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1.
Nat Med ; 25(12): 1839-1842, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31768065

RESUMO

Histiocytoses are clonal hematopoietic disorders frequently driven by mutations mapping to the BRAF and MEK1 and MEK2 kinases. Currently, however, the developmental origins of histiocytoses in patients are not well understood, and clinically meaningful therapeutic targets outside of BRAF and MEK are undefined. In this study, we uncovered activating mutations in CSF1R and rearrangements in RET and ALK that conferred dramatic responses to selective inhibition of RET (selpercatinib) and crizotinib, respectively, in patients with histiocytosis.


Assuntos
Quinase do Linfoma Anaplásico/genética , Histiocitose/genética , Proteínas Proto-Oncogênicas c-ret/genética , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/genética , Adolescente , Adulto , Aminopiridinas/farmacologia , Benzotiazóis/farmacologia , Criança , Pré-Escolar , Feminino , Genoma Humano , Neoplasias Hematológicas/tratamento farmacológico , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/patologia , Histiocitose/tratamento farmacológico , Histiocitose/patologia , Humanos , Lactente , Masculino , Mutação , Ácidos Picolínicos/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Pirazóis/farmacologia , Piridinas/farmacologia , Pirróis/farmacologia , Receptores Proteína Tirosina Quinases/genética , Gêmeos Monozigóticos , Sequenciamento Completo do Exoma , Adulto Jovem
2.
J Pathol Inform ; 10: 18, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31360593

RESUMO

Background: Online "e-modules" integrated into medical education may enhance traditional learning. Medical students use e-modules during clinical rotations, but these often lack histopathology correlates of diseases and minimal time is devoted to pathology teaching. To address this gap, we created pediatric pathology case-based e-modules to complement the clinical pediatric curriculum and enhance students' understanding of pediatric diseases. Methods: Philips Tutor is an interactive web-based program in which pediatric pathology e-modules were created with pre-/post-test questions. Each e-module contains a clinical vignette, virtual microscopy, and links to additional resources. Topics were selected based on established learning objectives for pediatric clinical rotations. Pre- and post-tests were administered at the beginning/end of each rotation. Test group had access to the e-modules, but control group did not. Both groups completed the pre/post-tests. Posttest was followed by a feedback survey. Results: Overall, 7% (9/123) in the control group and 8% (13/164) in the test group completed both tests and were included in the analysis. Test group improved their posttest scores by about one point on a 5-point scale (P = 0.01); control group did not (P = 1.00). Students responded that test questions were helpful in assessing their knowledge of pediatric pathology (90%) and experienced relative ease of use with the technology (80%). Conclusions: Students responded favorably to the new technology, but cited time constraints as a significant barrier to study participation. Access to the e-modules suggested an improved posttest score compared to the control group, but pilot data were limited by the small sample size. Incorporating pediatric case-based e-modules with anatomic and clinical pathology topics into the clinical medical education curriculum may heighten students' understanding of important diseases. Our model may serve as a pilot for other medical education platforms.

4.
Blood ; 134(2): 147-159, 2019 07 11.
Artigo em Inglês | MEDLINE | ID: mdl-31015190

RESUMO

Hemophagocytic lymphohistiocytosis (HLH) is an often-fatal disorder characterized by the overactivation of T cells and macrophages that excessively produce proinflammatory cytokines, including interferon-γ (IFN-γ). Previously, we reported that the JAK inhibitor ruxolitinib dampens T-cell activation and lessens inflammation in a model of HLH in which perforin-deficient (Prf1 -/-) mice are infected with lymphocytic choriomeningitis virus (LCMV). Ruxolitinib inhibits signaling downstream of IFN-γ, as well as several other JAK-dependent cytokines. As a consequence, it remained unclear whether ruxolitinib was exerting its beneficial effects in HLH by inhibiting IFN-γ signaling or by targeting signaling initiated by other proinflammatory cytokines. To address this question, we compared the effects of ruxolitinib with those obtained using an IFN-γ-neutralizing antibody (αIFN-γ) in 2 murine HLH models. In both models, ruxolitinib and αIFN-γ reduced inflammation-associated anemia, indicating that ruxolitinib operates in an IFN-γ-dependent manner to reverse this HLH manifestation. In contrast, the number and activation status of T cells and neutrophils, as well as their infiltration into tissues, were significantly reduced following treatment with ruxolitinib, but they remained unchanged or were increased following treatment with αIFN-γ. Notably, despite discontinuation of ruxolitinib, LCMV-infected Prf1 -/- mice exhibited enhanced survival compared with mice in which αIFN-γ was discontinued. This protective effect could be mimicked by transient treatment with αIFN-γ and a neutrophil-depleting antibody. Thus, ruxolitinib operates through IFN-γ-dependent and -independent mechanisms to dampen HLH by targeting the deleterious effects of T cells and neutrophils, with the latter representing an unappreciated and understudied cell type that contributes to HLH pathogenesis.


Assuntos
Linfo-Histiocitose Hemofagocítica/imunologia , Neutrófilos/efeitos dos fármacos , Pirazóis/farmacologia , Linfócitos T/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Ativação Linfocitária/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL
5.
Urology ; 128: 87-89, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30796991

RESUMO

Juvenile granulosa cell tumors of the ovary are rare sex cord-stromal ovarian tumors that are typically diagnosed during the first 2 decades of life. Most patients present with precocious puberty in the early stages of disease. We present a rare case of asymptomatic uterine torsion from a 15-cm juvenile granulosa cell tumors in a 5-year-old girl with elevated inhibin B, breast development, vaginal bleeding, and a palpable right-sided abdominal mass.


Assuntos
Tumor de Células da Granulosa/diagnóstico , Neoplasias Ovarianas/diagnóstico , Anormalidade Torcional/diagnóstico , Útero/diagnóstico por imagem , Pré-Escolar , Diagnóstico Diferencial , Feminino , Tumor de Células da Granulosa/complicações , Tumor de Células da Granulosa/cirurgia , Humanos , Neoplasias Ovarianas/complicações , Neoplasias Ovarianas/cirurgia , Ovariectomia/métodos , Doenças Raras , Tomografia Computadorizada por Raios X , Anormalidade Torcional/etiologia , Anormalidade Torcional/cirurgia
6.
Hum Pathol ; 83: 43-49, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30130631

RESUMO

Although littoral cell angiomas (LCAs) are phenotypically well characterized, the antibodies used to support the diagnosis identify many other cells in the normal spleen, and some may be found in other angiomatous lesions. Based on a langerin/CD207+ LCA index case, langerin and other selected immunohistochemical staining was performed on 10 LCAs, 20 other splenic angiomatous lesions, and 7 reactive lymph nodes to further investigate the role of langerin as a diagnostic tool. Ninety percent (9/10) of LCAs were langerin positive, whereas only 1 (5%) of 20 other splenic vascular lesions was partially positive (P < .00001). All LCAs were CD1a-, CD68+, CD34-, and CD8-; 20% were S100+, 70% CD21+, and 90% cyclin D1+. Ultrastructural studies of one LCA did not show Birbeck-type granules in definite lining cells. Sinus lining cells in 7 of 7 reactive lymph nodes showed partial langerin positivity, and 4 of 4 showed partial cyclin D1 positivity. In conclusion, langerin staining is an easily interpreted and highly sensitive and specific (sensitivity [0.90], specificity [0.95]) ancillary study to help distinguish LCA from other vascular tumors of the spleen. Whether this represents cross-reactivity or true CD207 expression is uncertain, as other immunohistochemical and ultrastructural studies do not support a Langerhans cell origin. The cyclin D1 staining seen in most LCA would be consistent with their expression of other selected vascular and histiocytic markers. The similar staining pattern in some lymph node sinus lining cells suggests a possible similar cell of origin, although LCA of lymph nodes is not described.


Assuntos
Antígenos CD/biossíntese , Biomarcadores Tumorais/análise , Hemangioma/diagnóstico , Lectinas Tipo C/biossíntese , Lectinas de Ligação a Manose/biossíntese , Neoplasias Esplênicas/diagnóstico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos CD/análise , Feminino , Humanos , Lectinas Tipo C/análise , Masculino , Lectinas de Ligação a Manose/análise , Pessoa de Meia-Idade , Sensibilidade e Especificidade , Adulto Jovem
7.
Blood ; 131(26): 2877-2890, 2018 06 28.
Artigo em Inglês | MEDLINE | ID: mdl-29720485

RESUMO

Rosai-Dorfman-Destombes disease (RDD) is a rare non-Langerhans cell histiocytosis characterized by accumulation of activated histiocytes within affected tissues. RDD, which now belongs to the R group of the 2016 revised histiocytosis classification, is a widely heterogeneous entity with a range of clinical phenotypes occurring in isolation or in association with autoimmune or malignant diseases. Recent studies have found NRAS, KRAS, MAP2K1, and ARAF mutations in lesional tissues, raising the possibility of a clonal origin in some forms of RDD. More than 1000 reports have been published in the English literature; however, there is a lack of consensus regarding approach for the clinical management of RDD. Although in most cases RDD can be observed or treated with local therapies, some patients with refractory or multifocal disease experience morbidity and mortality. Here we provide the first consensus multidisciplinary recommendations for the diagnosis and management of RDD. These recommendations were discussed at the 32nd Histiocyte Society Meeting by an international group of academic clinicians and pathologists with expertise in RDD. We include guidelines for clinical, laboratory, pathologic, and radiographic evaluation of patients with RDD together with treatment recommendations based on clinical experience and review of the literature.


Assuntos
Histiócitos/patologia , Histiocitose Sinusal/diagnóstico , Histiocitose Sinusal/terapia , Corticosteroides/uso terapêutico , Biópsia , Gerenciamento Clínico , Predisposição Genética para Doença , Histiócitos/metabolismo , Histiocitose Sinusal/genética , Histiocitose Sinusal/patologia , Humanos , Imunoterapia , Mutação , Guias de Prática Clínica como Assunto , Prognóstico , Radioterapia
8.
Cancer ; 124(12): 2607-2620, 2018 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-29624648

RESUMO

BACKGROUND: Central nervous system Langerhans cell histiocytosis (CNS-LCH) brain involvement may include mass lesions and/or a neurodegenerative disease (LCH-ND) of unknown etiology. The goal of this study was to define the mechanisms of pathogenesis that drive CNS-LCH. METHODS: Cerebrospinal fluid (CSF) biomarkers including CSF proteins and extracellular BRAFV600E DNA were analyzed in CSF from patients with CNS-LCH lesions compared with patients with brain tumors and other neurodegenerative conditions. Additionally, the presence of BRAFV600E was tested in peripheral mononuclear blood cells (PBMCs) as well as brain biopsies from LCH-ND patients, and the response to BRAF-V600E inhibitor was evaluated in 4 patients with progressive disease. RESULTS: Osteopontin was the only consistently elevated CSF protein in patients with CNS-LCH compared with patients with other brain pathologies. BRAFV600E DNA was detected in CSF of only 2/20 (10%) cases, both with LCH-ND and active lesions outside the CNS. However, BRAFV600E+ PBMCs were detected with significantly higher frequency at all stages of therapy in LCH patients who developed LCH-ND. Brain biopsies of patients with LCH-ND demonstrated diffuse perivascular infiltration by BRAFV600E+ cells with monocyte phenotype (CD14+ CD33+ CD163+ P2RY12- ) and associated osteopontin expression. Three of 4 patients with LCH-ND treated with BRAF-V600E inhibitor experienced significant clinical and radiologic improvement. CONCLUSION: In LCH-ND patients, BRAFV600E+ cells in PBMCs and infiltrating myeloid/monocytic cells in the brain is consistent with LCH-ND as an active demyelinating process arising from a mutated hematopoietic precursor from which LCH lesion CD207+ cells are also derived. Therapy directed against myeloid precursors with activated MAPK signaling may be effective for LCH-ND. Cancer 2018;124:2607-20. © 2018 American Cancer Society.


Assuntos
Neoplasias Encefálicas/diagnóstico , Histiocitose de Células de Langerhans/diagnóstico , Doenças Neurodegenerativas/diagnóstico , Osteopontina/líquido cefalorraquidiano , Proteínas Proto-Oncogênicas B-raf/genética , Adolescente , Adulto , Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Biópsia , Encéfalo/patologia , Neoplasias Encefálicas/líquido cefalorraquidiano , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Criança , Pré-Escolar , Diagnóstico Diferencial , Feminino , Células-Tronco Hematopoéticas/patologia , Histiocitose de Células de Langerhans/líquido cefalorraquidiano , Histiocitose de Células de Langerhans/genética , Histiocitose de Células de Langerhans/patologia , Humanos , Lactente , Recém-Nascido , Leucócitos Mononucleares/patologia , Sistema de Sinalização das MAP Quinases , Masculino , Doenças Neurodegenerativas/líquido cefalorraquidiano , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/patologia , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Estudos Retrospectivos , Adulto Jovem
9.
Blood ; 131(13): 1442-1455, 2018 03 29.
Artigo em Inglês | MEDLINE | ID: mdl-29326099

RESUMO

Hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS) are life-threatening hyperferritinemic systemic inflammatory disorders. Although profound cytotoxic impairment causes familial HLH (fHLH), the mechanisms driving non-fHLH and MAS are largely unknown. MAS occurs in patients with suspected rheumatic disease, but the mechanistic basis for its distinction is unclear. Recently, a syndrome of recurrent MAS with infantile enterocolitis caused by NLRC4 inflammasome hyperactivity highlighted the potential importance of interleukin-18 (IL-18). We tested this association in hyperferritinemic and autoinflammatory patients and found a dramatic correlation of MAS risk with chronic (sometimes lifelong) elevation of mature IL-18, particularly with IL-18 unbound by IL-18 binding protein, or free IL-18. In a mouse engineered to carry a disease-causing germ line NLRC4T337S mutation, we observed inflammasome-dependent, chronic IL-18 elevation. Surprisingly, this NLRC4T337S-induced systemic IL-18 elevation derived entirely from intestinal epithelia. NLRC4T337S intestines were histologically normal but showed increased epithelial turnover and upregulation of interferon-γ-induced genes. Assessing cellular and tissue expression, classical inflammasome components such as Il1b, Nlrp3, and Mefv predominated in neutrophils, whereas Nlrc4 and Il18 were distinctly epithelial. Demonstrating the importance of free IL-18, Il18 transgenic mice exhibited free IL-18 elevation and more severe experimental MAS. NLRC4T337S mice, whose free IL-18 levels were normal, did not. Thus, we describe a unique connection between MAS risk and chronic IL-18, identify epithelial inflammasome hyperactivity as a potential source, and demonstrate the pathogenicity of free IL-18. These data suggest an IL-18-driven pathway, complementary to the cytotoxic impairment of fHLH, with potential as a distinguishing biomarker and therapeutic target in MAS.


Assuntos
Interleucina-18/imunologia , Síndrome de Ativação Macrofágica/imunologia , Transdução de Sinais/imunologia , Substituição de Aminoácidos , Animais , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/imunologia , Proteínas Adaptadoras de Sinalização CARD/genética , Proteínas Adaptadoras de Sinalização CARD/imunologia , Proteínas de Ligação ao Cálcio/genética , Proteínas de Ligação ao Cálcio/imunologia , Humanos , Inflamassomos/genética , Inflamassomos/imunologia , Peptídeos e Proteínas de Sinalização Intercelular/genética , Peptídeos e Proteínas de Sinalização Intercelular/imunologia , Interleucina-18/genética , Interleucina-1beta/genética , Interleucina-1beta/imunologia , Mucosa Intestinal/imunologia , Mucosa Intestinal/patologia , Linfo-Histiocitose Hemofagocítica/genética , Linfo-Histiocitose Hemofagocítica/imunologia , Linfo-Histiocitose Hemofagocítica/patologia , Síndrome de Ativação Macrofágica/genética , Síndrome de Ativação Macrofágica/patologia , Camundongos , Camundongos Knockout , Mutação de Sentido Incorreto , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Pirina/genética , Pirina/imunologia , Transdução de Sinais/genética
10.
Urology ; 114: 175-180, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29305943

RESUMO

Capillary hemangioma is a rare benign lesion in the testicle, particularly in pediatrics. It can mimic malignancy, leading to radical orchiectomy. We present a case of a testicular hemangioma in a child, and review the literature on testicular hemangiomas in this age group. A hypervascular testicular lesion without elevated tumor markers may warrant intraoperative biopsy to direct surgical management, which may include testis-sparing surgery if amenable.


Assuntos
Hemangioma/cirurgia , Neoplasias Testiculares/cirurgia , Criança , Hemangioma/diagnóstico por imagem , Hemangioma/patologia , Humanos , Imuno-Histoquímica , Masculino , Orquiectomia , Neoplasias Testiculares/diagnóstico por imagem , Neoplasias Testiculares/patologia , Ultrassonografia
11.
J Heart Lung Transplant ; 36(12): 1336-1343, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29055602

RESUMO

BACKGROUND: Histopathologic features of late graft dysfunction (LGD) in endomyocardial biopsies (EMBs) after pediatric heart transplantation (HT) have been incompletely described and rarely quantified. We employed automated, morphometric analysis of whole-slide EMB images to objectively quantify fibrosis and microvasculopathy after pediatric HT. METHODS: Nine recipients with clinical LGD were matched with controls on age, listing diagnosis, crossmatch and time since HT. Fibrosis was quantified as percent tissue area with fibrosis and capillary density as capillaries per unit area, number of capillary "neighbors" within 30 µm of each myocyte and myocyte-to-nearest-capillary diffusion distance. Clinical data, including all EMB reports, were also reviewed. RESULTS: The groups were well matched for age at HT (median 4.0 vs 3.1 years), listing diagnosis (50% congenital heart disease for each), positive crossmatch (11% each) and days post-HT (2,628 vs 2,894, p = 0.69). Despite a similar number of previous EMBs (median 23 each, p = 0.43), areas occupied by fibrosis were greater in LGD cases (44.5% vs 23.2%, p = 0.012). Capillary number/area data were not statistically different between LGD cases and controls (378/mm2 vs 559/mm2, p = 0.57), but LGD cases more commonly had zero capillary neighbors (35% vs 20%, p = 0.02) and greater myocyte-to-nearest-capillary distances (27.1 µm vs 18.7 µm, p = 0.005). Cumulative rejection history correlated with fibrosis (r = 0.49, p = 0.039) and myocyte-to-nearest-capillary distance (r = 0.5, p = 0.036). CONCLUSIONS: LGD after pediatric HT is associated with previous rejection and characterized histologically by fibrosis and microvasculopathy, which are not readily appreciated by traditional semi-quantitative EMB analysis. Software-assisted EMB analysis may enable greater pathophysiologic understanding of LGD and identification of targets for future study and intervention.


Assuntos
Automação/métodos , Vasos Coronários/patologia , Função Retardada do Enxerto/patologia , Cardiopatias Congênitas/cirurgia , Transplante de Coração/efeitos adversos , Miocárdio/patologia , Aloenxertos , Biópsia , Criança , Pré-Escolar , Circulação Coronária , Vasos Coronários/fisiopatologia , Função Retardada do Enxerto/fisiopatologia , Feminino , Fibrose/patologia , Humanos , Lactente , Masculino , Estudos Retrospectivos , Fatores de Tempo
12.
Pediatr Dev Pathol ; 20(6): 498-505, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28403691

RESUMO

Autoinflammatory diseases are caused by pathologic activation of the innate immune system. Primary hemophagocytic lymphohistiocytosis (HLH) is an aggressive syndrome of excessive immune activation caused by monogenic mutations resulting in cytotoxic cell defects and subsequent failure to eliminate activated macrophages. Secondary HLH is often diagnosed in cases without a known Mendelian inheritance. However, some cases of "secondary" HLH have been shown to harbor mutations with partial dysfunction of the cytotoxic system. Recently, macrophage intrinsic abnormalities caused by NLRC4 inflammasome mutations have been linked to autoinflammation and recurrent macrophage activation syndromes resembling a primary HLH. We report a case of a former 28-week preterm infant with congenital anemia, ascites, and a heavy edematous placenta with fetal thrombotic vasculopathy, who developed hepatosplenomegaly and unexplained systemic inflammation with laboratory features of HLH in the early postnatal course and died at 2 months of age. Postmortem examination confirmed the hepatosplenomegaly with marked sinusoidal hemophagocytosis, along with striking hemophagocytosis in the bone marrow and lymph nodes. There was extensive acute and chronic ischemic bowel disease with matted bowel loops, fibrous adhesions, and patchy necrotizing enterocolitis features. Whole exome sequencing analysis demonstrated a novel mosaic heterozygous NLRC4 512 C> T (p.Ser171Phe) de novo mutation predicated to cause a dominant, gain-of-function mutation resulting in a constitutively active protein. The assembly of NLRC4-containing inflammasomes via an induced self-propagation mechanism likely enables a perpetuating process of systemic macrophage activation, presumed to be initiated in utero in this patient.


Assuntos
Proteínas Adaptadoras de Sinalização CARD/genética , Proteínas de Ligação ao Cálcio/genética , Mutação com Ganho de Função , Hepatomegalia/genética , Doenças Hereditárias Autoinflamatórias/genética , Linfo-Histiocitose Hemofagocítica/genética , Esplenomegalia/genética , Anemia/congênito , Anemia/diagnóstico , Anemia/genética , Ascite/congênito , Ascite/diagnóstico , Ascite/genética , Evolução Fatal , Feminino , Marcadores Genéticos , Hepatomegalia/congênito , Hepatomegalia/diagnóstico , Doenças Hereditárias Autoinflamatórias/diagnóstico , Heterozigoto , Humanos , Lactente , Linfo-Histiocitose Hemofagocítica/congênito , Linfo-Histiocitose Hemofagocítica/diagnóstico , Esplenomegalia/congênito , Esplenomegalia/diagnóstico , Síndrome , Trombose/congênito , Trombose/diagnóstico , Trombose/genética
13.
Cancer Cytopathol ; 124(6): 425-35, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-26992116

RESUMO

BACKGROUND: Post-transplant lymphoproliferative disorders (PTLDs) are well characterized in tissue sections, but their evaluation in exfoliative cytology specimens is limited. This study reports a 25-year experience with PTLDs in exfoliative cytology specimens. METHODS: All solid organ or allogeneic stem cell transplant recipients with PTLDs and exfoliative cytology specimens from 1987 to 2011 were identified. The cytomorphology, Epstein-Barr virus (EBV) status, flow cytometry, immunohistochemistry, and molecular studies were reviewed from all exfoliative cytology specimens previously diagnosed as atypical lymphoid proliferations or PTLDs. RESULTS: A total of 55 patients (age range, 1-72 years) with PTLDs had 434 exfoliative cytology specimens. Thirty-six of the 55 patients (65%) had 54 specimens with abnormal lymphoid proliferations (12% of the specimens), and 26 of these patients had 37 specimens available for review (15 cerebrospinal fluid specimens, 12 peritoneal fluid specimens, 9 pleural fluid specimens, and 1 bronchoalveolar lavage fluid specimen). Thirty percent of the reviewed cytology specimens were diagnostic of PTLDs, including 8 cases of monomorphic post-transplant lymphoproliferative disorder (M-PTLD) with abnormal B/T-cell populations identified with flow cytometry/immunohistochemistry and 3 EBV-positive specimens with a differential diagnosis of polymorphic PTLD versus M-PTLD. All cases diagnostic of a PTLD had 1 to 3 ancillary studies performed. Forty percent of the cytology specimens (15 of 37) were suspicious for a PTLD, but ancillary studies were performed for only a third of them, and they did not support a definitive diagnosis of a PTLD. Thirty percent of the cytology specimens (11 of 37) appeared reactive, but they lacked sufficient ancillary studies to exclude a PTLD. CONCLUSIONS: Atypical lymphoid proliferations are common in exfoliative cytology specimens from patients with PTLDs, and they require ancillary studies at least including immunophenotyping and EBV evaluations for a definitive diagnosis. Cancer Cytopathol 2016;124:425-35. © 2016 American Cancer Society.


Assuntos
Citodiagnóstico/métodos , Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/diagnóstico , Herpesvirus Humano 4/isolamento & purificação , Imunofenotipagem/métodos , Transtornos Linfoproliferativos/virologia , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Infecções por Vírus Epstein-Barr/virologia , Feminino , Humanos , Lactente , Transtornos Linfoproliferativos/patologia , Transtornos Linfoproliferativos/terapia , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Transplante de Células-Tronco , Adulto Jovem
14.
Blood ; 127(22): 2672-81, 2016 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-26966089

RESUMO

The histiocytoses are rare disorders characterized by the accumulation of macrophage, dendritic cell, or monocyte-derived cells in various tissues and organs of children and adults. More than 100 different subtypes have been described, with a wide range of clinical manifestations, presentations, and histologies. Since the first classification in 1987, a number of new findings regarding the cellular origins, molecular pathology, and clinical features of histiocytic disorders have been identified. We propose herein a revision of the classification of histiocytoses based on histology, phenotype, molecular alterations, and clinical and imaging characteristics. This revised classification system consists of 5 groups of diseases: (1) Langerhans-related, (2) cutaneous and mucocutaneous, and (3) malignant histiocytoses as well as (4) Rosai-Dorfman disease and (5) hemophagocytic lymphohistiocytosis and macrophage activation syndrome. Herein, we provide guidelines and recommendations for diagnoses of these disorders.


Assuntos
Células Dendríticas , Transtornos Histiocíticos Malignos , Histiocitose de Células de Langerhans , Histiocitose de Células não Langerhans , Macrófagos , Adulto , Células Dendríticas/classificação , Células Dendríticas/patologia , Feminino , Transtornos Histiocíticos Malignos/classificação , Transtornos Histiocíticos Malignos/patologia , Histiocitose de Células de Langerhans/classificação , Histiocitose de Células de Langerhans/patologia , Histiocitose de Células não Langerhans/classificação , Histiocitose de Células não Langerhans/patologia , Humanos , Macrófagos/classificação , Macrófagos/patologia , Masculino
15.
Nat Commun ; 7: 10713, 2016 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-26888176

RESUMO

Neonatal cholestasis is a potentially life-threatening condition requiring prompt diagnosis. Mutations in several different genes can cause progressive familial intrahepatic cholestasis, but known genes cannot account for all familial cases. Here we report four individuals from two unrelated families with neonatal cholestasis and mutations in NR1H4, which encodes the farnesoid X receptor (FXR), a bile acid-activated nuclear hormone receptor that regulates bile acid metabolism. Clinical features of severe, persistent NR1H4-related cholestasis include neonatal onset with rapid progression to end-stage liver disease, vitamin K-independent coagulopathy, low-to-normal serum gamma-glutamyl transferase activity, elevated serum alpha-fetoprotein and undetectable liver bile salt export pump (ABCB11) expression. Our findings demonstrate a pivotal function for FXR in bile acid homeostasis and liver protection.


Assuntos
Colestase Intra-Hepática/genética , Mutação , Receptores Citoplasmáticos e Nucleares/genética , Membro 11 da Subfamília B de Transportadores de Cassetes de Ligação de ATP , Transportadores de Cassetes de Ligação de ATP/genética , Transportadores de Cassetes de Ligação de ATP/metabolismo , Ácidos e Sais Biliares/metabolismo , Colestase Intra-Hepática/metabolismo , Feminino , Humanos , Masculino , Receptores Citoplasmáticos e Nucleares/metabolismo , Adulto Jovem
16.
J Cutan Pathol ; 43(3): 270-5, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26454140

RESUMO

Langerhans cell histocytosis (LCH) and Erdheim-Chester disease are two rare histiocytic disorders. Their occurrence in the same patient is more infrequent, but has been described. We report a case of a 38-year-old woman who presented with a diagnosis of single system cutaneous LCH. Subsequently, she developed multiple papules on her extremities consistent with a non-LCH xanthogranuloma type lesion. BRAF(V600E) mutation immunostain, VE1 was positive in the skin lesion, which was confirmed by molecular polymerase chain reaction (PCR) studies, initiating a complete systemic workup for Erdheim-Chester disease. Systemic involvement was confirmed with bilateral sclerotic bone lesions and retroperitoneal and pelvic fibrosing disease. She was also found to have a BRAF(V600E) mutation positive papillary thyroid carcinoma. New suspicious cutaneous lesions presenting in patients with a history of LCH need to be biopsied. A BRAF(V600E) mutation in a non-LCH histiocytic lesion with a xanthogranuloma phenotype (CD163/CD68/CD14/fascin/Factor 13a) should prompt an Erdheim-Chester disease workup. This is a unique case of a woman with BRAF(V600E) mutation positive Erdheim-Chester disease and cutaneous LCH, while also being, to our knowledge, the first reported case in the English literature of it occurring in a patient with a BRAF(V600E) mutation positive papillary thyroid carcinoma.


Assuntos
Carcinoma , Doença de Erdheim-Chester , Histiocitose de Células de Langerhans , Mutação de Sentido Incorreto , Proteínas Proto-Oncogênicas B-raf , Neoplasias da Glândula Tireoide , Adulto , Substituição de Aminoácidos , Carcinoma/genética , Carcinoma/metabolismo , Carcinoma/patologia , Carcinoma Papilar , Doença de Erdheim-Chester/genética , Doença de Erdheim-Chester/metabolismo , Doença de Erdheim-Chester/patologia , Feminino , Histiocitose de Células de Langerhans/genética , Histiocitose de Células de Langerhans/metabolismo , Histiocitose de Células de Langerhans/patologia , Humanos , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas B-raf/metabolismo , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia , Câncer Papilífero da Tireoide , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/metabolismo , Neoplasias da Glândula Tireoide/patologia
17.
Pediatr Dev Pathol ; 19(2): 115-22, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26367451

RESUMO

The aim of this study was to test the hypothesis that our 60-gene DNA/RNA ThyroSeq v2 next-generation sequence (NGS) assay would identify additional genetic markers, including gene fusions in sporadic pediatric differentiated thyroid carcinomas (DTC) that had no known molecular alterations. Sporadic pediatric DTCs with informative molecular testing (n=18) were studied. We previously tested 15 cases by our standard 7-gene (BRAF, NRAS, HRAS, KRAS, RET/PTC1, RET/PTC3, PAX8/PPARg) mutation panel. Three cases were not tested previously. The standard 7-gene panel identified molecular alterations in 9 of 15 tumors (60%). Cases analyzed by ThyroSeq v2 NGS included the six previously negative cases by the standard 7-gene panel and three cases not previously tested. The NGS assay revealed new gene fusions in four of six previously negative cases (67%). These gene fusions included ETV6/NTRK3 (n=3) and TPR/NTRK1 (n=1). A point mutation (BRAF-V600E) was detected in one of three untested cases. While standard testing could identify only molecular alterations in 60% of cases, with the addition of the ThyroSeq v2 NGS, this increased to 87% (n=13/15). Some cases with chromosomal rearrangements, including ETV6/NTRK3, appear to be associated with an aggressive histopathologic phenotype, but had no documented history of radiation exposure. Additional work is needed to investigate if pediatric DTCs could benefit from a reclassification based on molecular subtypes, which may better reflect their underlying biologic potential. Our data support the use of broad gene panels for the molecular diagnostics of pediatric thyroid nodules to aid future classification, treatment, and clinical management recommendations.


Assuntos
Biomarcadores Tumorais/genética , Carcinoma/genética , DNA de Neoplasias/genética , Sequenciamento de Nucleotídeos em Larga Escala , Técnicas de Diagnóstico Molecular , RNA Neoplásico/genética , Neoplasias da Glândula Tireoide/genética , Adolescente , Fatores Etários , Carcinoma/patologia , Carcinoma/terapia , Diferenciação Celular , Criança , Análise Mutacional de DNA , Feminino , Fusão Gênica , Predisposição Genética para Doença , Humanos , Masculino , Mutação , Fenótipo , Valor Preditivo dos Testes , Prognóstico , Fatores de Risco , Neoplasias da Glândula Tireoide/patologia , Neoplasias da Glândula Tireoide/terapia
18.
Hematol Oncol Clin North Am ; 29(5): 799-823, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26461144

RESUMO

The classification of the histiocytoses has evolved based on new understanding of the cell of origin as a bone marrow precursor. Although the pathologic features of the histiocytoses have not changed per se, molecular genetic information now needs to be integrated into the diagnosis. The basic lesions of the most common histiocytoses, their patterns in different sites, and ancillary diagnostics are now just one part of the classification. As more is understood about the cell of origin and molecular biology of the histiocytoses, future classifications will be refined.


Assuntos
Histiocitose de Células de Langerhans/diagnóstico , Histiocitose de Células de Langerhans/etiologia , Histiocitose de Células de Langerhans/patologia , Humanos
19.
Pediatr Dev Pathol ; 18(4): 318-23, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25751324

RESUMO

Papillary thyroid carcinoma (PTC) is rare in children, although it is a known secondary malignancy after treatment for neuroblastoma (NB). The interval between NB treatment completion and PTC is usually more than 5 years. A 4-year-old, female patient with a high risk adrenal NB was found to have a 2.9-cm, right thyroid nodule on surveillance chest computed tomography (CT) 6 months after completion of her NB treatment (induction chemotherapy, tumor resection, autologous stem cell transplantation, external beam radiation to the abdominal tumor site, immunotherapy, and retinoic acid). Posttreatment surveillance included iodine-123-metaiodobenzylguanidine scans and CT scans. Fine-needle aspiration of the thyroid nodule diagnosed a follicular neoplasm, which was negative for BRAF, NRAS, KRAS, HRAS, PAX8/PPARg, and RET/PTC mutations, without evidence of metastatic NB. Nodule histology demonstrated an encapsulated follicular variant of PTC (FVPTC). Next-generation sequence analysis for a 46 cancer-gene profile was performed on both tumors with subsequent peripheral blood DNA testing. A heterozygous missense mutation in STK11 (F354L) was identified in both the NB and FVPTC. This mutation was also detected in peripheral blood mononuclear cells. Two additional heterozygous somatic missense mutations of uncertain significance were identified: KDR/VEGF receptor 2 (Q472H) on chromosome 4 and MET (N375S) on chromosome 7. To our knowledge, this is the shortest reported duration from completion of NB treatment to detection of thyroid cancer. The association of the STK11 gene with Peutz-Jeghers syndrome, lung adenocarcinomas, and medullary thyroid cancer leads to a possible association between this genetic variant and our patient's tumors.


Assuntos
Adenocarcinoma Folicular/genética , Neoplasias das Glândulas Suprarrenais/terapia , Carcinoma/genética , Mutação em Linhagem Germinativa , Heterozigoto , Segunda Neoplasia Primária/genética , Neuroblastoma/terapia , Proteínas Serina-Treonina Quinases/genética , Neoplasias da Glândula Tireoide/genética , Adenocarcinoma Folicular/enzimologia , Adenocarcinoma Folicular/patologia , Adenocarcinoma Folicular/cirurgia , Neoplasias das Glândulas Suprarrenais/patologia , Biópsia , Carcinoma/enzimologia , Carcinoma/patologia , Carcinoma/cirurgia , Carcinoma Papilar , Pré-Escolar , Análise Mutacional de DNA , Feminino , Predisposição Genética para Doença , Humanos , Excisão de Linfonodo , Segunda Neoplasia Primária/enzimologia , Segunda Neoplasia Primária/patologia , Segunda Neoplasia Primária/cirurgia , Neuroblastoma/patologia , Fenótipo , Câncer Papilífero da Tireoide , Neoplasias da Glândula Tireoide/enzimologia , Neoplasias da Glândula Tireoide/patologia , Neoplasias da Glândula Tireoide/cirurgia , Tireoidectomia , Fatores de Tempo , Tomografia Computadorizada por Raios X , Resultado do Tratamento
20.
Pediatr Dev Pathol ; 18(2): 127-38, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25629953

RESUMO

Thymic involvement by Langerhans cell histiocytosis (LCH) has been described mainly in isolated case reports. A description of the histopathologic patterns of LCH proliferations in the thymus, together with therapeutic implications, has not, to our knowledge, been previously addressed. The pathology consultation files at Children's Hospital of Pittsburgh of the University of Pennsylvania Medical Center were reviewed for cases of thymic involvement by LCH. Relevant cases in the literature were also reviewed, and the histopathology and clinical course of those cases were collected. Nine consultation cases of thymic involvement were reviewed, together with 23 cases in the literature, which provided adequate pathologic description and ancillary confirmation (n  =  32), revealing 4 distinct pathologic groups. Group 1 showed microscopic collection of hyperplastic LCH-like cells in incidental thymectomies of patients without LCH disease, requiring no further treatment (n  =  7; 22%). Group 2 showed solitary and/or cystic LCH of the thymus with gland disruption, and at least 3 cases resolved without systemic therapy (n  =  10; 31%). Group 3 showed more variable thymic involvement in multisystemic LCH disease, with either a medullary restricted pattern or more diffuse gland involvement, requiring adjuvant therapy and having a higher mortality rate (n  =  13; 41%). Group 4 showed a mixed histiocytic lesion with a concurrent LCH and juvenile xanthogranuloma-like proliferation (n  =  2; 6%). Thymic involvement in LCH is quite rare. Based on our cases and those in the literature, we propose 4 distinct pathologic groups of thymic involvement in Langerhans cell proliferations with relevance for diagnosis and treatment.


Assuntos
Proliferação de Células , Histiocitose de Células de Langerhans/patologia , Células de Langerhans/patologia , Timo/patologia , Hiperplasia do Timo/patologia , Adolescente , Adulto , Biópsia , Criança , Pré-Escolar , Feminino , Histiocitose de Células de Langerhans/classificação , Histiocitose de Células de Langerhans/terapia , Hospitais Pediátricos , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Pennsylvania , Valor Preditivo dos Testes , Prognóstico , Hiperplasia do Timo/classificação , Hiperplasia do Timo/terapia , Adulto Jovem
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