BRAF V600E-Positive Multisite Langerhans Cell Histiocytosis in a Preterm Neonate

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Abstract

Hemorrhagic pustules with a “blueberry muffin” appearance accompanied by respiratory failure in a neonate present a challenging differential diagnosis that includes infections and neoplasms. We present a case of multiorgan, multisite Langerhans cell histiocytosis (LCH), positive for the oncogenic BRAF V600E mutation, in a preterm neonate. Infants with LCH pose a diagnostic challenge due to their heterogeneous presentations. This case is unusual in that the newborn presented with severe multiorgan involvement. Due to the rare incidence, wide spectrum of clinical manifestations, and high mortality rate, clinicians must maintain a high index of suspicion for LCH.

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Dramatic efficacy of vemurafenib in both multisystemic and refractory Erdheim-Chester disease and Langerhans cell histiocytosis harboring the BRAF V600E mutation.

Zahir Amoura, Laurent Arnaud, Frédéric Charlotte … (2013)

Histiocytoses are rare disorders of unknown origin with highly heterogeneous prognosis. BRAFV600E gain-of-function mutations have been observed in 57% of cases of Langerhans cell histiocytosis (LCH) and 54% of cases of Erdheim-Chester disease (ECD), but not in other types of histiocytoses. Targeted therapy with an inhibitor of mutated BRAF (vemurafenib) improves survival of patients with melanoma. Here, we report vemurafenib treatment of 3 patients with multisystemic and refractory ECD carrying the BRAFV600E mutation; 2 also had skin or lymph node LCH involvement. The patients were assessed clinically, biologically (CRP values), histologically (skin biopsy), and morphologically (positron emission tomography [PET], computed tomography and magnetic resonance imaging). For all patients, vemurafenib treatment led to substantial and rapid clinical and biologic improvement, and the tumor response was confirmed by PET, computed tomography, and/or magnetic resonance imaging 1 month after treatment initiation. For the first patient treated, the PET response increased between months 1 and 4 of treatment. The treatment remained effective after 4 months of follow-up although persistent disease activity was still observed. Treatment with vemurafenib, a newly approved BRAF inhibitor, should be considered for patients with severe and refractory BRAFV600E histiocytoses, particularly when the disease is life-threatening.

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Cell-specific gene expression in Langerhans cell histiocytosis lesions reveals a distinct profile compared with epidermal Langerhans cells.

Judith Allen, Anil Gaikwad, Brett T. Phillips … (2010)

Langerhans cell histiocytosis (LCH) is a rare disease characterized by heterogeneous lesions containing CD207(+) Langerhans cells (LCs) and lymphocytes that can arise in almost any tissue and cause significant morbidity and mortality. After decades of research, the cause of LCH remains speculative. A prevailing model suggests that LCH arises from malignant transformation and metastasis of epidermal LCs. In this study, CD207(+) cells and CD3(+) T cells were isolated from LCH lesions to determine cell-specific gene expression. Compared with control epidermal CD207(+) cells, the LCH CD207(+) cells yielded 2113 differentially expressed genes (false discovery rate < 0.01). Surprisingly, the expression of many genes previously associated with LCH, including cell-cycle regulators, proinflammatory cytokines, and chemokines, were not significantly different from control LCs in our study. However, several novel genes whose products activate and recruit T cells to sites of inflammation, including SPP1 (osteopontin), were highly overexpressed in LCH CD207(+) cells. Furthermore, several genes associated with immature myeloid dendritic cells were overexpressed in LCH CD207(+) cells. Compared with the peripheral CD3(+) cells from LCH patients, the LCH lesion CD3(+) cells yielded only 162 differentially regulated genes (false discovery rate < 0.01), and the expression profile of the LCH lesion CD3(+) cells was consistent with an activated regulatory T cell phenotype with increased expression of FOXP3, CTLA4, and SPP1. Results from this study support a model of LCH pathogenesis in which lesions do not arise from epidermal LCs but from accumulation of bone marrow-derived immature myeloid dendritic cells that recruit activated lymphocytes.

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Descriptive epidemiology of childhood Langerhans cell histiocytosis in France, 2000-2004.

Aurélie Guyot-Goubin, Jean Donadieu, Mohamed Barkaoui … (2008)

Childhood Langerhans cell histiocytosis (LCH) is a rare and poorly understood multisystemic disease. The French National Registry of Childhood Hematopoietic Malignancies (NRCH) has recorded LCH cases of all subtypes since 2000. The present study describes the data on LCH collected on a national scale over a 5-year period. The cases were children aged less than 15 years, diagnosed with LCH of any type between 2000 and 2004, and residing in mainland France at the time of diagnosis. Completeness was evaluated by capture-recapture after cross-checking against the database compiled by the French Langerhans Cell Histiocytosis Study Group. Two hundred fifty-eight cases of LCH were registered. The completeness of the NRCH was estimated to be 97%. The annual incidence rate was 4.6/10(6) children aged less than 15 years and the sex ratio was 1.2. Bone and skin were the most commonly involved organs at diagnosis. The incidence rate decreased with age from 15.3/10(6) before 1 year to 2.0/10(6) after 10 years. The disease was mainly unifocal (2.6/10(6)) and rarely disseminated (0.6/10(6)), but disseminated forms predominated in infants. The overall 2-year survival rate was 99% (95%CI: [97; 100]). About 30% of the LCH cases were enrolled in a clinical trial at first onset. No case was treated by radiotherapy. This study evidenced the main features of LCH incidence in the overall population and was consistent with previous studies. The NRCH thus appears to be a very promising tool for further elucidation of LCH. (c) 2008 Wiley-Liss, Inc.

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Author and article information

Journal

Journal ID (nlm-ta): AJP Rep

Journal ID (iso-abbrev): AJP Rep

Title: AJP Reports

Publisher: Thieme Medical Publishers (333 Seventh Avenue, New York, NY 10001, USA. )

ISSN (Print): 2157-6998

ISSN (Electronic): 2157-7005

Publication date (Electronic): 18 March 2013

Publication date (Print): October 2013

Volume: 3

Issue: 2

Pages: 63-66

Affiliations

[1 ]Division of Neonatology and Newborn Medicine, Department of Pediatrics, Massachusetts General Hospital for Children, Harvard Medical School, Boston, Massachusetts

[2 ]Division of Newborn and Infant Critical Care, Department of Pediatrics, Children's Hospital Los Angeles, Keck School of Medicine, Los Angeles, California

[3 ]Division of Hematology-Oncology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts

[4 ]Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts

[5 ]Department of Pathology, McMaster Children's Hospital, Hamilton, Ontario, Canada

[6 ]Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts

[7 ]Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts

[8 ]Department of Pediatrics, Division of Newborn Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts

[* ] These authors contributed equally as primary authors (co-first authors).,

[† ] These authors contributed equally as senior authors (co-senior authors).,

Author notes

Address for correspondence Sara V. Bates, MD Division of Newborn Medicine and Neonatology, Massachusetts General Hospital for Children 55 Fruit Street, Founders 530Boston, MA 02114 sbates@ 123456partners.org

Article

Publisher ID: 12r0046

DOI: 10.1055/s-0033-1338168

PMC ID: 3799712

PubMed ID: 24147236

SO-VID: 53d61b8f-0336-4621-9430-dc91740172b0

History

Date received : 13 December 2012

Date accepted : 24 January 2013

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BRAF V600E-Positive Multisite Langerhans Cell Histiocytosis in a Preterm Neonate

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Abstract

Most cited references 20

Dramatic efficacy of vemurafenib in both multisystemic and refractory Erdheim-Chester disease and Langerhans cell histiocytosis harboring the BRAF V600E mutation.

Cell-specific gene expression in Langerhans cell histiocytosis lesions reveals a distinct profile compared with epidermal Langerhans cells.

Descriptive epidemiology of childhood Langerhans cell histiocytosis in France, 2000-2004.

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