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Diagnostic Review of Neurofibromatosis Type 1

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 REVIEW
Diagnostic Review of Neurofibromatosis Type 1
Vineeta V. Batra, MD,*Þ Michael Mines, MD,Þþ and Fausto J. Rodriguez, MDÞ
Abstract: Neurofibromatosis type 1 (NF1) is an autosomal dominant
genetic syndrome associated with numerous neoplastic and nonneoplastic
manifestations affecting a variety of organ systems, including skin, eye,
nervous system, skeleton, and endocrine and gastrointestinal tract. The
syndrome results from heterozygous germline mutations in the NF1 gene
encoding for neurofibromin. Somatic inactivation of the remaining NF1
gene is a near-universal feature in tumors developing in these patients.
Tumors of the nervous system are an important cause of morbidity and
mortality in NF1 patients. These include low-grade neoplasms with little
malignant potential (eg, pilocytic astrocytomas and localized neurofi-
bromas), premalignant tumors (eg, plexiform neurofibromas), and high-
grade malignant tumors (eg, malignant peripheral nerve sheath tumors
and high-grade astrocytomas). It is important for pathologists to ac-
curately classify these tumors and to separate atypical from frank ma-
lignant changes in surgical specimens. Ancillary techniques may be
helpful in the diagnosis of malignant tumors in NF1 patients, including
immunohistochemistry for p53 and p16 protein, as well molecular
testing for CDKN2A loss. A subset of tumors occurring in NF1 patients
is difficult to classify or may contain hybrid features preventing unequiv-
ocal assignment to a single diagnostic category. Occurrence of specific
peripheral nerve sheath tumor types, such as deep/large plexiform neuro-
fibromas and massive soft-tissue neurofibromas, is essentially limited to
NF1 patients. Therefore, appropriate recognition of neoplasms occurring
in the context of NF1 has important ramifications for clinical management
in this unique patient population.
Key Words: neurofibromatosis, neurofibroma, malignant peripheral
nerve sheath tumor, glioma, astrocytoma, pilocytic astrocytoma,
plexiform neurofibroma
(Pathology Case Reviews 2014;19: 57Y65)
N eurofibromatosis type 1 (NF1) is a common autosomal
dominant genetic disorder with an approximate incidence
of 1 in 3000 individuals worldwide1 and affects individuals
of all races and geographical regions. Neurofibromatosis type 1
was first characterized as a distinct clinicopathologic disorder
in detail by von Recklinghausen2 in 1882. It is a multisystem
disorder and presents with involvement of the skin, eye, bone,
cardiovascular system, and central nervous system (CNS). The
culprit tumor suppressor gene was identified in 1990.3,4
Clinical Presentation
Neurofibromatosis type 1 is an extraordinarily variable
condition. Some patients have very mild manifestations, whereas
others are severely affected.5 Cutaneous manifestations such as
*From the Department of Pathology, GB Pant Hospital, New Delhi, India;
and †Department of Pathology, Johns Hopkins University, Baltimore;
‡Ophthalmology Division, Department of Surgery, Uniformed Services
University, Bethesda, MD.
Reprints: Fausto J. Rodriguez MD, Department of Pathology, Division of
Neuropathology, Johns Hopkins Hospital, Sheikh Zayed Tower,
Room M2101, 1800 Orleans St, Baltimore, MD 21231.
E-mail: frodrig4@jhmi.edu.
This work has been supported in part by the childhood brain tumor foundation.
The pilocytyl pilomyxoid fund and the Knights Templar Eye Foundation.
The authors have no funding or conflicts to declare.
Copyright * 2014 by Lippincott Williams & Wilkins
ISSN: 1082-9784
Pathology Case Reviews & Volume 19, Number 2, March/April 2014
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
café-au-lait (CAL) spots and cutaneous neurofibromas occur in
at least 95% of patients, whereas other features occur at a lesser
frequency.
Although it is thought that NF1 penetrance is 100%, with
appropriate follow-up, the extent of organ involvement and clin-
ical manifestations, even within families, is variable. Therefore,
the National Institutes of Health Consensus Development Con-
ference established formal diagnostic criteria for NF1.6 Diagnos-
tic criteria are summarized in Table 1.
Neurofibromatosis type 1 is a progressive condition; differ-
ent complications occur at specific times, and some complications
worsen over time. Café-au-lait spots, pseudoarthrosis, and exter-
nally visible plexiform neurofibromas are usually apparent within
the first year of life. Freckling, optic gliomas, and severe scoliosis
occur later. Cutaneous neurofibromas and iris Lisch nodules tend
to appear in teenage or young adult years. Malignant neoplasms
and pheochromocytomas occur mostly in adults.
Genetics of NF1
Neurofibromatosis type 1 is caused by a germline mutation
in the tumor suppressor gene NF1. Neurofibromatosis type 1 is
a dominantly inherited genetic condition in which all affected
individuals harbor a constitutional NF1 gene mutation. Thus,
they are born with 1 functional and 1 nonfunctional copy of NF1
gene. Approximately 50% of these mutations are inherited, and
50% are new mutations.
The NF1 gene resides on chromosome region 17q11.2 in
humans and encodes a 220- to 250-kd cytoplasmic protein called
neurofibromin. Neurofibromin acts as a tumor suppressor and
normally limits cell growth by acting as a negative regulator of
RAS, a key intracellular signaling protein that is important for
regulation of cell growth and survival. Loss of neurofibromin
results in unopposed RAS activity, constitutive downstream sig-
naling, and increased cell growth.7 As a result, NF1 presents as a
tumor predisposition syndrome in which children and adults are
prone to develop tumors, particularly of the peripheral nervous
system and CNS.
Increased RAS activity also leads to activation of several
important downstream signaling intermediates including the mam-
malian target of rapamycin (mTOR) protein. mTOR is activated in
NF1-deficient cells and associated tumors. mTOR inhibitors such
as rapamycin and their analogs may thus have a potential thera-
peutic role in NF1 as tumor cells lines derived from NF1 patients
are sensitive to mTOR inhibition.8 In addition to regulating RAS,
neurofibromin also binds to microtubules and modulates adenylyl
cyclise activity.9
Phenotypic Variability in NF1
Although the penetrance of NF1 is high, it has been found
to have a variable clinical presentation even within the same
family.5 This phenotypic variability could be produced by a high
rate of spontaneous mutations, somatic mosaicism, modifier genes,
or environmental factors.
Nonneoplastic Manifestations in NF1
Cutaneous
Multiple CAL spots are often the earliest presenting fea-
ture in a child with NF1. Café-au-lait spots are oval or rounded
www.pathologycasereviews.com 57
Batra et al
TABLE 1. Diagnostic Criteria for NF1 (National Institutes
of Health 1991)
Q6 Or more café-au-lait patches 915 mm in adults and 95 mm
in children
Q2 Neurofibromas or 1 plexiform neurofibroma
Axillary or groin freckling
Lisch nodules (iris hamartomas)
OPGs
A first degree relative with NF1
A distinctive osseous lesion such as sphenoid wing dysplasia or
thinning of the long bone cortex with or without pseudoarthrosis
At least 2 or more of the above criteria should be present to make a
clinical diagnosis of NF1.
hyperpigmented flat spots with fairly smooth borders, which
resemble freckles. They are often present at birth and increase
in size over the first 5 to 7 years of life. Pathologically, they are
characterized by increased melanin pigment in the basal layer
of the epidermis. Café-au-lait spots do not have any tendency
toward malignant transformation.
Skin-Fold Freckling
Axillary or inguinal freckling (Crowe sign) is detected most
frequently between 3 and 5 years of age. Additional sites for
freckling include the area above the eyelids, around the neck,
and under the breasts.
Neurological Manifestations
Neurocognitive Deficits
Children with NF1 often present with neurocognitive deficits
in the form of learning disabilities and attention-deficit disorder.
Mental retardation is uncommon, occurring in a minority of
patients with NF1. Learning deficits may include visual-spatial
and visual-motor deficits. Language disorders may also be seen
in children with NF1, who often show fine and gross motor
coordination defects.10
On magnetic resonance imaging, children with NF1 show
unidentified bright objects as focal areas of high intensity on
T2-weighted images. These do not cause neurological deficits
and mostly disappear by adulthood. Current evidence suggests
that they may represent localized areas of myelin abnormalities/
edema and are sometimes difficult to distinguish from low-
grade gliomas.
Musculoskeletal
Orthopedic problems in patients with NF1 include hypo-
tonia, poor coordination, short stature, dystrophic scoliosis, tibial
pseudoarthrosis, and sphenoid wing dysplasia. Short stature and
large head are common in patients of NF1 and are not associated
with hormonal dysfunction. Precocious puberty and gynecomas-
tia may occur in some patients with visual pathway tumors.
Scoliosis is another typical skeletal manifestation of NF1.11
Severe cases may cause spinal cord compression with associ-
ated neurological symptoms and may require surgical interven-
tion. Scoliosis can also occur secondary to pressure from adjacent
plexiform neurofibromas.
Cardiovascular Abnormalities
Cardiovascular abnormalities include congenital heart dis-
ease, vasculopathy, and hypertension. Coronary heart disease
occurs more commonly in patients with NF1 as compared with
58 www.pathologycasereviews.com
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Pathology Case Reviews & Volume 19, Number 2, March/April 2014
the general population. Pulmonary artery stenosis represents
25% of the malformations.12 Neurofibromatosis type 1 vascu-
lopathy includes stenoses, aneurysms, and arteriovenous malfor-
mations. Renal artery stenosis is one of the most common
manifestations of vasculopathy and should be suspected in any
young NF1 patient with hypertension. Histologically, vascular
lesions show fibromuscular dysplasia and intimal thickening, a
phenomenon that appears to be mediated by Ras-Erk pathway
signaling in macrophages with heterozygous neurofibromin loss
in murine models.13
Ocular Manifestations
The ophthalmologic hallmark of NF1 is the Lisch nodule,
the prevalence of which increases with age and approaches
100% by 21 years of age14,15 (Fig. 1). Lisch nodules are loca-
ted on the anterior iris surface and appear as domed, smooth
circumscribed lesions and are typically yellow to brown. They
vary in size up to 2 mm. Although clinically differing in ap-
pearance from iris nevi, which are generally less discrete, Lisch
nodules and iris nevi appear identical microscopically.16 In ad-
dition, structures with less well-defined boundaries but the same
histological features as Lisch nodules can also be found within
the iris stroma.
Periocular plexiform neurofibroma has a predilection for
the lateral eyelid. Classically, it creates S-shaped eyelid ptosis
and is described as having a ‘‘bag of worms’’ consistency. This
tumor frequently is associated with orbital extension, making
surgical intervention difficult. Traditionally, ipsilateral glauco-
ma is reportedly found in up to 50% of NF1 patients with eyelid
plexiform neurofibroma; however, a recent large series identi-
fied glaucoma in only 23%.17 Proposed mechanisms of NF1-
associated glaucoma include neurofibromatous infiltration of
the angle, secondary angle closure resulting from neurofibroma
of the ciliary body and choroid, coexisting congenital angle ab-
normalities, and angle endothelialization.18,19 Both plexiform neu-
rofibroma and the associated glaucoma are congenital in NF1
patients. Localized neurofibromas can also be located within
the orbit and like plexiform neurofibroma can result in prop-
tosis, diplopia, and optic neuropathy secondary to mass effect.
Optic nerve glioma is another cause of proptosis and vision
loss in NF1 patients. Many of these tumors are nonprogressive
and may even spontaneously regress in NF1 patients.20 There-
fore, aggressive surgical approaches for these tumors are rarely
attempted at present. Aplasia or hypoplasia of the greater wing
of the sphenoid bone is another potential finding in NF1 patients
and a diagnostic criterion. Anterior displacement of the temporal
lobe and transmittance of vascular fluid wave dynamics can result
in clinically apparent pulsatile exophthalmos.
Intraocular lesions in NF1 have long been identified and
can involve the ciliary body and choroid.21,22 Termed choroidal
neurofibromatosis by some, this lesion is composed of a ha-
martomatous melanocytic and neuronal infiltrate. A character-
istic feature is the ovoid body composed of concentrically
oriented Schwann cell processes.23 Clinically noted in 29% of
NF1 patients in 1 series, these lesions are described as discrete
areas of hyperpigmentation best appreciated with indirect
ophthalmoscopy and fluorescein angiography.14 More recent
reports suggest that other modalities such as infrared confocal
scanning laser ophthalmoscopy and indocyanine-green angi-
ography reveal the presence of lesions not evident with con-
ventional fundus examination in nearly 100% of patients and
could be diagnostically useful in NF1 patients.24,25 Retinal find-
ings associated with NF1 include combined hamartoma of the
retina and retinal pigment epithelium, retinal capillary hemangi-
oma, and astrocytic hamartoma.26 Other ophthalmic findings
* 2014 Lippincott Williams & Wilkins
Pathology Case Reviews & Volume 19, Number 2, March/April 2014 Diagnostic Pathology of NF1

FIGURE 1. Ocular manifestations of NF1. The most typical ocular manifestation is Lisch nodules, which are often multiple and occur in
the anterior surface of the iris (arrows) (A). They represent hamartomatous melanocytic aggregates with limited growth potential (B).
This plexiform neurofibroma was resected from the orbit of an NF1 patient and demonstrates the characteristic ‘‘bag of worms’’
appearance (C). Neurofibromas in NF1 patients may involve any periocular structures, including the eyelid. They may contain plexiform
(D) and diffuse (E) components. S100 immunostain highlights the neoplastic Schwann cell component (F).

noted in NF1 patients include periocular CAL spots and enlarged
corneal nerves.14
Peripheral Nerve Tumors
Neurofibromas
Neurofibromas, one of the hallmarks of NF1, usually arise
in childhood or adolescence following development of CAL
spots. They are Schwann cell tumors that often arise from the
peripheral nerve sheaths, or in the dermis, and are composed
of Schwann cells, fibroblasts, perineurial cells, myxoid matrix,
and inflammatory cells, including mast cells and lymphocytes
(Fig. 2). Despite the variety of cell types, the neoplastic cells are
Schwann cells, where homozygous NF1 inactivation occurs.27
There are several neurofibroma variants, based on clinical pre-
sentation and/or pathology, including localized, diffuse, cellular,
atypical, plexiform, and massive soft tissue neurofibroma. Of
these, plexiform neurofibromas and massive soft tissue neu-
rofibromas develop almost exclusively in NF1 patients. Numerous
cutaneous localized neurofibromas represent the main neo-
plastic manifestation in NF1 patients. Histologically, localized
neurofibromas are nonencapsulated soft tissue tumors with
a tan-white glistening cut surface. They may be well demarcated
or show diffuse infiltration of the surrounding soft tissue. Mi-
croscopically, they are composed of nodules of Schwann cells
with elongated wavy serpentine nuclei and wire-like collagen
fibrils. Other stromal cells may participate in the growth of
these tumors, including mast cells and macrophages.28 Diffuse
neurofibromas present as larger cutaneous plaques or visceral
involvement. Although they occur in NF1 patients, they are not
unique to the syndrome. Microscopically, pseudomeissnerian
corpuscles may be conspicuous.
Plexiform neurofibromas are almost pathognomonic for the
disease and are characterized by multiple tortuous enlargements
of peripheral nerve fascicles by neurofibroma, which is often
described at the gross level as a ‘‘bag of worms.’’ They may
arise from dorsal spinal roots, nerve plexi, large nerve trunks,
and sympathetic chains. They may be associated with bone de-
formities and have a potential for malignant degeneration into
malignant peripheral nerve sheath tumors (MPNSTs) (Fig. 3).
Massive soft tissue neurofibromas are a distinct variant
that is essentially limited to NF1 patients. These are usually large

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Batra et al Pathology Case Reviews & Volume 19, Number 2, March/April 2014

FIGURE 2. Peripheral nerve tumors in NF1: neurofibroma. Neurofibromas are an important hallmark of NF1 patients. These tumors
are characterized by the presence of neoplastic wavy Schwann cells, a myxoid stroma, and delicate collagen. Stromal cells such
as mast cells (arrows) are common and facilitate tumor growth (A). When arising in the spine, neurofibromas frequently extend to
associated ganglia, resulting in entrapped ganglion cells (arrows) (B). Enlarged hyperchromatic nuclei present in an NF1-associated
neurofibroma. This finding has no prognostic significance (C). Aggregates of pseudomeissnerian corpuscles are frequent in diffuse
neurofibromas (D). Although most neurofibromas arise sporadically, the plexiform (E) and massive soft tissue variants (F) are found almost
exclusively in NF1 patients.

tumors with conspicuous soft tissue infiltration, including skeletal
muscle, leading to negative cosmetic effects.29 They may contain
a cellular component composed of round cells with high nuclear-
cytoplasmic ratios, as well as numerous pseudomeissnerian cor-
puscles. Massive soft tissue neurofibromas generally have little
potential for malignant degeneration, although they may have a
plexiform neurofibroma component with a potential for trans-
formation into MPNST.
Hybrid Benign Peripheral Nerve Sheath Tumors
Most benign nerve sheath tumors exhibit diagnostic fea-
tures that allow them to be placed into a distinct category, such
as perineurioma, neurofibroma, or schwannoma. However, be-
nign nerve sheath tumors with ambiguous architectural and/or
immunohistochemical features or composite tumors occur in
a minority of cases. These include hybrid neurofibroma/
schwannoma,30 hybrid perineurioma/schwannoma,31 or rarely
hybrid neurofibroma/perineurioma.32 Recent data also suggest
that hybrid neurofibroma/schwannoma is overrepresented in the
setting of inherited tumor syndromes such as schwannomatosis,
NF1, or NF2.33
Peripheral Nervous System Neoplasms in the
Gastrointestinal Tract
Benign and MPNSTs may involve the gastrointestinal tract in
patients with NF1. Of interest, a subset of schwannomas develops
in patients with NF1 and may demonstrate loss of heterozygosity in
the NF1 gene locus.34 However, gastrointestinal schwannomas may
lack classic histological features of schwannomas at other sites, for
example, palisades, hyalinized vessels, and a well-defined capsule.
Ganglioneuromatosis is a peculiar hypertrophy involving
autonomic nervous system components of the intestines, partic-
ularly ganglia and plexi, in patients with NF1 or multiple en-
docrine neoplasia type 2b. Full-thickness involvement of the
intestinal wall is typical of multiple endocrine neoplasia type 2b,
whereas involvement limited to the submucosal plexus is the
usual finding in NF1-associated cases.

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Pathology Case Reviews & Volume 19, Number 2, March/April 2014 Diagnostic Pathology of NF1

FIGURE 3. Peripheral nerve tumors in NF1: MPNST. Malignant changes developed in this plexiform neurofibroma, characterized at
the gross level by yellow, necrotic areas (A). Malignant changes in an NF1 neurofibroma, characterized by hypercellularity (left) (B).
Nuclear hyperchromasia, enlargement, and crowding represent minimal criteria for MPNST as proposed by some authors (C). High-grade
MPNST involving a peripheral nerve fascicle (left). Uninvolved nerve fibers are present to the right (D). Most MPNSTs are high-grade
spindle cell neoplasms resembling fibrosarcoma (E). Others may demonstrate more conspicuous pleomorphism (F).

Malignant Peripheral Nerve Sheath Tumor
Patients with NF1 harbor a 7% to 12% lifetime risk of de-
veloping MPNST.35 They often arise from preexisting plexiform
neurofibromas and typically occur between 15 and 40 years of
age. Pain is a particularly worrisome sign for malignant transfor-
mation in nerve sheath tumors of NF1 patients. Malignant pe-
ripheral nerve sheath tumors are often multicentric and may
metastasize widely by the hematogenous route; lungs are a
common site of metastasis. Histologically, most MPNSTs are
cellular, high-grade spindle cell neoplasms. The presence of het-
erologous elements (ie, cartilage, bone, skeletal muscle, glands)
appears to be more frequent in the setting of NF1.36 The presence
of skeletal muscle differentiation defines the so-called ‘‘triton tu-
mor.’’ Immunohistochemical stains demonstrate partial or com-
plete loss of Schwann cell markers by immunohistochemistry
(S100, collagen IV).
One of the most challenging diagnostic exercises in the
evaluation of peripheral nerve sheath tumors is the separation
of transformation of plexiform neurofibroma into MPNST (low-
grade MPNST) from atypical/cellular neurofibroma in NF1 pa-
tients. Atypical neurofibroma has been used by some authors to
define neurofibromas containing cells with degenerative nu-
clear atypia of no clinical significance.37 However, it may also
describe tumors with worrisome histological features (ie,
hypercellularity, increased mitotic activity), but not quite satisfy-
ing criteria for malignancy.38 Of interest, recent molecular studies
have shown molecular alterations typical of MPNST (eg,
CDKN2A deletions) in atypical neurofibromas,39 defined as
neurofibromas with hypercellularity and nuclear enlargement/
hyperchromasia lacking mitotic activity. Increased p53 im-
munostaining40 and p16 protein loss/CDKN2A deletions41 may be
useful ancillary tests in the evaluation of MPNST. Proposed min-
imal criteria for low-/intermediate-grade MPNST include the triad
of hypercellularity, nuclear enlargement (È3 a conventional
neurofibroma nucleus), and hyperchromasia.37 At the molecular
level, multiple genetic alterations in tumor suppressor genes
(eg, TP53 and CDKN2A mutations) and activation of growth
factor pathways (eg, epidermal growth factor receptor, neuregulin
1/erbB receptors, hepatocyte growth factor/c-MET receptor,
and platelet-derived growth factor/platelet-derived growth factor
receptor) represent a biologic feature of MPNSTs (reviewed
in Carroll42).

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Batra et al Pathology Case Reviews & Volume 19, Number 2, March/April 2014

Central Nervous System Tumors
Gliomas in NF1
Gliomas are the most common brain tumors in patients
with NF1,43 with the most favored site being the optic nerve
pathways (optic nerves, optic chiasm, and hypothalamus). Optic
pathway gliomas (OPGs) are found in 15% to 20% of NF1
patients, predominantly children with NF1. Adult patients with
NF1 may also develop high-grade gliomas. The incidence of
newly diagnosed NFI patients/gliomas in NF1 patients is 50 to
100 times the incidence in the general population.44
When present, bilateral OPGs are almost pathognomonic
for NF1. Other sites of involvement include the brainstem and
cerebellum. In adults, higher-grade gliomas are found with in-
creasing frequency.45 Optic pathway gliomas have an indolent
growth pattern and often regress with time. Many of them are
asymptomatic and incidentally discovered on magnetic reso-
nance imaging examination. Symptomatic tumors present with
loss of visual acuity, abnormal pupillary function, decreased color
vision, proptosis, optic nerve atrophy, headache, and precocious
puberty. The most frequent pathology of brain tumors in NF1
patients is pilocytic astrocytoma, but the whole spectrum of as-
trocytic neoplasia may be encountered in these patients.46
There is a limited role for surgery in the treatment of OPG,
and radiotherapy is not recommended as patients with NF1 are
exquisitely sensitive to adverse effects of radiotherapy. In a
longitudinal study, 50% of patients with NF1 who received radi-
ation developed secondary tumors of the CNS including MPNSTs
and gliomas.47 In addition, radiation to the optic pathway in-
creases the risk of vascular abnormalities such as moyamoya
disease48 as well as endocrinologic and psychological prob-
lems (Figs. 4 and 5).
Pilocytic Astrocytoma
Neurofibromatosis type 1 low-grade gliomas are mostly
pilocytic astrocytomas. The histological features of these tumors
are similar to pilocytic astrocytomas in patients without NF1.
Microscopically, they are composed of dense, compact areas alter-
nating with more loose textured areas, although 1 component may
be dominant. The compact areas show bipolar piloid astrocytes.

FIGURE 4. Low-grade gliomas in NF1. Most low-grade gliomas in NF1 patients are pilocytic astrocytomas, containing compact areas
often rich in Rosenthal fibers (A), as well as loose, microcyst-rich areas (B). Oligodendroglial-like morphology may be present in some
examples (C). A subset of low-grade gliomas in NF1 is difficult to classify because they demonstrate infiltration of diffuse gliomas but
in addition subtle properties of pilocytic astrocytoma such as rare Rosenthal fibers (arrow) (D). Other difficult-to-classify low-grade
NF1-associated gliomas contain plump cytoplasm and macronucleoli (E). Classic diffuse astrocytomas (WHO grade II) may also develop in
NF1 patients (F).

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Pathology Case Reviews & Volume 19, Number 2, March/April 2014
FIGURE 5. High-grade gliomas in NF1. High-grade astrocytomas may also develop in NF1 patients, particularly adults, and present as
large intraparenchymal masses (A). Histologically, they may represent anaplastic astrocytomas characterized by frequent mitotic figures
(arrow) (B) or glioblastoma containing microvascular proliferation (arrows) (C). The whole spectrum of glioblastoma subtypes may
develop in these patients, such as giant cell glioblastoma (D).
Rosenthal fibers and eosinophilic granular bodies are frequent but
present in variable proportions. Mitotic activity is in general rare.
Microglia are an important stromal component in these tumors
that secrete factors contributing to neoplastic growth.49 Ana-
plastic changes, defined on the basis of brisk mitotic activity,
are rare in pilocytic astrocytomas. However, in 1 study, 24% of
pilocytic astrocytomas with anaplasia were NF1 associated.50
Neurofibromatosis type 1Yassociated pilocytic astrocytoma usu-
ally lacks genetic alterations involving the BRAF oncogene, un-
like its more common sporadic counterpart.51
Diffuse and High-Grade Astrocytomas
Patients with NF1 may also develop diffusely infiltrating
astrocytomas grades II to IV. As with their sporadic counter-
parts, these tumors are aggressive, with a high frequency of
progression and high mortality. The World Health Organization
(WHO) grading criteria are applicable to these tumors in most
instances. Diffuse astrocytoma (WHO grade II) is recognizable
as an infiltrative astrocytic tumor with atypia and sufficient
cellularity to recognize it as a neoplasm. Mitotic activity and
increased cellularity characterize anaplastic astrocytoma (WHO
grade III), whereas necrosis or microvascular proliferation, in
addition, characterizes glioblastoma (WHO grade IV). Rarer
subtypes of glioblastoma such as gliosarcoma and adenoid
glioblastoma may also develop in NF1 patients.52,53
Indeterminate Astrocytomas
In addition to astrocytomas that may be placed in a distinct
category, a subset of NF1-associated astrocytomas, primarily
low grade, remains difficult to classify using traditional criteria.
A subset may demonstrate conspicuous tissue infiltration but
contain cytologic features and/or Rosenthal fibers typical of
pilocytic astrocytoma. Another rare subset is characterized by
cells containing voluminous cytoplasm and macronucleoli as
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Diagnostic Pathology of NF1
well as a phenotype consistent with neuronal differentiation, at
least in part, and increased immunolabeling with markers ref-
lecting mTOR pathway activation.54
Other CNS Tumors
Rarer astrocytoma subtypes reported in NF1 patients include
pleomorphic xanthoastrocytomas55,56 and pilomyxoid astrocyto-
mas.57 Dysembryoplastic neuroepithelial tumors,58 rosette-forming
glioneuronal tumor,59 and other glioneuronal tumors60 have also
been reported in these patients.
Other Tumors Affecting NF1 Patients
Patients with NF1 are also predisposed to a variety of other
neoplasms outside the nervous system. These includes pheo-
chromocytoma (often bilateral), neuroendocrine neoplasms (ie,
carcinoid tumors), rhabdomyosarcoma, glomus tumors,61 and
gastrointestinal stromal tumors lacking KIT alterations.62 In
recent years, it has been recognized that women with NF1 have
an increased risk of breast carcinoma over the general popula-
tion. Children with NF1 are also predisposed to hematological
malignancies, particularly juvenile myelomonocytic leukemia
(È100 risk).
CONCLUSIONS
Patients with NF1 develop a variety of neoplastic and
nonneoplastic manifestations involving the nervous system and
other organs. The pathologist plays a key role in the classifi-
cation of these tumors, thereby facilitating appropriate man-
agement. Furthermore, NF1 patients are uniquely sensitive to
the adverse effects of available therapies for malignancy. Sepa-
rating atypical from frankly malignant changes is a difficult ex-
ercise in these patients, but the therapeutic implications are
particularly important.
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Batra et al
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