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2.
Pediatr Dermatol ; 2020 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-33325559

RESUMO

We report a rare case of a 14-year-old boy with Langerhans cell histiocytosis localized to the prepuce. The patient was treated with a topical corticosteroid followed by imiquimod cream resulting in significant clinical improvement of the lesion. Although spontaneous remission is possible, the use of imiquimod may be an effective alternative therapy in cases of cutaneous Langerhans cell histiocytosis refractory to topical corticosteroids.

3.
Pediatr Dermatol ; 2020 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-33010051

RESUMO

Fibrosarcomatous transformation of dermatofibrosarcoma protuberans is associated with a significantly worse prognosis in adults, but is a very rare feature in the pediatric population. Here, we report a case that occurred in a child. The diagnosis of fibrosarcomatous transformation of dermatofibrosarcoma protuberans was confirmed by a histopathological assessment and fluorescence in situ hybridization. A comparison with eleven other patients reported in the literature revealed that the local recurrence and mortality rates in children are similar to those observed in adults.

5.
Am J Dermatopathol ; 2020 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-32568831

RESUMO

Cutaneous mastocytosis is characterized by the abnormal accumulation of mast cells in the skin. However, mast cell counting is not always easy and reproducible with classical methods. This work aims to demonstrate the reliability, usability, and virtues of a new software used on digital tablets for counting mast cells in cutaneous specific lesions of mastocytosis, to assess differences in mast cell counts between clinical subtypes of mastocytosis in the skin, and to consider the feasibility of applying a diagnostic mast cell count cutoff to urticaria pigmentosa, which is the most frequent form of cutaneous mastocytosis. Using a new digital tablet software that was accessible by multiple observers through its own wireless network and allowed high resolution of the image without data compression, we counted the number of mast cells on slides of patients and control skins immunostained for CD117. We found that our counting method was highly reproducible and that the new software allowed very quick counting. We evidenced strong differences in the mast cell count between most of the clinical subtypes of mastocytosis in the skin. However, when applied to a subset of patients with urticaria pigmentosa, a diagnostic cutoff in the mast cell count lacked sensitivity. Thus, our digital method for counting CD117-immunostained mast cells was highly accurate and was of a significant value for the diagnosis of mastocytosis in the skin. However, some subtypes with low mast cell counts will still require the application of additional diagnostic criteria.

8.
Histopathology ; 77(2): 275-283, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32281140

RESUMO

AIMS: Congenital haemangiomas (CHs) can be subdivided into different subtypes [rapidly involuting CHs (RICHs), non-involuting CHs (NICHs), and partially involuting CHs (PICHs)]. During the first few days of life, RICHs may be associated with transient but sometimes marked thrombocytopenia. We sought to assess the histological aspects and clinicopathological correlations of the three subtypes. METHODS AND RESULTS: We assessed the histopathological features of 10 RICHs, 25 NICHs, and 20 PICHs, described the patients' long-term clinical outcomes, and assessed clinicopathological correlations. All CHs were located in the dermis and hypodermis, and comprised both capillary lobules (with three distinct histopathological patterns) and extralobular large vessels. Most of the extralobular vessels were abnormal veins and abnormal lymphatic vessels. We did not observe significant correlations between the CH subtype, the histopathological pattern, and the time of the histopathological assessment. Interestingly, unexpected intralobular expression of podoplanin was found in neonatal biopsies of five RICHs and PICHs. Four of these five patients had concomitant thrombocytopenia. The podoplanin staining intensity decreased over time as the thrombocytopenia resolved and the tumour shrank. CONCLUSION: The histopathological features were similar in all three subtypes of CH, and were related to the time since disease onset; we consider that RICH, PICH and NICH form a single entity and differ only in their involuting potential. Along with the transient expression of intralobular podoplanin observed in some specimens from the newborn, the lobular architecture might lead to misdiagnosis of tufted haemangioma or kaposiform haemangioendothelioma.

12.
Blood ; 135(13): 1058-1061, 2020 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-32005988
14.
Histopathology ; 76(4): 540-549, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31630434

RESUMO

AIM: Angiomatosis of soft tissue (AST) is a rare, high-flow, intramuscular vascular anomaly. In the context of PTEN hamartoma tumour syndrome (PHTS), this AST is referred to as PTEN hamartoma of soft tissue. Given that AST is observed in patients with no history of PHTS, we hypothesised that non-syndromic AST arises as a consequence of a somatic mutation. METHODS AND RESULTS: Thirteen patients with histologically confirmed AST were retrospectively studied. Details of the patients' personal and family medical histories and symptoms were retrieved from their medical records. The histological analyses were reviewed and a tissue sample was used for genetic testing. Somatic mutations in the PIK3CA gene (p.Glu542Lys; p.Glu545Lys; p.His1047Arg) were identified in the tissue samples from seven patients, all of whom had unremarkable medical histories and had presented with a single lesion located in the lower limb. Five pathogenic variations in the PTEN gene (mutations: p.Lys263Arg; c.1026+2T>A; p.Ala126Thr; p.Leu108Arg; deletion, log ratio -0.55) were identified in the lesions of four patients; two of the latter had multifocal lesions. All four patients displayed macrocephaly, three boys presented with penile freckles, but none had a family history of PHTS. There were no histological differences between the PIK3CA and PTEN groups. CONCLUSIONS: AST can be related to either PTEN or PIK3CA mutations and may be multifocal in PHTS. AST appears to be a manifestation of PHTS that occurs in early childhood. The patient's medical history and clinical presentation should prompt the physician to perform specific genetic testing.


Assuntos
Angiomatose/genética , Angiomatose/patologia , Classe I de Fosfatidilinositol 3-Quinases/genética , Adolescente , Braço , Criança , Pré-Escolar , Feminino , Síndrome do Hamartoma Múltiplo/genética , Humanos , Lactente , Perna (Membro) , Masculino , Mutação , PTEN Fosfo-Hidrolase/genética , Estudos Retrospectivos
15.
Am J Dermatopathol ; 42(1): 1-10, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31880634

RESUMO

INTRODUCTION: Pityriasis lichenoides (PL) is an infrequent skin disorder. The clinical manifestations are usually specific enough for a reliable diagnosis, although the histopathological assessment of a biopsy is sometimes needed to differentiate between PL and a range of other diseases. The objectives of this study were to review cases of PL managed in our hospital, confirm the classical histopathological features of PL, and identify signs that may be of value in the diagnosis of PL. MATERIALS AND METHODS: All cases of PL assessed in our pathology department between January 2007 and December 2017 were retrieved, and all slides were reviewed. Cases were selected only if a diagnosis of PL was initially suggested by a dermatologist and then confirmed by the histopathological assessment. RESULTS: Seventy-one cases met the study criteria. The following features were almost always present: vacuolar changes or necrotic keratinocytes (100%), both superficial and deep lymphocytic infiltrates (99%), and the infiltration of lymphocytes into the adnexal epithelium (97%). The inflammatory cells were always small- to medium-sized lymphocytes. There were no eosinophilic infiltrates. Superficial perivascular and/or intraepidermal red blood cells were observed in 83% of cases. DISCUSSION: We highlighted the presence of a deep dermal lymphocytic infiltrate, with a "T-shaped" periadnexal arrangement along the full length of the follicular and sudoral epithelia. This might be a feature that enables the differentiation of PL from other diseases. Our findings also prompted a number of physiopathological hypotheses for PL. CONCLUSIONS: Our present results confirmed the classical histological aspects of PL and provided some useful new diagnostic features.


Assuntos
Pitiríase Liquenoide/patologia , Adolescente , Criança , Feminino , Folículo Piloso/patologia , Humanos , Masculino , Pitiríase Liquenoide/diagnóstico , Adulto Jovem
16.
J Exp Med ; 216(12): 2800-2818, 2019 12 02.
Artigo em Inglês | MEDLINE | ID: mdl-31537641

RESUMO

Infection of T cells by Epstein-Barr virus (EBV) causes chronic active EBV infection (CAEBV) characterized by T cell lymphoproliferative disorders (T-LPD) of unclear etiology. Here, we identified two homozygous biallelic loss-of-function mutations in PIK3CD and TNFRSF9 in a patient who developed a fatal CAEBV. The mutation in TNFRSF9 gene coding CD137/4-1BB, a costimulatory molecule expressed by antigen-specific activated T cells, resulted in a complete loss of CD137 expression and impaired T cell expansion toward CD137 ligand-expressing cells. Isolated as observed in one sibling, CD137 deficiency resulted in persistent EBV-infected T cells but without clinical manifestations. The mutation in PIK3CD gene that encodes the catalytic subunit p110δ of the PI3K significantly reduced its kinase activity. Deficient T cells for PIK3CD exhibited reduced AKT signaling, while calcium flux, RAS-MAPK activation, and proliferation were increased, suggestive of an imbalance between the PLCγ1 and PI3K pathways. These skewed signals in T cells may sustain accumulation of EBV-infected T cells, a process controlled by the CD137-CD137L pathway, highlighting its critical role in immunity to EBV.


Assuntos
Classe I de Fosfatidilinositol 3-Quinases/deficiência , Infecções por Vírus Epstein-Barr/etiologia , Herpesvirus Humano 4/imunologia , Linfócitos T/imunologia , Linfócitos T/metabolismo , Membro 9 da Superfamília de Receptores de Fatores de Necrose Tumoral/deficiência , Ativação Viral/genética , Ativação Viral/imunologia , Classe I de Fosfatidilinositol 3-Quinases/química , Suscetibilidade a Doenças , Infecções por Vírus Epstein-Barr/diagnóstico , Mutação em Linhagem Germinativa , Histocitoquímica , Homozigoto , Humanos , Imunofenotipagem , Mutação com Perda de Função , Ativação Linfocitária , Transtornos Linfoproliferativos/diagnóstico , Transtornos Linfoproliferativos/etiologia , Transtornos Linfoproliferativos/metabolismo , Modelos Moleculares , Linhagem , Fosfolipase C gama/metabolismo , Conformação Proteica , Proteínas Proto-Oncogênicas c-akt , Proteínas Quinases S6 Ribossômicas/metabolismo , Análise de Sequência de DNA , Transdução de Sinais , Relação Estrutura-Atividade , Linfócitos T/virologia , Membro 9 da Superfamília de Receptores de Fatores de Necrose Tumoral/química
17.
J Invest Dermatol ; 139(9): 2004-2015.e13, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31059696

RESUMO

The management of large congenital melanocytic nevi (lCMN) is based exclusively on iterative surgical procedures in the absence of validated medical therapy. The aim of our study was to develop an intra-lesional medical treatment for lCMN. Seventeen patients harboring NRAS-mutated lCMN were included. Nevocytes obtained from lCMN displayed an overactivation of mitogen-activated protein kinase and phosphoinositide 3-kinase (Akt) pathways. Mitogen-activated protein kinase/extracellular signal-regulated kinase (MEK) and Akt inhibitors reduced the nevosphere diameter in sphere-forming assays, as well as cell viability and proliferation in in vitro assays. Standardized lCMN explants were then cultured ex vivo with the same inhibitors, which induced a decrease in MelanA+ and Sox10+ cells in both epidermis and dermis. Finally, intradermal injections of these inhibitors were administered within standardized lCMN xenografts in Rag2-/- mice. They induced a dramatic decrease in nevocytes in treated xenografts, which persisted 30 days after the end of treatment. Using original nevus explant and xenograft preclinical models, we demonstrated that intradermal MEK/Akt inhibition might serve as neoadjuvant therapy for the treatment of NRAS-mutated congenital melanocytic nevi to avoid iterative surgeries.


Assuntos
Antineoplásicos/administração & dosagem , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Nevo Pigmentado/tratamento farmacológico , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Neoplasias Cutâneas/tratamento farmacológico , Animais , Proliferação de Células/efeitos dos fármacos , Criança , Pré-Escolar , Feminino , GTP Fosfo-Hidrolases/genética , Humanos , Lactente , Injeções Intradérmicas , Injeções Intralesionais , Antígeno MART-1/metabolismo , Masculino , Melanócitos/efeitos dos fármacos , Melanócitos/patologia , Proteínas de Membrana/genética , Camundongos , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Nevo Pigmentado/congênito , Nevo Pigmentado/genética , Nevo Pigmentado/patologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fatores de Transcrição SOXE/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Pele/citologia , Pele/patologia , Neoplasias Cutâneas/congênito , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
18.
Pigment Cell Melanoma Res ; 32(5): 708-713, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-30945443

RESUMO

A girl, born with a posterior  lumbosacral giant congenital nevus, developed a central nodule that expanded over a period of 14 months into a 10-cm pedunculated mass. Histological analysis of the mass revealed melanoma of myxoid, small round-cell type with areas of  rhabdomyosarcomatous  transformation confirmed by immunohistochemistry. RNA sequencing identified an in-frame SASS6(e14)-RAF1(e8) fusion in both components and the nevus. A RAF1 FISH break-apart test found a balanced rearrangement pattern in the nevus and an unbalanced pattern in the malignant areas. Wild-type status of NRAS and BRAF was confirmed by NGS techniques. The array-CGH profile displayed copy number alterations commonly found in rhabdomyosarcomas. Despite intensive treatment, widespread metastatic evolution of the melanomatous component was observed.


Assuntos
Diferenciação Celular , Fusão Gênica , Melanoma/patologia , Nevo Pigmentado/patologia , Proteínas Proto-Oncogênicas c-raf/genética , Rabdomiossarcoma/patologia , Neoplasias Cutâneas/patologia , Pré-Escolar , Feminino , Humanos , Melanoma/complicações , Melanoma/genética , Nevo Pigmentado/complicações , Nevo Pigmentado/genética , Rabdomiossarcoma/complicações , Rabdomiossarcoma/genética , Neoplasias Cutâneas/complicações , Neoplasias Cutâneas/genética
19.
JAMA Dermatol ; 2019 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-31017643

RESUMO

Importance: Myofibroma is the most frequent fibrous tumor in children. Multicentric myofibroma (referred to as infantile myofibromatosis) is a life-threatening disease. Objective: To determine the frequency, spectrum, and clinical implications of mutations in the PDGFRB receptor tyrosine kinase found in sporadic myofibroma and myofibromatosis. Design, Setting, and Participants: In this retrospective study of 69 patients with sporadic myofibroma or myofibromatosis, 85 tumor samples were obtained and analyzed by targeted deep sequencing of PDGFRB. Mutations were confirmed by an alternative method of sequencing and were experimentally characterized to confirm gain of function and sensitivity to the tyrosine kinase inhibitor imatinib. Main Outcomes and Measures: Frequency of gain-of-function PDGFRB mutations in sporadic myofibroma and myofibromatosis. Sensitivity to imatinib, as assessed experimentally. Results: Of the 69 patients with tumor samples (mean [SD] age, 7.8 [12.7] years), 60 were children (87%; 29 girls [48%]) and 9 were adults (13%; 4 women [44%]). Gain-of-function PDGFRB mutations were found in samples from 25 children, with no mutation found in samples from adults. Mutations were particularly associated with severe multicentric disease (13 of 19 myofibromatosis cases [68%]). Although patients had no familial history, 3 of 25 mutations (12%) were likely to be germline, suggesting de novo heritable alterations. All of the PDGFRB mutations were associated with ligand-independent receptor activation, and all but one were sensitive to imatinib at clinically relevant concentrations. Conclusions and Relevance: Gain-of-function mutations of PDGFRB in myofibromas may affect only children and be more frequent in the multicentric form of disease, albeit present in solitary pediatric myofibromas. These alterations may be sensitive to tyrosine kinase inhibitors. The PDGFRB sequencing appears to have a high value for diagnosis, prognosis, and therapy of soft-tissue tumors in children.

20.
Virchows Arch ; 474(1): 111-115, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30187166

RESUMO

Cutaneous spindle-cell neoplasms in adults as well as children represent a frequent dilemma for pathologists. Along this neoplasm spectrum, the differential diagnosis with CD34-positive proliferations can be challenging, particularly concerning neoplasms of fibrohistiocytic and fibroblastic lineages. In children, cutaneous and superficial soft-tissue neoplasms with CD34-positive spindle cells are associated with benign to intermediate malignancy potential and include lipofibromatosis, plaque-like CD34-positive dermal fibroma, fibroblastic connective tissue nevus, and congenital dermatofibrosarcoma protuberans. Molecular biology has been valuable in showing dermatofibrosarcoma protuberans and infantile fibrosarcoma that are characterized by COL1A1-PDGFB and ETV6-NTRK3 rearrangements respectively. We report a case of congenital CD34-positive dermohypodermal spindle-cell neoplasm occurring in a female infant and harboring a novel KHDRBS1-NTRK3 fusion. This tumor could belong to a new subgroup of pediatric cutaneous spindle-cell neoplasms, be an atypical presentation of a plaque-like CD34-positive dermal fibroma, of a fibroblastic connective tissue nevus, or represent a dermatofibrosarcoma protuberans with an alternative gene rearrangement.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Antígenos CD34/imunologia , Biomarcadores Tumorais/genética , Proteínas de Ligação a DNA/genética , Fusão Gênica , Rearranjo Gênico , Proteínas de Ligação a RNA/genética , Receptor trkC/genética , Neoplasias Cutâneas/genética , Biomarcadores Tumorais/imunologia , Biópsia , Diagnóstico Diferencial , Feminino , Predisposição Genética para Doença , Humanos , Imuno-Histoquímica , Lactente , Imagem por Ressonância Magnética , Técnicas de Diagnóstico Molecular , Fenótipo , Valor Preditivo dos Testes , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/patologia
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