors involves all or part of the Y chromosome or different genes.
Asunto(s)
Disgenesia Gonadal/genética , Neoplasias de Células Germinales y Embrionarias/clasificación , Femenino , Humanos , Incidencia , Masculino , Neoplasias de Células Germinales y Embrionarias/genética , Factores de RiesgoRESUMEN
Metastatic testicular germ cell tumors are rare entities with a high cure rate owing to their major chemosensitivity. Current guidelines should be strictly followed to ensure maximal cure rate. Germ cell tumor treatment requires multidisciplinary skills and is based on cisplatin-based chemotherapy. The current challenge for these patients with favorable prognosis is to limit over- or under-treatment. Centralization of care for patients with these rare cancers is a key point to achieve the best chance of cure.
Asunto(s)
Neoplasias de Células Germinales y Embrionarias/secundario , Neoplasias de Células Germinales y Embrionarias/terapia , Neoplasias Testiculares/secundario , Neoplasias Testiculares/terapia , Antineoplásicos/uso terapéutico , Cisplatino/uso terapéutico , Terapia Combinada/métodos , Humanos , Masculino , Neoplasias de Células Germinales y Embrionarias/clasificación , Neoplasias de Células Germinales y Embrionarias/patología , Orquiectomía , Pronóstico , Neoplasias Testiculares/clasificación , Neoplasias Testiculares/patologíaAsunto(s)
Neoplasias de Células Germinales y Embrionarias/patología , Neoplasias de Células Germinales y Embrionarias/terapia , Neoplasias Ováricas/patología , Neoplasias Ováricas/terapia , Terapia Combinada , Manejo de la Enfermedad , Femenino , Humanos , Neoplasias de Células Germinales y Embrionarias/clasificación , Neoplasias Ováricas/clasificación , PronósticoRESUMEN
In 2016, the WHO classification of testicular germ cell tumors was revised considering advances in the understanding of their tumorigenesis and molecular features. This restructuring led to a division into two major groups with, on one hand, prepubertal-type tumors, not derived from germ cell neoplasia in situ (GCNIS), and on the other hand, postpubertal-type tumors, GCNIS-derived, which occur in youg men (seminoma and non seminomatous germ cell tumors - embryonal carcinoma, yolk sac tumor, teratoma and choriocarcinoma essentially). The term germ cell neoplasia in situ is consensually accepted as a new terminology for the precursor lesion. In this new classification, the term "spermatocytic seminoma" is replaced by "spermatocytic tumor", reclassified among non-GCNIS-derived tumors. The purpose of this change of nomenclature is to reflect the usually non-aggressive behaviour of this tumor and to avoid any confusion with usual seminoma. The spectrum of trophoblastic tumors continues to expand with the description of new rare entities such as the cystic trophoblastic tumor, the placental site trophoblastic tumor and the epithelioid trophoblastic tumor. This review aims to provide a focus on testicular germ cell tumors highlighting the new immunohistochemical and molecular features responsible for the restructuring of classification. The TNM staging is presented according to the AJCC 8th edition 2017 update.
Asunto(s)
Neoplasias de Células Germinales y Embrionarias/genética , Neoplasias de Células Germinales y Embrionarias/patología , Neoplasias Testiculares/genética , Neoplasias Testiculares/patología , Factores de Edad , Carcinoma Embrionario/clasificación , Carcinoma Embrionario/genética , Carcinoma Embrionario/patología , Coriocarcinoma/clasificación , Coriocarcinoma/genética , Coriocarcinoma/patología , Coriocarcinoma no Gestacional/clasificación , Coriocarcinoma no Gestacional/genética , Coriocarcinoma no Gestacional/patología , Eliminación de Gen , Humanos , Inmunohistoquímica , Masculino , Mutación/genética , Neoplasias de Células Germinales y Embrionarias/clasificación , Seminoma/clasificación , Seminoma/genética , Seminoma/patología , Teratoma/clasificación , Teratoma/genética , Teratoma/patología , Terminología como Asunto , Neoplasias Testiculares/clasificaciónRESUMEN
Post-pubertal testicular germ-cell tumours (TGCTs) can present with a variety of distinct histologies which are nevertheless lineage related and often co-occurring. The exact lineage relationships and developmental pathways leading to the different histologies is debated. In order to investigate the relationship of histologic populations, mate-pair sequencing (MPseq) and exome sequencing (ExomeSeq) were conducted on different histological populations within the same tumour. Ten TGCTs with 1-3 histologic types/tumour were sequenced. Junctions of somatic chromosomal rearrangements were identified on a per genome basis, with germ cell neoplasia in situ possessing the least (median 1, range 0-4) and embryonal carcinoma the most (median 8.5, range 6-12). Copy number variation revealed gains and losses, including isoform 12p (i12p) (10/10 samples), and chromosomes 7, 8, and 21 gains (7/10 samples). Mapping of shared junctions within a tumour revealed lineage relationships, but only i12p was shared between patients. ExomeSeq from two cases demonstrated a high level of copy-neutral loss of heterozygosity. Parallel assessment of separate histologies within a single TGCT demonstrated cumulative and divergent changes, suggesting the importance of parallel sequencing for detection of relevant biomarkers.
Asunto(s)
Aberraciones Cromosómicas , ADN de Neoplasias/análisis , Variación Estructural del Genoma , Mutación , Proteínas de Neoplasias/genética , Neoplasias de Células Germinales y Embrionarias/clasificación , Neoplasias de Células Germinales y Embrionarias/genética , Neoplasias Testiculares/clasificación , Neoplasias Testiculares/genética , Adolescente , Adulto , ADN de Neoplasias/genética , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Persona de Mediana Edad , Neoplasias de Células Germinales y Embrionarias/patología , Neoplasias Testiculares/patología , Adulto JovenRESUMEN
Fundamento: el tumor de células germinales de mediastino anterior, es una formación de células neoplásicas localizada en mediastino. Se forman por defectos congénitos en la etapa embrionaria por migración de la célula germinal primordial y derivan de células que están dentro de las gónadas (germinales), pueden migrar y localizarse fuera de estas (extra gonadal) como el caso que se presentó, y situarse en mediastino anterior (seminoma). La localización más reportada de los extra gonadales es en mediastino anterior. Objetivo: describir un enfermo con tumor primario de células germinales del mediastino anterior. Caso clínico:paciente de 23 años de edad, masculino, con antecedentes de asma bronquial, acudió al cuerpo de guardia con tos seca y frecuente, pérdida de peso de 7 kg en un mes y fiebre de 38˚C hace dos días. Al examen físico, ligera palidez cutáneo mucosa, murmullo vesicular abolido en hemitórax derecho sin estertores. Después de estudios analíticos, radiografía de tórax, tomografía axial computarizada de pulmón y estudio histológico, se concluyó como neoplasia de células germinales primitiva extra gonadal de mediastino anterior. Conclusiones: la localización más frecuente de los tumores de células germinales de mediastino, extragonadal, es mediastino anterior. Son los tumores sólidos de mediastino más frecuentes en varones y afecta entre los 20 y 40 años de edad, hecho infrecuente en la práctica clínica(AU)
Background: the anterior mediastinal germ cell tumor is a formation of neoplastic cells located in the mediastinum. They are formed by congenital defects in the embryonic stage by migration of the primordial germ cell and dermal cells that are within the gonads (germinal), being able to migrate and localize outside of these (extra gonadal) as the case presented, and to be located in the anterior mediastinum (Seminoma). The most reported location of the extra gonadal is in the anterior mediastinum. Objective: to describe a patient with primary tumor of germ cell of the anterior mediastinum. Clinical case: a 23-year-old male patient with a history of bronchial asthma attended the emergency room with a dry, frequent cough, weight loss of 7 kg in one month and fever of 38˚C for 2 days. At physical examination, slight mucous skin pallor, vesicular murmur abolished in right hemi-thorax without rales. After analytical studies, chest x-ray, computerized lung tomography and histological study, it was concluded as primitive extra-gonadal germ cell neoplastic of anterior mediastinum. Conclusions:the most frequent location of mediastinal germ cell tumors, extra-gonadal, is anterior mediastinum. They are the most frequent mediastinal solid tumors in men and affect between 20 and 40 years of age; being the case that occupies a male patient of 23 years, uncommon in clinical practice(AU)
Asunto(s)
Humanos , Masculino , Adulto Joven , Neoplasias de Células Germinales y Embrionarias/clasificación , Neoplasias de Células Germinales y Embrionarias/diagnóstico , Neoplasias de Células Germinales y Embrionarias/epidemiología , Neoplasias del Mediastino , SeminomaRESUMEN
PURPOSE: To investigate whether the use of pre-orchiectomy instead of pre-chemotherapy tumor marker (TM) levels has an impact on the International Germ Cell Consensus Classification (IGCCCG) risk group assignment in patients with metastatic germ cell tumors (GCT). METHODS: Demographic and clinical information of all patients treated for primary metastatic testicular non-seminomatous GCT in our tertiary care academic center were extracted from medical charts. IGCCCG risk group assignment was correctly performed with pre-chemotherapy marker levels and additionally with pre-orchiectomy marker levels. Agreement between pre-chemotherapy and pre-orchiectomy risk group assignments was assessed using Cohen's kappa. RESULTS: Our cohort consisted of 83 patients. The use of pre-orchiectomy TMs resulted in an IGCCCG risk group upstaging in 12 patients (16%, 8 patients from good to intermediate risk and 4 patients from intermediate to poor risk) and a downstaging in 1 patient (1.2%, from intermediate- to good-risk). The agreement between pre-orchiectomy and pre-chemotherapy IGCCCG risk groups resulted in a Cohen's kappa of 0.888 (p < 0.001). CONCLUSIONS: Using pre-orchiectomy TMs can result in incorrect IGCCCG risk group assignment, which in turn can impact on the clinical management and follow-up of patients with metastatic GCT. Thus, adherence to the IGCCCG standard using pre-chemotherapy TMs levels is recommended.
Asunto(s)
Biomarcadores de Tumor/análisis , Neoplasias de Células Germinales y Embrionarias/clasificación , Neoplasias Testiculares/clasificación , Adulto , Antineoplásicos , Supervivencia sin Enfermedad , Humanos , Masculino , Neoplasias de Células Germinales y Embrionarias/patología , Neoplasias de Células Germinales y Embrionarias/terapia , Orquiectomía , Pronóstico , Neoplasias Testiculares/patología , Neoplasias Testiculares/terapiaRESUMEN
This review describes the germ cell neoplasms that are malignant and most commonly associated with several types of gonadal dysgenesis. The most common neoplasm is gonadoblastoma, while others including dysgerminomas, yolk-sac tumors and teratomas are rare but can occur. The purpose of this review is to evaluate the incidences of these abnormalities and the circumstances surrounding these specific tumors. According to well-established methods, a PubMed systematic review was performed, to obtain relevant studies published in English and select those with the highest-quality data. Initially, the first search was performed using gonadal dysgenesis as the search term, resulting in 12,887 PubMed papers, published, from 1945 to 2017. A second search using ovarian germ cell tumors as the search term resulted in 10,473 papers, published from 1960 to 2017. Another search was performed in Medline, using germ cell neoplasia as the search term, and this search resulted in 7,560 papers that were published between 2003 to 2016, with 245 new papers assessing gonadoblastomas. The higher incidence of germ cell tumors in gonadal dysgenesis is associated with a chromosomal anomaly that leads to the absence of germ cells in these gonads and, consequently, a higher incidence of neoplasms when these tumors are located inside the abdomen. Several hypotheses suggest that increased incidence of germ cell tumors involves all or part of the Y chromosome or different genes.
Asunto(s)
Humanos , Masculino , Femenino , Neoplasias de Células Germinales y Embrionarias/clasificación , Disgenesia Gonadal/genética , Incidencia , Factores de Riesgo , Neoplasias de Células Germinales y Embrionarias/genéticaRESUMEN
OBJECTIVE The authors analyzed the efficacy of intensive chemotherapy followed by reduced-dose and reduced-field irradiation for intracranial germ cell tumors (GCTs) and evaluated the long-term late effects caused by chemoradiotherapy (CRT). METHODS The authors performed a retrospective study. The subjects were 24 patients who received CRT between April 1994 and April 2015. After surgery, intensive chemotherapy followed by reduced-dose and reduced-field irradiation was administered. For those with pure germinoma, who comprised the "good prognosis" group, five courses of conventional-dose chemotherapy (CDC) were administered, and radiotherapy (24 Gy) was applied to the whole ventricle. For all others, defined as the "intermediate and poor prognosis" group, two or three courses of CDC and high-dose chemotherapy were administered with peripheral blood stem cell transplantation and radiotherapy (2430 Gy) applied to the whole ventricle or a larger field with or without local boost irradiation (20 Gy), which was applied as needed. RESULTS The median period of follow-up was 112.5 months (range 28261 months), and the 5-/10-year overall and progression-free survival rates were 100%/83.5% and 91.3%/86.5%, respectively. The 5-/10-year overall survival rates determined based on the histological subtypes were 100%/100% for pure germinoma and 93.8%/78.7% for others, respectively. The late toxicities were as follows: endocrine disorder (33% in pure germinoma, 56% in others), involuntary movements (17% in pure germinoma, 39% in others), ear and labyrinth disorders (17% in pure germinoma, 33% in others), and psychiatric disorders (0% in pure germinoma, 33% in others). Nineteen of 24 patients underwent MRI (T2*- or susceptibility-weighted imaging) after radiotherapy, and 16 (84%) of those 19 patients had microbleeds detected, while 2 (10.5%) had radiation-induced cavernous vascular malformations detected. CONCLUSIONS Intensive chemotherapy followed by reduced-dose and reduced-field irradiation for intracranial GCTs had the same outcome as that reported in the literature, but late adverse effects after treatment were observed. Almost all of the complications were relatively mild but had the potential to lead to psychiatric disorders and intracranial hemorrhaging. ABBREVIATIONS AFP = alpha-fetoprotein; CDC = conventional-dose chemotherapy; CMB = cerebral microbleed; CRT = chemoradiotherapy; CSI = craniospinal irradiation; EP = etoposide and cisplatin; GCT = germ cell tumor; HCG = human chorionic gonadotropin; HDC = high-dose chemotherapy; ICE = ifosfamide, cisplatin, and etoposide; NGGCT = nongerminomatous GCT; OS = overall survival; PBSCT = peripheral blood stem cell transplantation; PFS = progression-free survival; RICM = radiation-induced cavernous malformation; STGC = syncytiotrophoblastic giant cell; SWI = susceptibility-weighted imaging.
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Antineoplásicos/administración & dosificación , Neoplasias Encefálicas/terapia , Quimioradioterapia/métodos , Neoplasias de Células Germinales y Embrionarias/terapia , Dosificación Radioterapéutica , Adolescente , Adulto , Antineoplásicos/efectos adversos , Neoplasias Encefálicas/mortalidad , Neoplasias Encefálicas/patología , Hemorragia Cerebral/etiología , Quimioradioterapia/efectos adversos , Niño , Preescolar , Irradiación Craneana/efectos adversos , Irradiación Craneana/métodos , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Germinoma/mortalidad , Germinoma/patología , Germinoma/terapia , Trasplante de Células Madre Hematopoyéticas , Humanos , Lactante , Masculino , Neoplasias de Células Germinales y Embrionarias/clasificación , Neoplasias de Células Germinales y Embrionarias/mortalidad , Neoplasias de Células Germinales y Embrionarias/patología , Pronóstico , Supervivencia sin Progresión , Estudios Retrospectivos , Tasa de Supervivencia , Factores de Tiempo , Adulto JovenRESUMEN
The American Joint Committee for Cancer eighth edition staging manual incorporated several critical changes regarding staging of testis germ cell tumors, and these changes are summarized and discussed in this article. Further challenges, however, remain, and these are also highlighted.
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Neoplasias de Células Germinales y Embrionarias/patología , Neoplasias Testiculares/patología , Biomarcadores de Tumor/sangre , Humanos , Metástasis Linfática , Masculino , Invasividad Neoplásica , Metástasis de la Neoplasia , Estadificación de Neoplasias , Neoplasias de Células Germinales y Embrionarias/clasificación , Pronóstico , Medición de Riesgo , Neoplasias Testiculares/clasificación , Testículo/anatomía & histología , Testículo/patologíaRESUMEN
AIM: Assess differential patterns of selected five genes' promoter methylation among testicular germ cell tumors (TGCT) subtypes. MATERIALS & METHODS: CRIPTO, HOXA9, MGMT, RASSF1A and SCGB3A1 promoter methylation levels were evaluated by quantitative methylation-specific PCR in 161 TGCT and 16 controls. Associations between clinicopathological parameters and promoter methylation levels were assessed, and receiver operating characteristics curve analysis was performed. RESULTS: Promoter methylation of CRIPTO/HOXA9/SCGB3A1 panel and RASSF1A best discriminated between controls and nonseminomatous tumors or seminomas, respectively, whereas HOXA9/RASSF1A panel displayed the best discriminative performance between nonseminomatous tumor and seminomas. Significant differences in CRIPTO, MGMT and RASSF1A methylation levels were depicted between pure forms and matched mixed components of seminomas and embryonal carcinoma. HOXA9, RASSF1A and SCGB3A1 promoter methylation significantly associated with tumor stage. CONCLUSION: Different combinations of five genes' promoter methylation levels discriminate among TGCT subtypes. Methylation patterns may also assist in identification of more clinically aggressive tumors.
Asunto(s)
Metilación de ADN , Neoplasias de Células Germinales y Embrionarias/clasificación , Regiones Promotoras Genéticas/genética , Neoplasias Testiculares/clasificación , Adolescente , Adulto , Citocinas/genética , Metilasas de Modificación del ADN/genética , Enzimas Reparadoras del ADN/genética , Proteínas Ligadas a GPI/genética , Proteínas de Homeodominio/genética , Humanos , Péptidos y Proteínas de Señalización Intercelular/genética , Masculino , Persona de Mediana Edad , Proteínas de Neoplasias/genética , Neoplasias de Células Germinales y Embrionarias/diagnóstico , Neoplasias de Células Germinales y Embrionarias/genética , Neoplasias de Células Germinales y Embrionarias/patología , Portugal , Pronóstico , Curva ROC , Neoplasias Testiculares/diagnóstico , Neoplasias Testiculares/genética , Neoplasias Testiculares/patología , Proteínas Supresoras de Tumor/genética , Adulto JovenRESUMEN
Mucinous ovarian tumors (MOTs) morphologically and epidemiologically resemble mucinous cystic neoplasms (MCNs) of the pancreas, sharing a similar stroma and both occurring disproportionately among young females. Additionally, MOTs and MCNs share similar clinical characteristics and immunohistochemical phenotypes. Exome sequencing has revealed frequent recurrent mutations in KRAS and RNF43 in both MOTs and MCNs. The cell of origin for these tumors remains unclear, but MOTs sometimes arise in the context of mature cystic teratomas and other primordial germ cell (PGC) tumors. We undertook the present study to investigate whether non-teratoma-associated MOTs and MCNs share a common cell of origin. Comparisons of the gene expression profiles of MOTs [including both the mucinous borderline ovarian tumors (MBOTs) and invasive mucinous ovarian carcinomas (MOCs)], high-grade serous ovarian carcinomas, ovarian surface epithelium, Fallopian tube epithelium, normal pancreatic tissue, pancreatic duct adenocarcinomas, MCNs, and single-cell RNA-sequencing of PGCs revealed that both MOTs and MCNs are more closely related to PGCs than to either eutopic epithelial tumors or normal epithelia. We hypothesize that MCNs may arise from PGCs that stopped in the dorsal pancreas during their descent to the gonads during early human embryogenesis, while MOTs arise from PGCs in the ovary. Together, these data suggest a common pathway for the development of MCNs and MOTs, and suggest that these tumors may be more properly classified as germ cell tumor variants. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.