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EGFR aberrations are reported in a subset of myofibroblastic lesions with kinase domain duplication (EGFR-KDD) and exon 20 mutations being assigned to infantile fibrosarcomas (IFS), mesoblastic nephroma, and fibrous hamartoma of infancy (FHI), respectively. In this retrospective study, we correlated molecular findings with the histomorphology of 14 myofibroblastic lesions harboring such genetic changes identified by NGS. We additionally performed DNA methylation profiling (DNAmp) and immunohistochemistry. Lesions were from 10 males and 4 females with a mean age of 3 years (range, 0.3-14) and occurred subcutaneously in the upper limbs (n = 5), lower limbs (n = 3), back/thorax (n = 5), and the nasal cavity (n = 1). Eleven were cured by surgery, including 1 relapsed case. Two patients were lost to follow-up. One case was very recent, and the patient was biopsied. Histologically, the lesions showed a wide spectrum varying from classic FHI (n = 9) to IFS (n = 1) or lipofibromatosis-like tumors (LFT-like) (n = 2) or dermatofibrosarcoma protuberans-like (DFSP-like) (n = 1) to a predominantly myxoid spindle cell lesion (n = 1). Immunohistochemically, all neoplasms stained with CD34, whereas S100 was positive in 2/14. EGFR expression was observed in 9/10 cases. Molecularly, the IFS and 1 LFT-like harbored EGFR-KDD, whereas an exon 20 mutation was identified in all FHI, 1 LFT-like, the DFSP-like, and in predominant myxoid spindle cell lesion. By DNAmp, all but 2 cases formed a well-defined cluster, demonstrating that these lesions are also epigenetically related. In conclusion, EGFR kinase domain aberrations found in FHI, IFS, LFT-like, DFSP-like, and a spindle cell lesion with a predominant myxoid stroma of children and adolescents showed that these neoplasms with a broad morphologic spectrum belong to the group of protein kinase-related lesions with a distinct epigenetic signature. Molecular analyses, including DNAmp, help to identify and characterize this emerging category and become mandatory when targeted treatment is considered.
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INTRODUCTION: Patients affected by metastatic germ cell tumors may occasionally experience enlargement of masses with concurrent normalization of tumor markers during or after chemotherapy. This phenomenon is described as growing teratoma syndrome (GTS). The aim of the pre sent study is to assess the prevalence of GTS in the pediatric population and its implications in terms of surgical outcome. PATIENTS AND METHODS: The clinical notes of patients diagnosed with stage III and IV malignant germ cell tumors from January 2010 until December 2020 at our Institution were retrospectively reviewed. The prevalence of GTS, treatment strategies, survival, and outcome were analyzed. RESULTS: Thirty-three patients with high-stage malignant germ cell tumors were diagnosed in our institution in the analyzed period. Nine patients (28%) had radiologic evidence of enlargement of persistent masses with normal markers after chemotherapy; these patients were classified as GTS patients. All nine patients underwent resection of metastatic lymph nodes, and six had surgery on visceral metastases. In six patients, radical excision of all metastatic sites was achieved; five patients are alive and in complete remission, while one died because of peri-operative complications. Out of the three patients who could not achieve radical excision of the metastases, two died of progressive disease, and one is alive with progressive disease. CONCLUSIONS: Patients affected by GTS have a risk of progression of chemotherapy-resistant disease and death. Radical surgical excision is essential to achieve disease control and long-term survival.
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Teratoma , Humanos , Teratoma/cirurgia , Teratoma/patologia , Teratoma/epidemiologia , Teratoma/mortalidade , Teratoma/tratamento farmacológico , Masculino , Adolescente , Criança , Estudos Retrospectivos , Prevalência , Feminino , Prognóstico , Taxa de Sobrevida , Pré-Escolar , Seguimentos , Síndrome , Neoplasias Testiculares/cirurgia , Neoplasias Testiculares/patologia , Neoplasias Testiculares/epidemiologia , Neoplasias Testiculares/mortalidadeRESUMO
Background: Primary ciliary dyskinesia (PCD) is considered a rare cause of chronic rhinosinusitis with nasal polyposis (CRSwNP), which is reported in 6% of children with PCD. The forms of PCD associated with the variants of the GAS8 gene identified so far seem to be linked to recurrent respiratory infections (sinusitis, otitis, and bronchiectasis) without situs inversus. Case presentation: We report a case of an 11-year-old girl with recurrent otitis media, productive cough, and chronic rhinosinusitis with nasal polyposis with homozygosity for a novel nonsense mutation in the GAS8. Conclusion: Children with CRSwNP should be treated in a multidisciplinary manner (ENT, pulmonologist, allergist, pathologist, pediatrician, and geneticist) because nasal polyposis often hides etiologies that must be recognized.
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The prognosis of relapsed/refractory (R/R) neuroblastoma (NB) is dismal, calling for new therapeutic strategies. Venetoclax (VEN) is a highly selective, potent, orally bioavailable, BCL-2 inhibitor small-molecule that showed a synergistic effect with cyclophosphamide and topotecan (Cy-Topo) in murine NB models. Our aim was to evaluate the feasibility of VEN plus Cy-Topo in children with R/R NB. Four patients, who had previously failed > 3 lines of treatment, were treated with VEN plus Cy-Topo based on a 28-day schedule in an outpatient setting. BCL-2 expression in immunochemistry on tumor samples at relapse and the BCL2 gene status was evaluated in all patients. The main toxicity was hematological, with grade 4 neutropenia and thrombocytopenia occurring in all courses and leading to transient VEN discontinuation. Grade 3 oral mucositis was observed in 1/8 courses. No other grade 2-4 toxicities were observed. BCL-2 was expressed in all tumors, while no molecular abnormalities in the BCL-2 genes were detected. A stable disease was observed in all patients, without any progression during the study period. VEN plus Cy-Topo is well tolerated, with encouraging results that may be improved by testing the schedule in less advanced patients.
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Segunda Neoplasia Primária , Neuroblastoma , Criança , Humanos , Animais , Camundongos , Topotecan , Recidiva Local de Neoplasia/etiologia , Ciclofosfamida/uso terapêutico , Neuroblastoma/patologia , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Proteínas Proto-Oncogênicas c-bcl-2/genética , Segunda Neoplasia Primária/etiologia , Doença Crônica , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversosRESUMO
The increased availability of genetic technologies has significantly improved the detection of novel germline variants conferring a predisposition to tumor development in patients with malignant disease. The identification of variants of uncertain significance (VUS) represents a challenge for the clinician, leading to difficulties in decision-making regarding medical management, the surveillance program, and genetic counseling. Moreover, it can generate confusion and anxiety for patients and their family members. Herein, we report a 5-year-old girl carrying a VUS in the Succinate Dehydrogenase Complex Subunit C (SHDC) gene who had been previously treated for high-risk neuroblastoma and subsequently followed by the development of secondary acute myeloid leukemia. In this context, we describe how functional studies can provide additional insight on gene function determining whether the variant interferes with normal protein function or stability.
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Neuroblastic tumors (NTs) represent the most common extracranial neoplasm occurring in childhood. Although ganglioneuroblastoma intermixed (GNBI) and ganglioneuroma (GN) are classified as very low-risk tumors, neuroblastoma (NB) and ganglioneuroblastoma-nodular (GNBN) may represent a serious risk to survival. Unfortunately, areas of GNBI and GNBN can coexist in the same mass, leading to incorrect risk staging when only biopsy is performed. Herein, we describe a case of multifocal NT (thoracic and abdominal localization) occurring in a 4-year-old male. Different histological subtypes, namely GNBI and GNBN, were revealed in the two lesions. We focus on the difficulties of proper diagnosis and risk stratification, underlining the usefulness of several diagnostic tools for appropriate management and therapeutic choices.
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Uterine leiomyomas are rare in the pediatric population with less than 20 cases in adolescences reported in the literature. Furthermore, these masses represent a common presentation of gynecologic tumors with increasing age. We report a case of a 14-year-old female who presented with abdominal pain and increasing abdominal girth. Workup with ultrasound, CT and MRI demonstrated a large pelvic mass. Complete resection by median laparotomy was performed. The mass weighed 5,596â g and was 29.5â cm × 27â cm × 19â cm; the pathological examination confirmed the hypothesis of leiomyoma. The patient remained asymptomatic at 3 months follow up.
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Burkitt's lymphoma (BL) is defined as a highly invasive B-cell lymphoma, usually characterized by an excellent prognosis, more than 90% of children and adolescents being cured with highly dose-intensive multiagent chemotherapy. Primary ovarian localization without involvement of other organs is a rare manifestation of BL, especially in pediatric population. Symptoms at diagnosis are similar to other ovarian lesions and differential diagnosis may be challenging for clinicians. A 12-year-old girl was referred to our institution for abdominal pain and palpable mass observed by the pediatrician. Diagnostic work-up demonstrated a large mass arising from the right ovary, causing compression on abdominal aorta, inferior vena cava, ureters and bowel, with a second smaller lesion on the left ovary. At surgery, a 15â cm-large, ruptured mass arising from the right ovary was found, associated with a second lesion originating from the left ovary (8â cm) and multiple nodules of the greater omentum. Right salpingo-oophorectomy was performed, incisional biopsies were taken from the left ovary and omental nodules and peritoneal fluid samples were collected for cytology. Pathology revealed a Burkitt lymphoma and the patient underwent chemotherapy according to AIEOP LNH-97 Protocol, group R3 with Rituximab. Preoperative diagnosis of primary ovarian lymphoma is extremely difficult. Surgical exploration is often necessary in patients presenting with acute abdominal or pelvic pain; when the suspicion of primary ovarian lymphoma arises intraoperatively, every effort should be made to minimize invasive procedure in order to enhance post-operative recovery.
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The neonatal and paediatric spectrum of small bowel disorders encompass a wide variety of conditions, ranging from food allergies to life-threatening surgical emergencies or life-long medical conditions and, as such, it comes with a whole set of diagnostic challenges for the non-paediatric pathologist. Histologic examination is a cornerstone of diagnosis in a large number of diseases and may still provide important diagnostic clues in the appropriate clinical context. In this review, divided in two sections, we aim to provide a comprehensive histopathological summary of paediatric small bowel alteration and their differential diagnoses with a reference to the main clinical aspects required for appropriate interpretation. Specifically, in this first part, we describe congenital and metabolic disorders, intestinal lymphangiectasia, immunodeficiencies, GVHD, and necrotising enterocolitis.
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Enterocolite Necrosante , Criança , Duodeno , Humanos , Recém-Nascido , Intestino DelgadoRESUMO
In this paper, we will continue the description of histological findings of infantile and paediatric small bowel alterations with the main clinical pictures and differential diagnosis. We emphasise once again the need to evaluate the biopsies in an adequate clinical contest and with a systematic approach, including epithelial alterations, lamina propria changes, mucosal architecture, and the distribution of inflammation, together with other morphological signs more specific of certain diseases. We describe the histological findings of coeliac and Crohn's disease, gastrointestinal food allergic diseases, Langerhans cell histiocytosis, nutritional deficiencies and infections. Finally, we suggest the principal issues in the drafting the pathological report for appropriate interpretation and usefulness in clinical practice.
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Doença de Crohn , Mucosa Intestinal , Criança , Duodeno/patologia , Humanos , Inflamação/patologia , Mucosa Intestinal/patologia , Intestino Delgado/patologiaRESUMO
Background: Neuroblastoma is the most common solid extracranial tumor in children. Patients affected by neuroblastoma are stratified into low, intermediate, and high risk in terms of event-free and overall survival. Some high-risk patients have an additional risk of acute hemorrhagic complications during induction chemotherapy. Aim: To find easily and rapidly assessed parameters that help clinicians identify those patients affected by high-risk neuroblastoma who have an additional risk of hemorrhagic complications. Methods: The clinical notes of patients diagnosed with high-risk neuroblastoma from January 2013 until February 2021 were retrospectively reviewed. Clinical, demographic and laboratory data, biological characteristics of the tumor, and information about treatment and hospital stay were identified. Results: In the examined period, 44 patients were diagnosed with high-risk neuroblastoma. Four of these patients had hemorrhagic complications within 2-7 days after the initiation of induction chemotherapy; two patients had hemothorax, one patient had hemoperitoneum and one patient had hemothorax and hemoperitoneum. The patient with isolated hemoperitoneum was treated with blood components transfusions, clotting factors and colloids infusions; the three patients with hemothorax underwent thoracostomy tube placement and respiratory support. At initial presentation, patients who suffered from hemorrhagic complications had a higher degree of hypertension (stage 2, p = 0.0003), higher levels of LDH (median 3,745 U/L, p = 0.009) and lower levels of hemoglobin (mean 7.6 gr/dl, p = 0.0007) compared to other high-risk patients. Conclusions: A subgroup of "additional" high-risk patients can be identified within the high-risk neuroblastoma patients based on mean arterial pressure, LDH levels and hemoglobin levels at presentation. Further studies to define cut-off values and optimal management strategies for these patients are needed.
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INTRODUCTION: DICER1 syndrome is characterized by increased susceptibility to malignancies, mostly occurring in childhood. The range of phenotypic effects of DICER1 variants is under investigation, and the syndrome's phenotypic spectrum is steadily widening. We report on three Italian families showing heterogeneous clinical presentation and reduced penetrance in family members. CASE DESCRIPTIONS: Patient 1 is a 10-year-old girl with a Sertoli-Leydig cell tumor. Although family history was unremarkable, genetic testing identified a DICER1 germline variant, inherited from her healthy father. Benign thyroid nodules were subsequently diagnosed in both the proband and her father. Patient 2 is an 8-month-old boy with type 1 pleuropulmonary blastoma. His sister developed a nephroblastoma at age 2 years. A DICER1 novel variant was identified in both siblings and their healthy father. Patient 3 is a 22-year-old man who developed a spinal extramedullary intradural mass diagnosed as rhabdomyosarcoma with a peculiar tubular, gland-like component. Tumor testing revealed two pathogenic DICER1 variants, one of which was confirmed to be germline and identified in his 17-year-old healthy brother and in his father, who showed multiple thyroid nodules. CONCLUSIONS: Among our patients, three developed tumors most frequently associated with DICER1 syndrome (i.e. pleuropulmonary blastoma, nephroblastoma, and Sertoli-Leydig cell tumor). One developed a peculiar sarcoma of the spinal cord not previously described in DICER1 syndrome. Genetic testing in relatives highlighted the paternal origin and reduced penetrance in all families, with thyroid benign lesions as the most common features in otherwise unaffected individuals.
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Variação Biológica da População , RNA Helicases DEAD-box/genética , Variação Genética , Neoplasias/diagnóstico , Neoplasias/etiologia , Penetrância , Ribonuclease III/genética , Adolescente , Alelos , Criança , Terapia Combinada , Gerenciamento Clínico , Família , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Mutação em Linhagem Germinativa , Humanos , Masculino , Mutação , Neoplasias/terapia , Síndrome , Resultado do Tratamento , Adulto JovemRESUMO
Inflammatory myofibroblastic tumor (IMT) is a rare disease that mainly involves the lung and the abdomen with an intermediate clinical course but a recurrence rate between 15-30%. Radical surgery represents the gold standard of treatment, while chemotherapy and radiotherapy are considered for unresectable lesions. The identification of ALK translocations in IMT opened the option for the use of target therapies. Indeed, the ALK inhibitors have changed the treatment approach for aggressive lesions, improving the prognosis. Intraluminal upper-way IMT is extremely rare and represents a medical challenge. We reported an endotracheal IMT case presenting a previously unknown TRAF3-ALK fusion transcript.
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DICER1 syndrome is characterized by a unique combination of features and a growing list of associated rare tumors. Traditionally, gonadal or extra-gonadal teratomas have not been considered part of this spectrum, with only rare DICER1-related teratoid neoplasms recently reported. Besides, their methylation profiles remain elusive. We report two DICER1-associated malignancies involving the lumbar spine of a 22-year-old man (case 1) and the pelvic cavity of a 14-year-old girl (case 2). Both tumors exhibited teratoma-like features with a high-grade malignant somatic component, including rhabdomyosarcomatous elements for case 1 and a malignant neuroectodermal neoplasm with features of an embryonal tumor with multilayered rosettes (ETMR) for case 2. Both tumors showed strong SALL4 expression and H3K27me3 loss by immunohistochemistry. Next-generation sequencing studies confirmed biallelic DICER1 mutations with additional pathogenic missense mutations in KRAS (case 1) and CTNNB1 (case 2). The methylation profile of case 1 clustered with DICER1-associated sarcomas, whereas case 2 classified as an ETMR (albeit low raw and calibrated score). In conclusion, we report two DICER1-related malignancies with teratoma-like features, further expanding their morphologic spectrum and highlighting the multipotentiality of their presumed cell of origin. Notably, we describe the first ETMR identified outside the CNS with a documented DICER1 biallelic inactivation. Our findings also highlight the potential role of other molecular alterations such as KRAS and CTNNB1 mutations in defining the phenotype of embryonal and primitive DICER1-associated neoplasms, a notion that deserves further studies.
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Neoplasias Ósseas/diagnóstico , RNA Helicases DEAD-box/genética , Neoplasias Embrionárias de Células Germinativas/diagnóstico , Rabdomiossarcoma Embrionário/diagnóstico , Ribonuclease III/genética , Adolescente , Neoplasias Ósseas/genética , Neoplasias Ósseas/patologia , Metilação de DNA , Diagnóstico Diferencial , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Neoplasias Embrionárias de Células Germinativas/genética , Neoplasias Embrionárias de Células Germinativas/patologia , Rabdomiossarcoma Embrionário/genética , Rabdomiossarcoma Embrionário/patologia , Adulto JovemRESUMO
Malignant epithelioid soft tissue tumors encompass a wide spectrum of lesions. Among them, Epithelioid Malignant Peripheral Nerve Sheath Tumors (MPNST) constitute a distinct subgroup, accounting for <5% of all MPNST. Epithelioid MPNST are infrequently associated with neurofibromatosis type 1, occasionally arise in a schwannoma and show diffuse S100 and CD34 expression, often combined with INI-1 loss. However, the molecular mechanisms underlying the tumorigenesis of epithelioid MPNST remain largely unknown. We describe a case of a 10-year-old girl with an epithelioid malignancy of the orbit. The tumor proved positive for S100, CD34 and SOX10, and, although INI-1 expression was maintained, the overall features suggested the possibility of an epithelioid MPNST, arising in an unusual location. NGS analysis revealed a novel in-frame BRD4-LEUTX fusion gene. LEUTX plays an important role in embryonal genome activation and its expression is mostly suppressed postnatally. We were able to detect increased levels of LEUTX transcript in the tumor, indicating that BRD4-LEUTX fusion leads to LEUTX re-activation. To our knowledge, this fusion has never been reported previously. Whether the current case represents an example of epithelioid MPNST or a distinct tumor entity remains to be determined.
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Biomarcadores Tumorais/genética , Proteínas de Fusão Oncogênica/genética , Neoplasias Orbitárias/genética , Sarcoma/genética , Antígenos CD34/genética , Antígenos CD34/metabolismo , Biomarcadores Tumorais/metabolismo , Proteínas de Ciclo Celular/genética , Criança , Feminino , Proteínas de Homeodomínio/genética , Humanos , Neoplasias Orbitárias/patologia , Proteínas S100/genética , Proteínas S100/metabolismo , Proteína SMARCB1/genética , Proteína SMARCB1/metabolismo , Fatores de Transcrição SOXE/genética , Fatores de Transcrição SOXE/metabolismo , Sarcoma/patologia , Fatores de Transcrição/genéticaRESUMO
OBJECTIVES: Benign tumors with skeletal muscle differentiation are rare and their characterization in the literature is limited. We present a series of twelve pediatric benign tumors with rhabdomyomatous differentiation including seven rhabdomyomatous mesenchymal hamartomas, four fetal rhabdomyomas, and one benign triton tumor, analyzing myogenic markers as well as clinicopathologic and molecular features. A review of the literature was also performed with an emphasis on myogenic marker expression and correlation with molecular features. METHODS AND RESULTS: Cases obtained from three tertiary pediatric hospitals were retrospectively reviewed. Eleven of twelve cases expressed myogenin in rare to greater than 15% of cells. Five of nine cases had rare to 70-80% of cells positive for MyoD1. One fetal rhabdomyoma demonstrated homozygous deletions in ZEB2. The benign triton tumor harbored a CTNNB1 mutation. Review of the literature identified 160 pediatric benign tumors with skeletal muscle differentiation of which 9 reported myogenin positivity. CONCLUSIONS: Myogenin and MyoD1 may be variably expressed in benign lesions with skeletal muscle differentiation. Recognition of key morphologic features remains critical to diagnose these lesions and, in rhabdomyoma, to exclude malignancy. Our series expands the knowledge of the relationship between rhabdomyoma and rhabdomyosarcoma (RMS) by identifying a shared molecular alteration in ZEB2.
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Miogenina/metabolismo , Neoplasias de Tecido Muscular/patologia , Biomarcadores Tumorais/metabolismo , Criança , Pré-Escolar , Diagnóstico Diferencial , Feminino , Humanos , Lactente , MasculinoAssuntos
Neoplasias da Mama , Derrame Papilar , Pré-Escolar , Dilatação Patológica , Feminino , Humanos , MamilosRESUMO
INTRODUCTION: Osteoblastomas are primary bone tumors, rarer than osteoid osteomas, and <10% of these lesions occurs in the spine. Aneurysmal bone cysts (ABCs) are rare, benign lesion of the bone and approximately 8-30% of ABCs arise in the spine, mostly in the thoracic and the lumbar regions. The association between them is quite rare in the general population. CASE REPORT: We report a case of a 14-year-old boy, soccer player, with an osteoblastoma of the left posterior neural arc of L2 and a secondary aneurismal bone cyst compressing the left L2 nerve root, causing severe antalgic scoliosis and back pain with radiculopathy. A complete surgical excision with radicular decompression has been performed, and the histologic examination confirmed the diagnostic hypothesis (osteoblastoma + ABC). At 6 months follow-up, the patient presented a complete resolution of symptoms, but the trunk imbalance was not completely resolved. CONCLUSION: Spine localization of osteoblastoma + ABC is rare and its diagnosis and treatment are often challenging. Complete surgical excision seems to be confirmed as the gold standard of treatment, but the option of instrumented arthrodesis should be carefully evaluated.