Neuroradiology (2003) 45: 618–625
DOI 10.1007/s00234-003-0964-6
V.F. Mautner
R.E. Friedrich
A. von Deimling
C. Hagel
B. Korf
M.T. Knöfel
R. Wenzel
C. Fünsterer
Received: 30 December 2002
Accepted: 4 February 2003
Published online: 24 July 2003

Springer-Verlag 2003
V.F. Mautner (&)
Department of Neurology,
Klinikum Nord Hamburg,
Langenhorner Chaussee 560,
22419 Hamburg, Germany
E-mail: VRGes@aol.com
Tel.: +49-40-52712872
Fax: +49-40-5277462
R.E. Friedrich
Department of Maxillofacial Surgery,
Universitätsklinikum Eppendorf,
Hamburg, Germany
A. von Deimling
Department of Neuropathology,
Charité, Berlin, Germany
C. Hagel
Department of Neuropathology,
Universitätsklinikum Eppendorf,
Hamburg, Germany
B. Korf
Partners Center for Human Genetics,
Harvard Institutes of Medicine,
Boston, USA
M.T. Knöfel
Department of Surgery,
Universitätsklinikum Eppendorf,
Hamburg, Germany
R. Wenzel Æ C. Fünsterer
MRI-Institute Hamburg Othmarschen,
Hamburg, Germany
Introduction
Neurofibromatosis 1 (NF1) is a common autosomal
dominant neurocutaneous disease, with an estimated
DIAGNOSTIC NEURORADIOLOGY
Malignant peripheral nerve sheath tumours
in neurofibromatosis type 1: MRI supports
the diagnosis of malignant plexiform
neurofibroma
Abstract Plexiform neurofibroma on T1- and T2-weighted images be-
(PNF) is a typical feature of neuro- fore and after contrast enhancement.
fibromatosis 1 (NF1). About 10% of All three asymptomatic patients with
patients with NF1 develop malig- inhomogeneous lesions were shown
nant peripheral nerve-sheath tu- to have MPNST.
mours (MPNST), usually arising
from PNF, and this is the major Keywords Neurofibromatosis
cause of poor survival. A better type 1 Æ Malignant peripheral
prognosis can be achieved if the nerve-sheath tumour Æ Plexiform
tumours are diagnosed at an early neurofibroma Æ Magnetic resonance
stage. Our objective was to establish imaging
MRI criteria for MPNST and to test
their usefulness in detecting early
malignant change in PNF. MRI was
performed on 50 patients with NF1
and nerve-sheath tumours, of whom
seven had atypical pain, tumour
growth or neurological deficits
indicative of malignancy; the other
43 were asymptomatic. On MRI all
seven symptomatic patients had
inhomogeneous lesions, due to
necrosis and haemorrhage and pat-
chy contrast enhancement. In one
patient, the multiplicity of confluent
tumours with inhomogeneous areas
in addition to central lesions did not
allow exclusion of malignancy. Only
three of the 43 asymptomatic pa-
tients had comparable changes; the
other 40 patients had tumours being
of relatively homogeneous structure
birth incidence of 1:3,000–4,000, and a spontaneous
mutation rate of about 50%. The NF1 gene is
on chromosome 17q11. The gene product, neurofi-
bromin, is thought to act as a tumour suppressor by
 619

down-regulating p21-ras and thereby inhibiting cell
growth and proliferation. The principal and defining
features of NF1 are café-au-lait spots, freckling, Lisch
nodules, dermal neurofibromas and plexiform neuro-
fibromas. Neurofibromas are benign tumours which
arise from the connective tissue of nerve sheaths,
especially the endoneurium. In contrast to the typical
dermal neurofibroma, nodular neurofibromas are firm,
discrete lesions, which arise from major peripheral
nerve trunks; they infrequently undergo malignant
change. Plexiform neurofibromas (PNF) are composed
of the same cell types as dermal neurofibromas, but
have an expanded extracellular matrix. They may
grow along the length of a nerve, involving multiple
fascicles and branches, and extend into surrounding
structures. Superficial PNF were reported in about
30% of affected individuals in a population-based
study [1], but internal PNF are frequently undetected
without imaging [2].
About 10% of patients with NF1 develop malignant
peripheral nerve sheath tumours (MPNST), which usu-
ally arise within a pre-existing PNF [3]. These are the
main cause of limited survival, especially for NF1 gene
carriers aged less than 40 years [4]. Clinical indicators of
malignancy are persistent pain, increasing size and
neurological deficits [5]. Patients with malignant tu-
mours often have a poor prognosis and the tumour may
metastasise at an early stage [6, 7, 8 ]. In our experience,
a better prognosis can be achieved if MPNST are diag-
nosed at an early stage, with ablative surgery with wide
resection margins. To optimise early detection it is nec-
essary to determine if there are characteristic features on
MRI and to clarify if the different growth patterns
of PNF described recently (invasive, superficial and
displacing) relate to neoplastic proliferation of Schwann
cells [9]. It is also important to be able to characterise
patients with NF1 on clinical grounds to ascertain
whether a specific subset is more likely to develop
MPNST.
We report ten patients with NF1 who developed a
MPNST arising from a pre existing PNF, investigated
primarily by MRI.
Materials and methods
The patients presented to the Outpatient Department for Neuro-
fibromatosis in the Klinikum Nord Hamburg between 1997 and
2002. All underwent a complete dermatological, ophthalmological
and neurological examination and ultrasonography of the abdo-
men. NF1 was diagnosed according to the National Institutes of
Health criteria. The study was approved by our ethics committee
and all patients gave informed consent to analysis of their records
and tumour material.
MRI was at 1.5 or 1.0 tesla, with T1- and T2-weighted se-
quences including a short-tau inversion-recovery (STIR) se-
quence. Ultra-rapid half-Fourier single-shot turbo spin-echo
(HASTE) sequences were used for imaging the trunk. We gave
intravenous contrast medium to all patients with no contraindi-
cation.
We investigated 50 patients with NF1 and a PNF, of whom
seven presented with complaints such as tumour growth, pain or
neurological deficit. The other 43 patients without clinical com-
plaints connected with the PNF were examined as part of a regular
clinical and radiological investigation. The MRI of all patients was
analysed by two radiologists for inhomogeneity of the tumour or
surrounding tissue and of contrast enhancement. There were ten
tumours involving the face, 11 the head and neck, 14 the trunk and
15 the limbs.
For patients 1 and 8 an amputated limb was available for
macroscopic investigation. All light microscopy and immunohis-
tochemical studies were performed on formalin-fixed, paraffin

Fig. 1A, B Case 1. Coronal

images: A before, B after intra-
venous contrast medium: a
smoothly marginated tumour of
the right thigh gives inhomoge-
neous signal, and enhances
brightly, but again inhomoge-
neously. The leg was amputated
at the hip joint. A soft, white,
glassy tumour was found in the
flexor compartment. The sciatic
nerve, separate from the
tumour, formed a 20 mm thick
white cord. The tumour,
approximately 12·6·6 cm, was
multinodular with haemorrhage
and necrosis, lying in the biceps
femoris. The sciatic nerve was
partially covered by the
tumour, which focally
destroyed the fascia of the
muscle; however, the epineu-
rium was macroscopically
intact
620

wax-embedded material. The diagnosis was based on the light

microscopy features of cellularity, mitotic rate, size of necrotic
areas, nuclear pleomorphism and the presence of rhabdomyoblasts.
Histological grading was according to the National Cancer Insti-
tute system and tumour differentiation was scored according to
histological type in the updated version by the Fédération National
des Centres de Lutte Contre le Cancer.

Case reports

Case 1

A 19-year-old girl with familial NF1 presented with more than ten
discrete skin tumours, one of which was painful. She had a small
number of skin neurofibromas, axillary freckling and Lisch nod-
ules. Sonography of the abdomen and spinal MRI revealed internal
PNF in all regions of the body. During follow-up the patient
developed pain in the right thigh, then swelling (Fig. 1). Her father
also had NF1 and died from an MPNST. Pathology: We found a
hypercellular MPNST with moderately pleomorphic epithelioid
cells, buckled, vesicular nuclei with 1–2 prominent nucleoli, large
areas (>50%) of necrosis and hypocellular hyalinosis/fibrosis.
There was a high mitotic rate: 15–17/high-power field (HPF).
Grading: WHO 2, Coindre 2.

Case 2

A 21-year-old woman with sporadic NF1 presented with cough and

hoarseness induced by a mediastinal PNF compressing the trachea.
Examination revealed four PNF of the skin, multiple café-au-lait
spots, axillary and inguinal freckling and 50 cutaneous neurofi-
bromas. She also had internal tumours. She was otherwise
asymptomatic, and the diagnosis was made on MRI (Fig. 2).
Pathology: we found a hypercellular MPNST composed of Schw-
ann cell-like cells, elongated, vesicular nucleoli, moderate pleo-
morphism and large (>50%) areas of necrosis. There was high
mitotic activity: 12–14/HPF. Grading: WHO 2, Coindre 3.
Fig. 2A, B Case 2. A Contrast-enhanced T1-weighted coronal
section, showing a paratracheal mass on the right in the upper
Case 3 mediastinum, with slightly inhomogeneous enhancement, more
marked superiorly. B T2-weighted image showing a smooth mass
A 20-year-old girl with familial NF1 and slight mental retardation giving increased signal
and discrete skin tumours was followed annually. She had Lisch
nodules and axillary freckling, a solitary neurofibroma in the Case 5
abdomen, a cerebral pilocytic astrocytoma and an asymptomatic
congenital PNF of the neck and mediastinum. The diagnosis was A 30-year-old woman with familial NF1 presented with intractable
made on MRI (Fig. 3). The patient’s father had NF1 and died from pain and swelling in the left buttock. She had undergone amputation
an MPNST. Pathology: There was an MPNST of high cellularity of the leg as a child because of a congenital PNF. She had less than
composed of Schwann-cell-like cells, oval nuclei without prominent 20 discrete skin tumours, Lisch nodules, freckling and abdominal,
nucleoli, high pleomorphism and hyperchromatism, large (>50%) gluteal and pelvic tumours (Fig. 5). Pathology: a PNF with focal
areas of necrosis and high mitotic activity, 10–12/HPF. Grading: malignant transformation, low cellularity, moderate pleomorphism
WHO 2, Coindre 2. and with nuclear atypia consisting of nuclear enlargement and hy-
perchromatism without prominent nucleoli. Necrosis was >50%
and mitotic activity low (4–5/HPF). Grading: WHO 2, Coindre 2.
Case 4

A 24-year-old man with sporadic NF1 presented with pain and a
feeling of swelling of the abdomen (Fig. 4). Examination showed
more than 600 skin tumours, ocular, spinal, abdominal and pelvic
PNF and slight mental retardation. Pathology: we found a hyper-
cellular MPNST composed of highly pleomorphic Schwann cell-
like cells, moderate nuclear atypia with large, pleomorphic nuclei,
low mitotic activity (3–4/HPF) and large (>50%) necrotic areas.
Grading: WHO 2, Coindre 2.
Case 6
A 31-year-old man with sporadic NF1 presented with intense pain
in the right upper leg, increased at night, and swelling of the leg. He
had less than five cutaneous neurofibromas, but MRI showed
extensive confluent spinal tumours, and PNF in the limbs (Fig. 6).
Pathology: a PNF with focal malignant transformation, high cel-
lularity, Schwann-cell-like cells with moderate pleomorphism,

Fig. 3A, B Case 3. A Coronal and B axial T2-weighted images
showing a very large mass, nodular, pseudo-encapsulated, an
inhomogeneous tumour in the left upper mediastinum and para-
aortic with patchy contrast enhancement
elongated, misshapen nuclei, mitotic activity 7–9/HPF and >50%
necrosis. Grading: WHO Grade 2, Coindre 2.
Case 7
A 35-year-old woman with sporadic NF1 presented with a painful
relapse of an axillary MPNST (Fig. 7) for which she had surgery a
second time in 2000, after a first operation in 1987 for a painful,
suddenly growing nodular PNF of the distal ulnar nerve. Exami-
nation showed a mentally retarded patient with more than 300 skin
tumours, multiple café-au-lait spots and inguinal freckling; no
significant internal masses were present. Pathology showed an
MPNST with areas of rounded cells with buckled, hyperchromatic
nuclei, and cells arranged in sweeping fascicles, moderate pleo-
morphism is moderate, high mitotic activity (15–17/HPF) and large
(>50%) areas of necrosis. Grading: WHO 2, Coindre 3.
Case 8
A 35-year-old man with sporadic NF1 presented with a painful,
rapidly growing axillary tumour extending to the right arm (Fig. 8).
621
Fig. 4A, B Case 4. Axial images: A T2-weighted, B contrast-
enhanced T1-weighted, showing a very extensive, confluent,
inhomogeneous tumour in the middle and lower abdomen. Signal
intensity low at its margins. There is also an extensive, relatively
symmetrical, retroperitoneal plexiform neurofibroma (PNF)
Ten years previously he underwent surgery for a painful abdominal
PNF, which proved to be an MPNST. He had fewer than ten
cutaneous neurofibromas, plus café-au-lait spots. First symptoms
were pain, tumour growth, and neurological deficits. Pathology: the
right arm and scapula were examined. There was no tumour visible
upon inspection but dissection revealed a 15·10·10 cm smooth
mass beneath the clavicle, extending into the upper arm. The bra-
chial artery was completely enclosed in tumour but the radial and
median nerves lay on its surface, firmly adherent to it; distal to the
mass the nerves appeared free of tumour. The tumour was white
colour and had a crisp consistency; its cut surface showed numer-
ous haemorrhagic foci, necrotic areas and cysts of variable size
(Fig. 8C). Histologically, it was a neurofibroma with focal malig-
nant transformation. The MPNST portions showed high cellular-
ity, with elongated, bipolar Schwann cell-like cells, elongated nuclei
and marked pleomorphism, with >50% necrosis and 2–3 mitoses/
HPF. Grading: WHO 2, Coindre 2.
Case 9
A 13-year-old girl with sporadic NF1 presented with a tumour
distally on the forearm which had been there since childhood but
622

Fig. 5A, B Case 5. A T2-weighted short-tau inversion-recovery

(STIR) and B contrast enhanced, fat-suppressed T1-weighted
images reveal an extensive PNF of the whole pelvic region with
an outgrowth to the left buttock and thigh. A 15 cm nodule in the
buttock shows less contrast enhancement than the intensely
enhancing margins of the tumour. However, the enhancement
and the signal intensity in innumerable adjacent nodules do not Fig. 6A–C Case 6. A, B Coronal STIR and contrast-enhanced fat-
differ significantly from that of the main tumour, except for the suppressed T1-weighted spin-echo images and C an axial T1-
large poorly vascularised central zone weighted image show extensive nodular thickening of the femoral
nerve, with inhomogeneous, predominantly high signal. There is
less intense enhancement in the inhomogeneous nodule in the
was now growing rapidly. She had multiple café-au-lait spots, ax- popliteal fossa. The contours of the tumour are sharply demar-
illary freckling, but no skin neurofibromas and a mild neurological cated, excluding invasive growth
deficit. There were no internal tumours. Pathology: we found a
hypercellular MPNST with markedly pleomorphic cells, large
(>50%) areas of necrosis and hyalinosis/fibrosis, with a high mi-
totic rate: 10/HPF. Grading: WHO 3, Coindre 3.
Results

Case 10 In seven of the ten patients the diagnosis of MPNST

A 56-year-old man with sporadic NF1 presented with more than
500 cutaneous neurofibromas, café-au-lait spots, Lisch nodules,
axillary freckling and a congenital PNF of the left leg, without
internal tumours. MPNST was detected during MRI follow-up of a
large PNF that had enlarged slowly, over several decades.
Pathology: a PNF with focal malignant transformation. The tu-
mour cells had features of Schwann cells with elongated or oval
nuclei, low cellularity and pleomorphism. There were large
(>50%) necrotic areas and hyalinosis; mitotic activity was low
(4–5/HPF). Grading: WHO 2, Coindre 2.
was suggested clinically, intractable, constant pain and
swelling being commonest complaints. In three cases
the diagnosis was suggested by MRI. All patients had
inhomogeneous tumours, this being more evident with
contrast enhancement. In one patient, the multiplicity
of confluent inhomogeneous tumours did not allow us
to exclude malignancy. Five patients had a high inter-
nal tumour burden, and two had a parent with NF1
who died from an MPNST. One patient developed an
 623

Fig. 7A, B Case 7. Contrast-

enhanced, fat-suppressed
images show a mass in the left
upper arm with necrosis and
inhomogeneous enhancement.
Pulmonary nodules and tumour
infiltration of the axilla are
evident

Fig. 8A–C Case 8. A Contrast-

enhanced fat-suppressed
T1-weighted and B T2-weighted
STIR images show a nodular
8 cm lesion in the right axilla,
with intense, inhomogeneous
contrast enhancement with
numerous unenhancing foci.
B Shows the tumour to have
indistinct margins in the axilla.
C Macroscopic appearance of
the main tumour, showing
numerous cysts which were
filled with blood or amber-
coloured plasma

MPNST for the first time 10 years previously. In the

other 40 consecutive patients with NF1 and a PNF Discussion
MRI showed a homogeneous lesion on T1- and T2-
weighted images before and after contrast enhance- Patients with NF1 characteristically have multiple
ment. cutaneous lesions, including neurofibromas and PNF,
624

Table 1 First symptoms and pathology of malignant peripheral nerve-sheath tumours

Patient Age (years) at diagnosis Tumour Site Type Growth Pain Neurological Grade Coindre

1 19 Limb Displacing Yes Yes No 2 2

2 21 Trunk Displacing No No No 2 3
3 20 Trunk Invasive No No No 2 2
4 24 Trunk Invasive Yes Yes No 2 2
5 30 Trunk Displacing Yes Yes No 2 2
6 31 Limb Displacing Yes Yes No 2 2
7 35 Limb Invasive Yes Yes Yes 2 3
8 35 Limb Invasive Yes Yes Yes 2 2
9 13 Limb Invasive Yes Yes Yes 3 3
10 56 Limb Invasive No No No 2 2

which primarily cause disfigurement and are basically
benign. Recent death certificate and population-based
studies showed that about 10% of patients with NF1
have a reduced life expectancy due to MPNST; indeed,
these tumours, arising from PNF are the main cause of
death in adults with NF1. Resection of the malignant
tumour with wide margins is the treatment of choice.
However, diagnostic delay of MPNST is frequent and
surgery is less effective when tumour growth is ad-
vanced. It is therefore highly desirable to detect MPNST
as early as possible. Most of our patients complained of
pain and an enlarging mass, signs of malignancy. MRI
showed an inhomogeneous structure, as described, in
contrast to the common image of a PNF, a relatively
homogeneous lesion, as in 40 of our 50 patients [10].
This fact has been mentioned in two other studies, but
with controversial results [11]. We agree that MRI
cannot reliably distinguish malignant and benign nerve-
sheath neoplasms [12], especially when many confluent
tumours show inhomogeneous areas.
Earlier studies have certain limitations. A study re-
ported in 1997 did not include injection of contrast
medium [11]. Today’s MRI is superior for detecting
neural tumours than it was only a few years ago, in
terms of both hardware (higher gradient-field strength)
and software (fat-saturation). There was no strict anal-
ysis of the patients’ symptoms with regard to evidence of
malignancy. The terms neurofibroma and PNF were not
separated clearly, which makes a difference to histology,
the likelihood of developing an MPNST, and radiolog-
ical features.
In our small cohort, MPNST in patients with NF1
frequently show inhomogeneous contrast enhancement.
This inhomogeneity is due to necrosis and haemor-
rhage, as shown on by macroscopic and histological
analysis of amputated limbs in two of our patients
(Fig. 8). In three cases we were able to detect MPNST
in PNF on follow-up MRI, even though the patients
did not have significant clinical features. The develop-
ment of the malignant tumours was detected because of
imaging changes, in inhomogeneous contrast enhance-
ment. It may therefore be possible to detect malignant
transformation at an early stage. Careful follow-up will
determine how frequently early malignancy can be de-
tected and if it is worthwhile carrying out MRI at
defined intervals.
We graded the tumours using mitotic rate, areas of
necrosis and cell pleomorphism; these features were not
reflected by any particular signs on MRI scan (Table 1),
implying that imaging is not valuable for predicting the
outcome. Internal tumour burden, family history or
previous diagnosis of MPNST may be criteria for
identification of patients with NF1 at higher risk of
developing MPNST, whereas skin tumours seem to have
no predictive value. All our patients had expansive,
invasive lesions, indicating that those with this type of
tumour may be at greater risk of malignant transfor-
mation than those with a superficial PNF.
Acknowledgements This study was supported by Deutsche Kreb-
shilfe Grant No. 70-2794-De 1 and the Hamburger Stiftung zur
Förderung der Krebsbekämpfung No. 161.

References

1. Huson SM, Harper PS, Compston DAS
(1988) Von Recklinghausen neurofi-
bromatosis – a clinical and population
study in South-East Wales. Brain 111:
1355–1381
2. Tonsgard JH, Kwak SM, Short P,
Dachman AH (1988) CT imaging in
adults with neurofibromatosis 1. Fre-
quent asymptomatic plexiform lesions.
Neurology 50: 1755–1760
3. McGaughran JM, Harris DI, Donnai
D, et al (1999) A clinical study of type 1
neurofibromatosis in north west Eng-
land. J Med Genet 36: 197–203

4. Rasmussen SA, Quanhe Y, Friedman
JM (2001) Mortality in neurofibroma-
tosis 1: an analysis using U.S. death
certificates. Am J Hum Genet 68: 1110–
1118
5. Ferner RE, Gutmann D (2002) Inter-
national consensus statement on malig-
nant peripheral nerve sheath tumors in
neurofibromatosis 1. Cancer Res 62:
1573–777
6. Leroy K, Dumas V, Martin-Garcı́a N,
et al (2001) Malignant peripheral nerve
sheath tumors associated with neurofi-
bromatosis type 1. Arch Dermatol 137:
908–913
10. Cerofolini E, Landi A, DeSantis G,
7. King AA, DeBaun MR, Riccardi VM,
Gutmann DH (2000) Malignant
peripheral nerve sheath tumors in neu-
rofibromatosis 1. Am J Med Genet 93:
388–392
8. Wong WW, Hirose T, Scheithauer BW,
Schild SE, Gunderson LL (1998)
Malignant peripheral nerve sheath tu-
mor: analysis of treatment outcome. Int
J Radiat Oncol Biol Phys 42: 351–360
9. Kluwe L, Friedrich RE, Korf B, Fah-
sold R, Mautner VF (2002) NF1
mutations in neurofibromatosis 1 pa-
tients with plexiform neurofibromas.
Hum Mut 19: 309
Maiorana A, Canossi G, Romagnoli R
(1991) MR of benign peripheral nerve
sheath tumors. J Comput Assist To-
mogr 15: 593–597
625
11. Bhargava R, Parham DM, Lasater OE,
Chari RS, Chen G, Fletcher BD (1997)
MR imaging differentiation of benign
and malignant peripheral nerve sheath
tumors: use of the target sign. Pediatr
Radiol 27: 124–129
12. Levine E, Huntrakoon M, Wetzel LH
(1987) Malignant nerve-sheath neo-
plasms in neurofibromatosis: distinction
from benign tumors by using imaging
techniques. Am J Roentgenol 149:
1059–1064