RESUMEN
Bietti crystalline dystrophy (BCD) is a rare heritable retinal disease characterized by crystal deposition primarily in the retina. It is associated with atrophy of the retinal pigment epithelium (RPE) and is caused by variants in CYP4V2 , which encodes a cytochrome P450 hemethiolate protein superfamily member. CYP4V2 is involved in the selective hydrolysis of saturated medium chain fatty acids, and patients with BCD demonstrate abnormalities in fatty acid metabolism, including abnormal lipid profiles and the accumulation of the pathogenic crystals within the RPE, which leads to the visual pathologies characteristic of BCD. However, the precise identity of the crystals is currently unknown, and BCD has no established extraocular manifestations. Here, we report granulomatous hepatitis associated with abundant diffuse crystalline clefts in the hepatic parenchyma in 3 patients with retinal dystrophy and dyslipidemia: 2 with pathogenic CYP4V2 variants and 1 patient with clinical ophthalmologic findings suggestive of BCD but without available genetic testing. The unique and striking histologic features unifying the liver biopsies in all 3 patients strongly support a process related to abnormal fatty acid metabolism underlying the genetic disease of BCD, expanding the spectrum of BCD and shedding light on the importance of CYP4V2 in systemic fatty acid metabolism.
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Distrofias Hereditarias de la Córnea , Familia 4 del Citocromo P450 , Ácidos Grasos , Humanos , Distrofias Hereditarias de la Córnea/genética , Distrofias Hereditarias de la Córnea/patología , Distrofias Hereditarias de la Córnea/metabolismo , Familia 4 del Citocromo P450/genética , Familia 4 del Citocromo P450/metabolismo , Femenino , Masculino , Ácidos Grasos/metabolismo , Persona de Mediana Edad , Enfermedades de la Retina/genética , Enfermedades de la Retina/patología , Adulto , Hígado/patología , Hepatopatías/patología , Hepatopatías/genética , Hepatopatías/metabolismo , Biopsia , Dislipidemias/genética , Dislipidemias/patologíaRESUMEN
CONTEXT.: Perivascular epithelioid cell tumors (PEComas) are rare mesenchymal tumors of uncertain histogenesis expressing smooth muscle and melanocytic markers. The clinicopathologic spectrum in young patients is not well documented. OBJECTIVE.: To describe a multi-institutional series of PEComas in children, adolescents, and young adults. DESIGN.: PEComas, not otherwise specified (NOS); angiomyolipomas (AMLs); lymphangioleiomyomatosis; and clear cell sugar tumors were retrospectively identified from 6 institutions and authors' files. RESULTS.: Seventy PEComas in 64 patients (median age, 15 years) were identified. They were more common in females (45 of 64 patients), occurring predominately in kidney (53 of 70), followed by liver (6 of 70). Thirty-four patients had confirmed tuberous sclerosis complex (TSC), 3 suspected TSC mosaicism, 2 Li-Fraumeni syndrome (LFS) and 1 neurofibromatosis type 1. Most common variants were classic (49 of 70) and epithelioid (8 of 70) AML. Among patients with AMLs, most (34 of 47) had TSC, and more TSC patients had multiple AMLs (15 of 36) than non-TSC patients (2 of 13). Two TSC patients developed malignant transformation of classic AMLs: 1 angiosarcomatous and 1 malignant epithelioid. Lymphangioleiomyomatosis (5 of 70) occurred in females only, usually in the TSC context (4 of 5). PEComas-NOS (6 of 70) occurred exclusively in non-TSC patients, 2 of whom had LFS (2 of 6). Three were malignant, 1 had uncertain malignant potential, and 2 were benign. All 4 PEComas-NOS in non-LFS patients had TFE3 rearrangements. CONCLUSIONS.: Compared to the general population, TSC was more prevalent in our cohort; PEComas-NOS showed more frequent TFE3 rearrangements and possible association with LFS. This series expands the spectrum of PEComas in young patients and demonstrates molecular features and germline contexts that set them apart from older patients.
RESUMEN
Perivascular epithelioid cell tumors (PEComas) are a heterogenous group of mesenchymal neoplasms with a mixed myomelanocytic immunophenotype. PEComa-family tumors include angiomyolipoma, lymphangioleiomyomatosis, and a large category of rare neoplasms throughout the body that are now classified under the umbrella term "PEComa." This review focuses on recent advances in the clinicopathological and molecular features of PEComas, with an emphasis on PEComas that originate in soft tissue.
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Neoplasias de los Tejidos Conjuntivo y Blando , Neoplasias de Células Epitelioides Perivasculares , Humanos , Biomarcadores de Tumor/genética , Neoplasias de Células Epitelioides Perivasculares/diagnóstico , Neoplasias de Células Epitelioides Perivasculares/genética , Neoplasias de Células Epitelioides Perivasculares/patologíaRESUMEN
We describe the first cases of pediatric melanoma with ALK fusion gene arising within giant congenital melanocytic nevi. Two newborn boys presented with large pigmented nodular plaques and numerous smaller satellite nevi. Additional expansile nodules developed within both nevi and invasive melanomas were diagnosed before 10 months of age in both boys. Oncogenic driver mutations in NRAS and BRAF were absent in both cases. Instead, oncogenic ZEB2::ALK fusion genes were identified in both the nevus and melanoma developing within the nevus. In both cases, tumors were noted by ultrasound in utero, demonstrated significant nodularity at birth, and progressed to melanoma in the first year of life suggesting that congenital nevi with ALK fusion genes may behave more aggressively than those with other mutations. As ALK kinase inhibitors are effective against a range of tumors with similar ALK fusion kinases, identifying ALK fusion genes in congenital melanocytic nevi may provide an opportunity for targeted therapy.
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Melanoma , Nevo de Células Epitelioides y Fusiformes , Nevo Pigmentado , Neoplasias Cutáneas , Niño , Humanos , Lactante , Recién Nacido , Masculino , Quinasa de Linfoma Anaplásico/genética , Fusión Génica/genética , Melanoma/genética , Melanoma/patología , Nevo Pigmentado/patología , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/patologíaRESUMEN
CONTEXT.: Pediatric soft tissue tumors are one of the areas of pediatric pathology that frequently generate consult requests. Evolving classification systems, ancillary testing methods, new treatment options, research enrollment opportunities, and tissue archival processes create additional complexity in handling these unique specimens. Pathologists are at the heart of this critical decision-making, balancing responsibilities to consider expediency, accessibility, and cost-effectiveness of ancillary testing during pathologic examination and reporting. OBJECTIVE.: To provide a practical approach to handling pediatric soft tissue tumor specimens, including volume considerations, immunohistochemical staining panel recommendations, genetic and molecular testing approaches, and other processes that impact the quality and efficiency of tumor tissue triage. DATA SOURCES.: The World Health Organization Classification of Soft Tissue and Bone Tumors, 5th edition, other recent literature investigating tissue handling, and the collective clinical experience of the group are used in this manuscript. CONCLUSIONS.: Pediatric soft tissue tumors can be difficult to diagnose, and evaluation can be improved by adopting a thoughtful, algorithmic approach to maximize available tissue and minimize time to diagnosis.
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Neoplasias Óseas , Sarcoma , Neoplasias de los Tejidos Blandos , Niño , Humanos , Medicina Molecular , Opinión Pública , Sarcoma/diagnóstico , Sarcoma/genética , Sarcoma/patología , Neoplasias de los Tejidos Blandos/diagnóstico , Neoplasias de los Tejidos Blandos/genética , Neoplasias de los Tejidos Blandos/patología , Neoplasias Óseas/diagnósticoRESUMEN
Molecular characterization of cell types using single-cell transcriptome sequencing is revolutionizing cell biology and enabling new insights into the physiology of human organs. We created a human reference atlas comprising nearly 500,000 cells from 24 different tissues and organs, many from the same donor. This atlas enabled molecular characterization of more than 400 cell types, their distribution across tissues, and tissue-specific variation in gene expression. Using multiple tissues from a single donor enabled identification of the clonal distribution of T cells between tissues, identification of the tissue-specific mutation rate in B cells, and analysis of the cell cycle state and proliferative potential of shared cell types across tissues. Cell type-specific RNA splicing was discovered and analyzed across tissues within an individual.
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Atlas como Asunto , Células , Especificidad de Órganos , Empalme del ARN , Análisis de la Célula Individual , Transcriptoma , Linfocitos B/metabolismo , Células/metabolismo , Humanos , Especificidad de Órganos/genética , Linfocitos T/metabolismoRESUMEN
Heterozygous loss-of-function variants in the suppressor of fused protein gene (SUFU) can result in Gorlin syndrome, which is characterized by an increased frequency of basal cell carcinoma, medulloblastoma, odontogenic keratocysts, as well as other tumors. We describe a case of a 5-month-old female who presented with multiple intra-abdominal leiomyomata and was found to have a likely pathogenic splice site variant in the SUFU gene. This is the first reported case of leiomyomatosis secondary to a pathogenic SUFU variant in an infant and may represent an early, atypical presentation of Gorlin syndrome.
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Síndrome del Nevo Basocelular , Neoplasias Cerebelosas , Leiomiomatosis , Meduloblastoma , Neoplasias Cerebelosas/patología , Femenino , Humanos , Lactante , Leiomiomatosis/complicaciones , Leiomiomatosis/genética , Meduloblastoma/patología , Proteínas Represoras/genéticaRESUMEN
AIMS: Recurrent alterations in receptor tyrosine kinase (RTK) and downstream effectors are described in infantile fibrosarcoma (IFS)/cellular congenital mesoblastic nephroma (cCMN) and a subset of spindle cell sarcomas, provisionally designated 'NTRK-rearranged' spindle cell neoplasms. These two groups of tumours demonstrate overlapping morphologies and harbour alterations in NTRK1/2/3, RET, MET, ABL1, ROS1, RAF1 and BRAF, although their relationship is not fully elucidated. We describe herein a cohort of paediatric tumours with clinicopathological features not typical for inflammatory myofibroblastic tumour, but rather with similarities to cCMN/IFS harbouring ALK fusions. METHODS AND RESULTS: Clinicopathological features were assessed and partner agnostic targeted RNA sequencing on clinically validated platforms were performed. Tumours occurred in patients aged from 2 to 10 years (median age 2 years) with a 2:2 male to female ratio and an average size of 8.4 cm. Two tumours arose in soft tissues and two in the kidney. Morphological features included spindle to ovoid cells arranged in long fascicles or haphazardly within a myxoid to collagenised stroma; a subset of cases had either dilated, ectatic vessels or focal perivascular hyalinosis. By immunohistochemistry, all cases tested showed cytoplasmic expression of anaplastic lymphoma kinase (ALK) and one case demonstrated co-expression of CD34 and S100. CONCLUSIONS: This series of ALK-rearranged IFS-like tumours expands the spectrum of targetable kinases altered in these tumours and reinforces the potential overlap between IFS/cCMN-like tumours and the provisional entity of 'NTRK-rearranged' spindle cell neoplasms.
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Quinasa de Linfoma Anaplásico/genética , Fibrosarcoma/genética , Reordenamiento Génico , Neoplasias Renales/genética , Sarcoma/genética , Neoplasias de los Tejidos Blandos/genética , Niño , Preescolar , Femenino , Humanos , MasculinoRESUMEN
OBJECTIVES: Drug reaction with eosinophilia and systemic symptoms (DRESS) is a severe, delayed hypersensitivity reaction (DHR). We observed DRESS to inhibitors of interleukin 1 (IL-1) or IL-6 in a small group of patients with Still's disease with atypical lung disease. We sought to characterise features of patients with Still's disease with DRESS compared with drug-tolerant Still's controls. We analysed human leucocyte antigen (HLA) alleles for association to inhibitor-related DHR, including in a small Kawasaki disease (KD) cohort. METHODS: In a case/control study, we collected a multicentre series of patients with Still's disease with features of inhibitor-related DRESS (n=66) and drug-tolerant Still's controls (n=65). We retrospectively analysed clinical data from all Still's subjects and typed 94/131 for HLA. European Still's-DRESS cases were ancestry matched to International Childhood Arthritis Genetics Consortium paediatric Still's cases (n=550) and compared for HLA allele frequencies. HLA association also was analysed using Still's-DRESS cases (n=64) compared with drug-tolerant Still's controls (n=30). KD subjects (n=19) were similarly studied. RESULTS: Still's-DRESS features included eosinophilia (89%), AST-ALT elevation (75%) and non-evanescent rash (95%; 88% involving face). Macrophage activation syndrome during treatment was frequent in Still's-DRESS (64%) versus drug-tolerant Still's (3%; p=1.2×10-14). We found striking enrichment for HLA-DRB1*15 haplotypes in Still's-DRESS cases versus INCHARGE Still's controls (p=7.5×10-13) and versus self-identified, ancestry-matched Still's controls (p=6.3×10-10). In the KD cohort, DRB1*15:01 was present only in those with suspected anakinra reactions. CONCLUSIONS: DRESS-type reactions occur among patients treated with IL-1/IL-6 inhibitors and strongly associate with common HLA-DRB1*15 haplotypes. Consideration of preprescription HLA typing and vigilance for serious reactions to these drugs are warranted.
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Antirreumáticos/efectos adversos , Cadenas HLA-DRB1/genética , Hipersensibilidad Tardía/genética , Enfermedad de Still del Adulto/tratamiento farmacológico , Enfermedad de Still del Adulto/genética , Adulto , Alelos , Estudios de Casos y Controles , Síndrome de Hipersensibilidad a Medicamentos/genética , Síndrome de Hipersensibilidad a Medicamentos/inmunología , Tolerancia a Medicamentos/genética , Femenino , Cadenas HLA-DRB1/inmunología , Haplotipos , Humanos , Hipersensibilidad Tardía/inmunología , Interleucina-1/antagonistas & inhibidores , Interleucina-6/antagonistas & inhibidores , Masculino , Síndrome Mucocutáneo Linfonodular/tratamiento farmacológico , Síndrome Mucocutáneo Linfonodular/genética , Estudios Retrospectivos , Enfermedad de Still del Adulto/inmunologíaRESUMEN
The extent splicing is regulated at single-cell resolution has remained controversial due to both available data and methods to interpret it. We apply the SpliZ, a new statistical approach, to detect cell-type-specific splicing in >110K cells from 12 human tissues. Using 10X Chromium data for discovery, 9.1% of genes with computable SpliZ scores are cell-type-specifically spliced, including ubiquitously expressed genes MYL6 and RPS24. These results are validated with RNA FISH, single-cell PCR, and Smart-seq2. SpliZ analysis reveals 170 genes with regulated splicing during human spermatogenesis, including examples conserved in mouse and mouse lemur. The SpliZ allows model-based identification of subpopulations indistinguishable based on gene expression, illustrated by subpopulation-specific splicing of classical monocytes involving an ultraconserved exon in SAT1. Together, this analysis of differential splicing across multiple organs establishes that splicing is regulated cell-type-specifically.
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Cheirogaleidae/genética , Ratones/genética , Empalme del ARN , Análisis de la Célula Individual , AnimalesRESUMEN
Arteriovenous malformations are a vascular anomaly typically present at birth, characterized by an abnormal connection between an artery and a vein (bypassing the capillaries). These high flow lesions can vary in size and location. Therapeutic approaches are limited, and AVMs can cause significant morbidity and mortality. Here, we describe our current understanding of the pathogenesis of arteriovenous malformations based on preclinical and clinical findings. We discuss past and present accomplishments and challenges in the field and identify research gaps that need to be filled for the successful development of therapeutic strategies in the future.
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Malformaciones Arteriovenosas/genética , Animales , Arterias/patología , Malformaciones Arteriovenosas/diagnóstico por imagen , Malformaciones Arteriovenosas/patología , Malformaciones Arteriovenosas/terapia , Modelos Animales de Enfermedad , Humanos , Terapia Molecular Dirigida , Receptor Cross-Talk , Venas/patologíaRESUMEN
Sclerosing epithelioid fibrosarcoma (SEF) is a rare variant of fibrosarcoma primarily arising in the deep soft tissue of the extremities and trunk. Despite having the morphologic appearance of a low-grade sarcoma, it generally has an aggressive clinical course with frequent local recurrences and distant metastases. It typically occurs in middle aged adults and is characterized by immunoexpression of MUC4 and recurrent gene fusions, most commonly EWSR1-CREB3L1. We report a primary renal SEF in a 4-year-old male. To our knowledge, this is the youngest patient reported with SEF and the second case of SEF in a pre-adolescent child. It is the eleventh reported case of primary renal SEF in the literature. While SEF arising in visceral organs is rare, the kidney is the most common primary site of any visceral organ. This case demonstrates SEF can occur in pre-adolescents, is an important consideration when evaluating sarcomas in young children, and should be considered in the differential diagnosis for primary renal tumors.
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Fibrosarcoma/diagnóstico , Neoplasias Renales/diagnóstico , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Preescolar , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/genética , Fibrosarcoma/genética , Fibrosarcoma/metabolismo , Fibrosarcoma/patología , Fusión Génica , Humanos , Neoplasias Renales/genética , Neoplasias Renales/metabolismo , Neoplasias Renales/patología , Masculino , Mucina 4/metabolismo , Proteínas del Tejido Nervioso/genética , Proteína EWS de Unión a ARN/genéticaRESUMEN
In the mammalian lung, an apparently homogenous mesh of capillary vessels surrounds each alveolus, forming the vast respiratory surface across which oxygen transfers to the blood1. Here we use single-cell analysis to elucidate the cell types, development, renewal and evolution of the alveolar capillary endothelium. We show that alveolar capillaries are mosaics; similar to the epithelium that lines the alveolus, the alveolar endothelium is made up of two intermingled cell types, with complex 'Swiss-cheese'-like morphologies and distinct functions. The first cell type, which we term the 'aerocyte', is specialized for gas exchange and the trafficking of leukocytes, and is unique to the lung. The other cell type, termed gCap ('general' capillary), is specialized to regulate vasomotor tone, and functions as a stem/progenitor cell in capillary homeostasis and repair. The two cell types develop from bipotent progenitors, mature gradually and are affected differently in disease and during ageing. This cell-type specialization is conserved between mouse and human lungs but is not found in alligator or turtle lungs, suggesting it arose during the evolution of the mammalian lung. The discovery of cell type specialization in alveolar capillaries transforms our understanding of the structure, function, regulation and maintenance of the air-blood barrier and gas exchange in health, disease and evolution.
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Capilares/citología , Alveolos Pulmonares/irrigación sanguínea , Alveolos Pulmonares/citología , Intercambio Gaseoso Pulmonar , Envejecimiento , Caimanes y Cocodrilos/anatomía & histología , Animales , Evolución Biológica , Capilares/metabolismo , División Celular , Autorrenovación de las Células , Senescencia Celular , Humanos , Masculino , Ratones , Alveolos Pulmonares/metabolismo , Células Madre/clasificación , Células Madre/citología , Tortugas/anatomía & histologíaRESUMEN
BACKGROUND: Pathologic examination of conduction system (CS) is not routinely performed, and histologic changes are mostly reported in forensic practice. METHODS: We studied the value of dissecting the CS in a cohort of pediatric patients with unexplained sudden death or severe, inexplicable arrhythmias. Histopathologic changes present in CS components were recorded and correlated with findings noted in other cardiac structures. RESULTS: Twenty-one subjects (11 unexplained sudden deaths and 10 life-threatening arrhythmias) were identified; 18 (86%) had CS pathologic abnormalities. In 13 patients (62%), the CS findings mirrored those found in other cardiac sections (inflammation, allograft vasculopathy, vascular fibromuscular dysplasia, cardiomyopathy-related changes, and tumor/tumor-like conditions). Five cases (24%) had abnormalities restricted to CS (bundle of His [BH] with fibrotic scar and patch material following ventricular septal defect repair, inflammation, BH with fibrosis and calcifications, and intimal fibroplasia of sinoatrial node artery). CONCLUSIONS: Pathologic changes within the CS are present in a high number of pediatric patients presenting with unexplained sudden death or life-threatening arrhythmias. Frequently, the findings mirror those observed in other cardiac structures. However, in a significant number of cases (24%), the changes are restricted to CS and likely explain the patients' symptoms or cause of death, suggesting that systematic dissection of CS unveils valuable information.
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Arritmias Cardíacas/patología , Causas de Muerte , Muerte Súbita Cardíaca/patología , Sistema de Conducción Cardíaco/patología , Adolescente , Arritmias Cardíacas/mortalidad , Niño , Preescolar , Estudios de Cohortes , Muerte Súbita Cardíaca/etiología , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Adulto JovenAsunto(s)
Esófago de Barrett , Niño , Unión Esofagogástrica , Estudios de Seguimiento , Humanos , MetaplasiaRESUMEN
OBJECTIVES: Barrett esophagus (BE) and intestinal metaplasia of gastroesophageal junction (IMGEJ) are rare in the pediatric population. This multi-institutional retrospective study evaluated the clinicopathologic characteristics and natural history of BE and IMGEJ in children. METHODS: Data from 20 BE patients (70% boys, mean age: 14.9 years) and 17 IMGEJ patients (71% boys, mean age: 14 years) were retrospectively obtained from chart review. Endoscopic and pathologic findings from index and follow-up endoscopies were analyzed. RESULTS: Most patients (70% BE and 59% IMGEJ) had underlying conditions which put them at risk for gastroesophageal reflux disease. Increased body mass index (BMI) was observed in patients without underlying conditions (BE: 30.1â±â9.8; IMGEJ: 23.9â±â6.3) compared with those with underlying conditions (BE: 19.6â±â7.8; IMGEJ: 16.4â±â2.1) (BE, Pâ=â0.02; IMGEJ, Pâ=â0.01). Incomplete intestinal metaplasia (IM) was the predominant histology seen in BE (80%) and IMGEJ patients (75%). Dysplasia and malignancy were not identified in the initial and follow-up biopsies. Concurrent gastric biopsies showed various findings (79% BE and 40% IMGEJ were normal), with 1 IMGEJ patient showing coexisting gastric IM (7%). Follow-up in 12 BE patients (mean follow-up time 51.6 months) showed 100% persistent endoscopic disease and 58% persistent IM histologically. Three of 6 IMGEJ patients (mean follow-up time 24 months) demonstrated endoscopic and histologic features consistent with BE on subsequent procedures. Moreover, a subset of BE (57%) and IMGEJ patients (67%) who underwent endoscopy before initial diagnosis showed nongoblet columnar mucosa above the anatomic gastroesophageal junction. CONCLUSIONS: Increased BMI may be a risk factor for BE and IMGEJ in pediatric patients without underlying conditions. Nongoblet columnar metaplasia and IMGEJ might represent incomplete forms of BE. Our data suggest that these patients should be closely monitored.
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Esófago de Barrett , Reflujo Gastroesofágico , Adolescente , Biopsia , Niño , Unión Esofagogástrica , Femenino , Reflujo Gastroesofágico/etiología , Humanos , Masculino , Metaplasia , Estudios RetrospectivosRESUMEN
INTRODUCTION: Infertility is common for individuals with differences of sex development (DSD) and is a significant concern to these individuals. Fertility potential in many DSD conditions is poorly understood. Gonadal tissue cryopreservation (GTC) for fertility preservation (FP) is offered to children with cancer undergoing gonadotoxic therapy. Our team sought to expand the field of FP by offering and evaluating the success of GTC for individuals with DSD. MATERIALS AND METHODS: GTC was offered to patients with DSD undergoing prophylactic gonadectomy, after extensive multidisciplinary counseling. For those who elected to attempt GTC, data were retrospectively abstracted, including: DSD diagnosis, age at gonadectomy, indication for gonadectomy, pathology results, and final decision about long-term gonadal tissue storage. RESULTS: Ten patients were enrolled to attempt GTC, with a mean age of 11.5 years (range 1-18). Five of the 10 patients had germ cells (GCs) present. Diagnoses (age at gonadectomy) for patients with GCs included ovotesticular DSD (13 months), mixed gonadal dysgenesis (17 months), partial gonadal dysgenesis (3 years), partial androgen insensitivity syndrome (11 years), and mixed gonadal dysgenesis (12 years). Four of the 5 subjects with GCs elected for GTC. One opted against GTC, citing immature gametes that did not match gender identity. CONCLUSION: GTC at the time of gonadectomy for patients with DSD is feasible. In many patients, GCs are present. While questions remain about the timing of gonadectomy, quality of GCs, and future success for use of the tissue based on technological advancement, GTC represents a novel approach to experimental FP for individuals with DSD.
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Criopreservación , Trastornos del Desarrollo Sexual/terapia , Preservación de la Fertilidad , Desarrollo Sexual , Adolescente , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Estudios RetrospectivosRESUMEN
Pathological diagnosis of solitary fibrous tumor (SFT) in the pediatric population is challenging, as it occurs uncommonly in this age-group and resembles other spindle cell neoplasms. SFT contains a NAB2-STAT6 fusion gene, which can be reliably detected using STAT6 immunohistochemistry. Positive staining is highly sensitive and specific. We sought to investigate the utility of STAT6 immunohistochemistry, to show how commonly SFT was historically recognized at 3 academic pediatric institutions, to reclassify them when appropriate, and to demonstrate features of major mimics of SFT. Our series included cases with a previous diagnosis of SFT or for which SFT was among key considerations, from 3 major academic pediatric hospitals seen over the past 30 years. Of 18 tumors identified, only 3 tumors from 2 patients demonstrated positive STAT6 staining as well as the typical histology and immunophenotype seen in SFT. The remaining 15 tumors were reclassified based on morphology, additional immunohistochemistry and fluorescence in situ hybridization as desmoid-type fibromatosis (3 tumors), nerve sheath/neural tumors (3 tumors), low-grade fibromyxoid sarcoma, medallion-like dermal fibroma, poorly differentiated Sertoli cell tumor, nodular/proliferative fasciitis, calcifying fibrous tumor, aneurysmal bone cyst of soft tissue, STAT6-negative SFT with adipocytic differentiation, undifferentiated small round blue cell tumor, and scar (1 tumor each). Our study confirms that SFT is rare in the pediatric population and that it is potentially overdiagnosed. STAT6 immunohistochemistry is recommended to confirm the diagnosis of SFT in the pediatric population.
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Biomarcadores de Tumor/metabolismo , Errores Diagnósticos/estadística & datos numéricos , Uso Excesivo de los Servicios de Salud/estadística & datos numéricos , Factor de Transcripción STAT6/metabolismo , Neoplasias de los Tejidos Blandos/diagnóstico , Tumores Fibrosos Solitarios/diagnóstico , Adolescente , Niño , Preescolar , Diagnóstico Diferencial , Femenino , Humanos , Inmunohistoquímica , Masculino , Estudios Retrospectivos , Neoplasias de los Tejidos Blandos/metabolismo , Neoplasias de los Tejidos Blandos/patología , Tumores Fibrosos Solitarios/metabolismo , Tumores Fibrosos Solitarios/patologíaRESUMEN
Macrophages are specialized phagocytic cells, present in all tissues, which engulf and digest pathogens, infected and dying cells, and debris, and can recruit and regulate other immune cells and the inflammatory response and aid in tissue repair. Macrophage subpopulations play distinct roles in these processes and in disease, and are typically recognized by differences in marker expression, immune function, or tissue of residency. Although macrophage subpopulations in the brain have been found to have distinct developmental origins, the extent to which development contributes to macrophage diversity between tissues and within tissues is not well understood. Here, we investigate the development and maintenance of mouse lung macrophages by marker expression patterns, genetic lineage tracing and parabiosis. We show that macrophages populate the lung in three developmental waves, each giving rise to a distinct lineage. These lineages express different markers, reside in different locations, renew in different ways, and show little or no interconversion. Thus, development contributes significantly to lung macrophage diversity and targets each lineage to a different anatomical domain.