ARTICLE OPEN ACCESS

Cutaneous neurofibromasCurrent clinical and pathologic issues

Nicolas Ortonne, MD, PhD,* Pierre Wolkenstein, MD, PhD,* Jaishri O. Blakeley, MD, Bruce Korf, MD, PhD,

Scott R. Plotkin, MD, PhD, Vincent M. Riccardi, MD, MBA, Douglas C. Miller, MD, PhD, Susan Huson, MD,

Juha Peltonen, MD, PhD, Andrew Rosenberg, MD, Steven L. Carroll, MD, PhD, Sharad K. Verma, PhD,

Victor Mautner, MD, Meena Upadhyaya, PhD, and Anat Stemmer-Rachamimov, MD

Neurology® 2018;91 (Suppl 1):S5-S13. doi:10.1212/WNL.0000000000005792

Correspondence

Dr. Wolkenstein

pierre.wolkenstein@aphp.fr

AbstractObjectiveTo present the current terminology and natural history of neurofibromatosis 1 (NF1) cuta-neous neurofibromas (cNF).

MethodsNF1 experts from various research and clinical backgrounds reviewed the terms currently in usefor cNF as well as the clinical, histologic, and radiographic features of these tumors usingpublished and unpublished data.

ResultsNeurofibromas develop within nerves, soft tissue, and skin. The primary distinction betweencNF and other neurofibromas is that cNF are limited to the skin whereas other neurofibromasmay involve the skin, but are not limited to the skin. There are important cellular, molecular,histologic, and clinical features of cNF. Each of these factors is discussed in consideration ofa clinicopathologic framework for cNF.

ConclusionThe development of effective therapies for cNF requires formulation of diagnostic criteria thatencompass the clinical and histologic features of these tumors. However, there are several areasof overlap between cNF and other neurofibromas that make distinctions between cutaneousand other neurofibromas more difficult, requiring careful deliberation with input across themultiple disciplines that encounter these tumors and ultimately, prospective validation. Theultimate goal of this work is to facilitate accurate diagnosis andmeaningful therapeutics for cNF.

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*These authors contributed equally to this work.

From the Departments of Pathology (N.O.) and Dermatology (P.W.), French Referral Center for Neurofibromatoses, Henri-Mondor Hospital, AP-HP, University Paris Est Creteil,France; Department of Neurology (J.O.B., S.K.V.), Johns Hopkins University School of Medicine, The Neurofibromatosis Therapuetic Acceleration Program, Baltimore, MD; University ofAlabama at Birmingham (B.K.); Cancer Center and Department of Neurology (S.R.P.) and Department of Pathology, Division of Neuropathology (A.S.-R.), Massachusetts GeneralHospital, Boston; The Neurofibromatosis Institute (V.M.R.), La Crescenta, CA; Department of Pathology & Anatomical Sciences (D.C.M.), University of Missouri School of Medicine,Columbia; Manchester Centre for GenomicMedicine (S.H.), Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, UK; Instituteof Biomedicine (J.P.), University of Turku, Finland; Department of Pathology and Laboratory Medicine (A.R.), Jackson Memorial Hospital/University of Miami Miller School of Medicine,FL; Department of Pathology and Laboratory Medicine (S.L.C.), Medical University of South Carolina, Charleston; Clinics and Polyclinics of Neurology (V.M.), University HospitalHamburg-Eppendorf, Hamburg, Germany; and Division of Cancer and Genetics (M.U.), Institute of Medical Genetics, Cardiff University, UK.

Go to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.

The Article Processing Charge was funded by The Neurofibromatosis Therapeutic Acceleration Program at Johns Hopkins.

This is an open access article distributed under the terms of the Creative Commons Attribution License 4.0 (CC BY), which permits unrestricted use, distribution, and reproduction in anymedium, provided the original work is properly cited.

Copyright © 2018 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology. S5

There are many clinical features associated with the neuro-genetic condition neurofibromatosis type 1 (NF1). However,the feature that affects the majority of NF1 patients is thedevelopment of cutaneous neurofibromas (cNF).1 Neuro-fibromas are defined as histologically benign (WHO grade I)tumors composed of multiple cell types including Schwanncells, fibroblasts, immune cells (such as mast cells and mac-rophages), and other elements of nerve.2 Regardless of theirlocation, all neurofibromas share certain histologic and cel-lular characteristics.

The most common and prominent location of neurofibromasis the skin (skin is defined in this article as including epidermisand dermis). Discrete lesions are often referred to as dermalor cutaneous neurofibromas. cNF are benign and, unlikeplexiform neurofibromas (pNF), are not known to have anymalignant potential.3

Although not life-threatening, cNF have a major effect uponquality of life (QoL) for most patients with NF1 due to theirprevalence and disfigurement.4–12 Furthermore, the numberof cNF increases with age after adolescence and throughouta patient’s lifespan. Despite the high prevalence of cNF inpeople with NF1 and their documented influence on QoL,current treatment is limited to surgical removal or physicaldestruction.

There have been several efforts to define the various forms ofneurofibromas, resulting in a number of classification systemsproposed by neurologists, clinical geneticists, dermatologists,pathologists, and basic researchers (table 1).3,13–16 Some ofthese schemes are incompatible with one another, which mayimpede, rather than enhance, the transfer of knowledge frombasic and translational science to clinical care. An agreed-uponclassification system would facilitate research addressingcritical questions such as the comparisons between humandisease and Nf1 mouse models of cNF, whether there arespecific responses to treatments based on potential subtypesof cNF, or if cNF might respond similarly or differently totherapies than other neurofibromas (potentially allowing cNFto serve as a surrogate for pNF). This article reviews the termsin current use for cNF and outlines the critical factors con-tributing to the definition of cNF, with the ultimate goal ofcreating a draft framework for a classification system to bevalidated in future prospective studies.

MethodsThis work is the result of 2 multidisciplinary meetings, onesponsored by the Neurofibromatosis Therapeutics Acceleration

Program in 2016, and another by The European Neurofibro-matosis Group in 2008. Across these 2 meetings, internationalexperts from within and outside the NF field (with expertise indermatology, genetics, neurology, neuro-oncology, dermatopa-thology, neuropathology, regenerative medicine, and plasticsurgery) reviewed different aspects of cNF, including clinicalfeatures, biology, effects on QoL, and existing proposed classi-fication schemes of neurofibromas (table 1).

A literature search using the terms NF1, cNF, plexiform neu-rofibroma, dermal neurofibroma, classification, pain, itching,and QoL was completed. Although cNF may be sporadic insome instances, this review is focused on the cNF arising in thecontext of NF1. The investigators met to review these areas,including critical elements of each proposed classification sys-tem, with the intent of using this information as a frameworkfor the longer-term goal of developing a single unified, data-driven classification system for cNF incorporating core featuresof cNF including pattern of growth (localized or diffuse) andanatomical location (skin, subcutaneous tissue, or deep nerve).

ResultsCutaneous neurofibromas: Clinical definitionsor descriptorsThis article is focused on cNF, which are benign and arise in andare limited to the skin. They are localized but not encapsulatedand do not show clear association to myelinated nerves. Theypresent clinically as a well-defined cutaneous lesion, most oftenas a nodule or plaque.3 cNF is the preferred term over dermalneurofibroma, as the term cNF distinguishes between discreteneurofibromas of the skin and neurofibromas that arise indeeper tissues but invade into the dermis. The term cNF doesnot encompass deep, large, or diffusely infiltrating tumors thatinvolve the dermis.3 However, the skin may also be secondarilyinvolved by extension of a deep or plexiform neurofibroma,either by involvement of cutaneous nerves (i.e., plexiformgrowth pattern) or by diffuse infiltration of the subcutaneousand cutaneous tissue (i.e., diffuse growth pattern). The impor-tance of distinguishing true cNF from extension of deep neu-rofibromas into the skin is particularly important when atypicalchanges are present. The presence of cytologic atypia or pro-liferation in a cNF represents reactive or degenerative changesand is not worrisome, while similar changes in a plexiformneurofibroma that may involve the skin can be a manifestationof malignant transformation.17

Natural history of cNFcNF most commonly become clinically apparent after pu-berty.1 However, there is a wide range of clinical presentation

GlossarycNF = cutaneous neurofibromas; NF1 = neurofibromatosis type 1; NOS = not otherwise specified; OCT = optical coherencetomography; pNF = plexiform neurofibromas; QoL = quality of life; US = ultrasound.

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with select genotype–phenotype correlations. In the smallsubset of people with NF1 microdeletions, cNF are morelikely to be apparent earlier in childhood.18 In contrast, inpeople with NF1 deletion in p.Met992del, or a missensemutation affecting p.Arg1809, there are few to no cNFthroughout life.19–22 Additional details around the biol-ogy of genotype–phenotype correlations are discussed byBrosseau et al.23 in this series. In the majority of peoplewith NF1, the number of cNF increases with age such thatthere are more tumors present in older patients.1 There areno known predictive factors to determine the eventual

number or types of cNF that will appear on an individualwith NF1 (other than the small subsets with specific typesof mutation listed above). Furthermore, there is dramaticvariability in cNF burden between patients, and evenwithin families harboring the same NF1 mutation. Retro-spective studies suggest that women experience an increasein the size and numbers of cNF during pregnancy.24–26

Finally, it has been suggested that people with NF1 havelow serum vitamin D concentrations, especially those withmany cNF. However, it is not clear if these factors arecausative or correlative.27

Table 1 Clinicopathologic classification of neurofibromas

Proposed classification Proposed by

Cutaneous neurofibromas Jouhilahti et al.3

Subcutaneous neurofibromas

Intraneural neurofibromas

Plexiform neurofibromas

Localized cutaneous neurofibromas Carroll and Ratner13

Diffuse cutaneous neurofibromas

Localized intraneural neurofibromas

Plexiform neurofibromas

Massive soft tissue

Localized neurofibromas Rosenberg14

Plexiform neurofibromas

Diffuse neurofibromas

Pigmented neurofibromas

Dermal neurofibromas Huson15

Nodular neurofibromas

Plexiform neurofibromas

Discrete cutaneous neurofibromas of the dermis and epidermis (endoneurialneurofibroma)

Friedman and Riccardi16

Discrete subcutaneous neurofibromas that lie deeper in the skin (perineurialneurofibroma)

Nodular plexiform neurofibromas (perineurial neurofibroma)

Diffuse plexiform neurofibromas (epineurial neurofibroma)

Cutaneous neurofibromas Goldblum et al.44

Subcutaneous neurofibromas

Diffuse neurofibromas

Localized cutaneous neurofibromas Stemmer-Rachamimov, Wolkenstein, and Ortonne(unpublished, 2008)

Localized subcutaneous neurofibromas

Diffuse cutaneous and subcutaneous neurofibromas

Localized intraneural neurofibromas

Plexiform neurofibromas

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Clinical features and effect on QoLPatients and clinicians report multiple different appearances ofcNF, ranging from barely visible flat nodules with subtle dis-coloration to large and pedunculated masses (figure 1). Itremains unknown if this variability in appearance is an expres-sion of the various stages of the evolution of a single tumor, orrepresents different subtypes of cNF. One proposed classifica-tion system assigns 1 of 5 subcategories to describe the clinicalappearance of cNF28: nascent, flat, sessile, globular, or pedun-culated (figure 2). The nascent/latent cNF (figure 2A) is notapparent by inspection or palpation of the skin, but can beappreciated by proper imaging techniques, such as high-resolution ultrasound (US) and optical coherence tomography(OCT) imaging, which are discussed by Cannon et al.29 in thisseries. The flat cNF (figure 2B) is visible at the skin surface, andis distinguished primarily by its slightly raised surface. Thesurface may appear thinner and somewhat pale compared toadjacent uninvolved skin, or there may be some increasedpigmentation and peripheral coarse hairs (bristles). Flat cNFtend to range in size from 0.5 to 12millimeters. The sessile cNF(figure 2C) is raised compared to the adjacent skin and there isusually an apparent apex. The height of the apex may be as high

as 8–10 mm. The surface and texture are essentially the same asthat of the flat lesion. There may be erythema or hyperpig-mentation, as well as bristle hirsutism. These lesions typicallyhave a maximal diameter of roughly 1.0 to 10–12 mm. Imaging(US or OCT) may reveal more extensive cNF elements belowthe surface of the skin. The globular cNF (figure 2D) has a baseat the surface of the skin that may be 20–30 mm in diameter,with a comparable height and a globular shape. Moving theraised portion of globular neurofibromas (i.e., above the sur-rounding uninvolved skin surface) can help a clinical examiner

Figure 1 Polymorphism of cutaneous neurofibromas (cNF)in a single patient

Many different aspects of cNF can be seen in this patient, including sessilecNF (arrows), globular cNF (arrowheads), and pedunculated cNF (asterisks).NF = neurofibromas.

Figure 2 Proposed categories of clinically observed cuta-neous neurofibromas (cNF) to be considered inthe prospective validation study

(A) Nascent/latent cNF. (B) Flat cNF. (C) Sessile cNF. (D) Globular cNF. (E)Pedunculated cNF.

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to identify a deeper part of the lesion. The pedunculated cNF(figure 2E) has a stalk that joins the portions above and belowthe skin surface. The stalk is usually several millimeters long and1–3 mm in diameter. The diameter of the superficial portion isusually between 5 and 25 millimeters.

Roughly 20% of people with NF1 report pruritus.30 Chronicpruritus can be an independent factor for altered QoL as itcauses sleep disruption as well as the emotional experience ofchronic pain.30 Among those with pruritus, 52.5% complainedof pruritus localized to one or more cNF. The pathophysi-ology of pruritus in NF1 is not well-understood. It is hy-pothesized that mast cells and components released fromtheir degranulation are a major cause of pruritus, as mast cellsare well-known to be present in the cNF microenvironmentand may contribute to tumor initiation, progression, andangiogenesis.31–36 However, it is also possible that pruritus isa manifestation of a neuropathy affecting the small nervetributaries in the skin, which are integral to the developmentof these tumors.30,37 Indeed, anecdotally, people with NF1report improvement in pruritus after therapy with anti-neuropathic agents such as gabapentin or mast cell stabilizingagents such as ketotifen, indicating that bothmechanismsmaybe active.

Although cNF are not life-threatening, the majority of patientsreport cNF-associated disfigurement as their major problemrelated to NF1. Combined responses from several surveysshow that between 97% and 100% of adults with NF1 whoparticipated reported skin lesions and >60% reportedmoderateto severe visibility of these lesions.8,9,11,12 In all of these studies,the visibility of disease was independently associated with ad-verse emotional state, physical symptoms, and poor function

assessed with skin-disease-specific QoL and general healthmeasures.11,12 The effect of disfigurement on QoL has beenevaluated through the use of dermatologic scales such asSkindex.8,9,12 Using this tool as well as measures of overalldisease-associated QoL (i.e., Short Form–36), the burden ofdisfigurement on QoL in patients with NF1 has been high-lighted across multiple studies.5,6,8–11,38 The greatest effect onQoL from cNF is emotional: patients with more visible tumorsreport significantly greater overall negative effects on their skin-disease-specific QoL, and visible features of cNF are associatedwith severe depression. The magnitude of this effect is similarto that reported in the literature for patients with psoriasis,a skin condition traditionally regarded as causing significantdisability. These results underscore the link between cNF dis-ease visibility and psychological well-being.11 As such, reducingdeformity is a priority in adult patients with NF1.11 For ex-ample, people with NF1 who graded themselves to be moreseverely affected expressed greater fear about the appearance ofthe lesions.12

Histology of cNFHistologically, all neurofibromas are mixed tumors consistingof cells of diverse lineages. cNF are composed of neoplasticSchwann cells and non-neoplastic elements including mast cellsand fibroblasts.39 There are also often other cells includingnerve sheath elements (i.e., perineurial cells) and cells fromvarious skin adnexae (e.g., hair follicles, eccrine sweat glands,sebaceous glands).13 On occasion, adipocytes may be seques-tered in or intrinsic to the lesion.40 Correspondingly, the use oftraditional histologic stains, as well as immunohistochemistrywith a variety of biomarkers and electron microscopy, hasshown the involvement of S100+ Schwann cells, EMA+ peri-neurial cells, mast cells, lymphocytes, CD34+ fibroblasts, as well

Figure 3 Cutaneous neurofibromas (cNF), morphologic aspect

The lesion is made of scatteredspindle cells (arrowheads) that cor-respond to Schwann cells and fibro-blasts, admixed with numerouscapillaries and veins (asterisks) andmast cells (arrows) (hematoxylin andeosin, ×400, and inset ×25).

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as axonal elements41,42 (figures 3 and 4). Pigmented cNF maybe associated with melanocytic cells (or the neoplastic Schwanncells that may become melanotic).43 Other notable featuresseen on occasion include the formation of Meissner-like cor-puscles.44 It is presumed that the Schwann cells are neoplastic(NF1−/−) and that the other cells are either present initially orrecruited into the lesion, but are not neoplastic (NF1−/+).However, the definitive cell of origin for human cNF has yetto be defined but has been postulated to be a progenitor cellcalled a skin-derived precursor cell. Preclinical models suggestthat these cells are distinct from the cells that give rise topNF.45 There are additional data indicating that multipotentneurofibroma-derived precursor cells, perhaps arising from

stem cells around hair roots closely associated with cNF, are thecausative cells.3 Together, these data suggest that cNF and otherforms of neurofibromas may arise from different precursor cellseven though they have similar cellular compositions.

The diverse cellular components of neurofibromas areembedded in an abundant collagenous and often myxoidextracellular matrix. Histologically, cNF cannot be differ-entiated from neurofibromas elsewhere in the body as thefeatures and cell composition are present in the variousforms of neurofibromas. Hence, to accurately identify a le-sion as cNF, the surgical specimen must include a margin ofuninvolved skin.

Figure 4 Histopathologic features of cutaneous neurofibromas (cNF)

cNF in which various cell types areevidenced using immunostainings. (A,B) Hematoxylin & eosin at 25 and 200magnification show a cNF presentingas a self-limiting tumor in the skin withno peripheral capsule and in whichnumerous spindle cells are seen. (C–G)Immunostainings developedwith DABwith antibodies to CD117 (C, ×200),S100 protein (D ×25 and E ×100), andCD34 (F ×25 and G ×100). These stainsdemonstrate numerous mast cellsshowing strong membrane expres-sion of CD117 (C), Schwann cells dis-playing heterogeneous cytoplasmicand nuclear expression of S100 pro-tein (D, E), and CD34+ fibroblasts (F,G).

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Cutaneous neurofibromas as a subset of allneurofibromas: Plan to address the challengesin creating a modern classification systemIn addition to classifications already published in articles ortextbooks, other unpublished classification systems have beenproposed. Two unpublished systems were presented at theEuropean NF meeting (2008) by Ortonne et al. and Stemmer-Rachamimov et al., in which a comprehensive synthesis ofclinical and pathologic features was attempted (table 1 andfigure 5). These 2 systems are very similar and may be the basisof a new integrated classification system, if validated pro-spectively. These schemes propose defining neurofibromasby their clinical appearance and histologic features: growthpattern (diffuse/infiltrating or localized), relationship to nerve(intraneural or extraneural, without any perineurial capsule),and anatomic location (cutaneous, cutaneous/subcutaneous,deep). The resulting categories proposed were cutaneous NF(discrete) and larger NF involving skin and subcutaneous tissue

(diffuse, with or without atypia) (table 2). This scheme for cNF(table 2 and figure 5) aims to differentiate classic cNF fromdeep neurofibromas that may involve skin and subcutaneoustissues. As above, it is important to appreciate that an un-derlying plexiform NF extending into the skin (plexiformintraneural, diffuse associated with plexiform) has different riskprofiles than cNF purely limited to the skin. This histologicdistinction cannot be made if the sample provided does notreveal the underlying plexiform lesion and shows only theextraneural diffusely infiltrating portion of the tumor in skin. Insuch instances, histologic distinction from a true cNF is im-possible and the term NF involving skin and subcutaneoustissue; diffuse, not otherwise specified (NOS) is most appro-priate. Although molecular information is lacking, there is anopportunity to apply common terminology to classify neuro-fibromas clinically and pathologically in a systematic fashion.Based on the current state of the field, a modern classificationsystem for cNF will be built on the defined clinical and

Figure 5 Unified clinicopathologic aspects of neurofibromas

(A) Clinical pictures show the various subtypes of cutaneous neurofibromas (cNF). This includes digital photographs of nascent (visible by ultrasound, but notthe naked eye), flat, sessile, globular, and pedunculated cNF. The ultrasound image is courtesy of Dominique Pichard. The red arrow tip indicates the cNFinvolving the epidermis and dermis. (B) Gross and histologic pictures show the various NF subtypes involving skin and subcutaneous tissue (diffuse, with orwithout atypia). The upper panels show a cutaneous and subcutaneous NF with diffuse growth pattern replacing the dermis (upper right picture) and thesubcutaneous fat tissue (hematoxylin & eosin, ×25 and ×100). The middle panels show a neurofibroma involving the dermis and subcutaneous tissue with 2distinct growth patterns including plexiform (arrowheads) and diffuse (hematoxylin & eosin, ×25). The lower panels show a neurofibroma located entirely inthe subcutaneous tissue with a plexiform neurofibroma with intraneural growth pattern (hematoxylin & eosin, ×100).

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pathologic features (table 2) with a plan to incorporate mo-lecular and imaging data as they become available. An ongoingstudy is evaluating the accuracy of this system with a blindedreview by dermatopathologists and neuropathologists. Thelong-term goal is to have an integrated molecular, clinical, andpathologic classification that best reflects the biology of cNF.

As a first step, the term cNF should be reserved for the discreteneurofibroma limited to the skin, which develop into andmainly involve the dermis, never show a plexiform architecture,and never transform into a malignant peripheral nerve sheathtumor. Further research is needed to determine if there aresubtypes of cNF. The term diffuse neurofibroma is advisablefor neurofibromas that involve the skin and subcutaneous tis-sues without clear margins. These tumors may have a diffuse,plexiform, or both patterns. Inherent in these terms is an am-biguity between neurofibromas that are clinically localized buthave no perineurial capsule and so could be histologically dif-fuse and those that are clinically more diffuse. In the case ofpartial biopsies or superficial excisions, one may miss a deeperplexiform organization or the involvement of a definable nervetrunk, and so the category for diffuse, NOSwas introduced. It isimportant to note that the approach for resection and clinicaldescription of the lesion is particularly important for thesetumors. The term plexiform is applied to intraneural neuro-fibromas. These initial definitions will be applied to prospectivevalidation studies across dermatopathologists and neuro-pathologists to formalize the pathologic definitions of cNF.

DiscussioncNF are common and a major clinical burden for people withNF1, prominently affecting QoL and emotional well-being as

well as physical comfort. Currently, the only way of treatingcNF is removal by procedural methods such as electro-dessication, CO2 laser, or surgery.46 Developing effectivemedical therapies for existing cNF and prevention of cNFare priorities for the majority of adults with NF1. De-velopment of a reliable and widely accepted nosology basedon clinical, genetic, and radiologic features of cNF is a crucialstep in investigating these tumors to better understand theirdevelopment and start to uncover opportunities for tumor-specific therapies that will allow reduction in the clinicalsymptoms and burdens of cNF for people with NF1. Thework presented here creates a framework for prospectivevalidation studies to more accurately define cNF. Ultimately,this will facilitate score diagnosis of these lesions and theefficient development of therapeutics.

Author contributionsN. Ortonne: drafting the manuscript, development of recom-mendations. P. Wolkenstein: drafting the manuscript, de-velopment of recommendations. J. Blakeley: drafting themanuscript, development of recommendations. B. Korf: reviewof manuscript, development of recommendations. S. Plotkin:review of manuscript, development of recommendations. V.M.Riccardi: drafting and review of manuscript, development ofrecommendations. D.C. Miller: review of manuscript, de-velopment of recommendations. S. Huson: review of manu-script, development of recommendations. J. Peltonen: reviewof manuscript, development of recommendations. A. Rosen-berg: review of manuscript, development of recommendations.S. Carroll: review of manuscript, development of recom-mendations. S. Verma: drafting and review of manuscript,development of recommendations. V. Mautner: review ofmanuscript, development of recommendations. M. Upad-hyaya: review of manuscript, development of recom-mendations. A. Stemmer-Rachamimov: drafting and review ofmanuscript, development of recommendations.

Study fundingThis publication was supported by an agreement from TheJohns Hopkins University School of Medicine and the Neu-rofibromatosis Therapeutic Acceleration Program (NTAP).Its contents are solely the responsibilities of the authors anddo not necessarily represent the official views of The JohnsHopkins University School of Medicine.

DisclosureN. Ortonne reports no disclosures relevant to the manu-script. P. Wolkenstein receives fees from Pierre FabreDermatologie. J. Blakeley reports no disclosures relevant tothe manuscript. B. Korf reports consulting fees fromNovartis. S. Plotkin reports ownership in NFlection andconsulting fees from Novartis. V. Riccardi, D. Miller,S. Huson, J. Peltonen, A. Rosenberg, S. Carroll, S. Verma,V.Mautner,M. Upadhyaya, and A. Stemmer-Rachamimov reportno disclosures relevant to the manuscript. Go to Neurology.org/N for full disclosures.

Table 2 Potential unified classification system forcutaneous neurofibromas

A. Cutaneous neurofibromas (discrete)

Clinical variants

• Nascent (seen on ultrasound or similar imaging only)

• Flat

• Sessile

• Globular

• Pedunculated

B. Extensive neurofibromas (with or without atypia)

Histologic variants

• Diffuse with or without particular differentiation (melanocytic, Meissner/round cells)

• Diffuse associated with plexiform (plexiform and diffuse)

• Diffuse, not otherwise specified

• Plexiform intraneural

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Received November 1, 2017. Accepted in final form April 16, 2018.

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Neurology.org/N Neurology | Volume 91 (Suppl 1) | July 10, 2018 S13

DOI 10.1212/WNL.00000000000057922018;91;S5-S13 Neurology 

Nicolas Ortonne, Pierre Wolkenstein, Jaishri O. Blakeley, et al. Cutaneous neurofibromas: Current clinical and pathologic issues

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