Article

Plexiform neurofibromas in NF1: Toward biologic-based therapy

Department of Neurology, Children's National Medical Center, George Washington University, Washington, DC 20010, USA.
Neurology (Impact Factor: 8.3). 06/2002; 58(10):1461-70. DOI: 10.1212/WNL.58.10.1461
Source: PubMed

ABSTRACT Neurofibromatosis type 1 (NF1) is one of the most common neurogenetic diseases affecting adults and children. Neurofibromas are one of the most common of the protean manifestations of NF1. Plexiform neurofibromas, which will frequently cause cosmetic abnormalities, pain, and neurologic deficits, are composed of "neoplastic" Schwann cells accompanied by other participating cellular and noncellular components. There is increasing evidence that loss of NF1 expression in neoplastic Schwann cells is associated with elevated levels of activated RAS, supporting the notion that the NF1 gene product, neurofibromin, acts as a growth regulator by inhibiting ras growth-promoting activity. In addition, there is increasing evidence that other cooperating events, which may be under cytokine modulation, are important for neurofibroma development and growth. Treatment of plexiform neurofibromas has been empiric, with surgery being the primary option for those with progressive lesions causing a major degree of morbidity. The efficacy of alternative treatment approaches, including the use of antihistamines, maturation agents, and antiangiogenic drugs, has been questionable. More recently, biologic-based therapeutic approaches, using drugs that target the molecular genetic underpinnings of plexiform neurofibromas or cytokines believed important in tumor growth, have been initiated. Evaluation of such trials is hindered by the unpredictable natural history of plexiform neurofibromas and difficulties in determining objective response in tumors that are notoriously large and irregular in shape. Innovative neuroimaging techniques and the incorporation of quality-of-life scales may be helpful in evaluation of therapeutic interventions. The ability to design more rational therapies for NF1-associated neurofibromas is heavily predicated on an improved understanding of the molecular and cellular biology of the cells involved in neurofibroma formation and growth.

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    • "Thus, it may be difficult to justify resection of a small plexiform neurofibroma in a child with a plexiform neurofibroma on the assumption that the tumor might grow at some time in the future. Therefore, surgical resection of PNs is usually reserved for markedly symptomatic lesions that compromise function [15] [16]. "
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    • "At least 95% of NF1 patients carry a constitutional mutation of a tumor suppressor gene located on the long arm of chromosome 17 (17q11.2) together with a functional copy of this same gene (Messiaen et al., 2000). Analyses of family pedigrees suggest that while the mutated gene may be inherited from a parent, new mutations occur at a high rate in the NF1 locus and up to 50% of cases are new mutations (Packer et al., 2002); indeed, NF1 has the highest rate of new mutation of any known single gene disorder (Theos and Korf, 2006). "
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    ABSTRACT: Neurofibromas are benign tumors of peripheral nerve that occur sporadically or in patients with the autosomal dominant tumor predisposition syndrome neurofibromatosis type 1 (NF1). Multiple neurofibroma subtypes exist which differ in their site of occurrence, their association with NF1, and their tendency to undergo transformation to become malignant peripheral nerve sheath tumors (MPNSTs), the most common malignancy associated with NF1. Most NF1 patients carry a constitutional mutation of the NF1 tumor suppressor gene. Neurofibromas develop in these patients when an unknown cell type in the Schwann cell lineage loses its remaining functional NF1 gene and initiates a complex series of interactions with other cell types; these interactions may be influenced by aberrant expression of growth factors and growth factor receptors and the action of modifier genes. Cells within certain neurofibroma subtypes subsequently accumulate additional mutations affecting the p19(ARF)-MDM2-TP53 and p16INK4A-Rb signaling cascades, mutations of other as yet unidentified genes, and amplification of growth factor receptor genes, resulting in their transformation into MPNSTs. These observations have been validated using a variety of transgenic and knockout mouse models that recapitulate neurofibroma and MPNST pathogenesis. A new generation of mouse models is also providing important new insights into the identity of the cell type in the Schwann cell lineage that gives rise to neurofibromas. Our improving understanding of the mechanisms underlying the pathogenesis of neurofibromas and MPNSTs raises intriguing new questions about the origin and pathogenesis of these neoplasms and establishes models for the development of new therapies targeting these neoplasms.
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    • "It has been reported [Karvonen et al., 2000] that many tiny neurofibromas have been found in the normallooking skin of NF1 patients, indicating a more widespread occurrence than was previously understood . Large neurofibromas can also arise from multiple nerves within plexuses, termed plexiform neurofibromas [Packer et al., 2002]. Plexiform neurofibromas, generally first arising in early childhood, are often relatively stable for a number of years, but are capable of aggressive growth, particularly as puberty approaches or during pregnancy. "
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