Spinal
Schwannomatosis without NF Syndrome: State of the Art
Alessandro Landi,
Demo Eugenio Dugoni, Roberto Delfini
Alessandro Landi,
Demo Eugenio Dugoni, Roberto Delfini, Department of Neurology and
Phsychiatry, Division of Neurosurgery, University of Rome, Sapienza, Italy
Correspondence
to: Alessandro Landi MD, PhD, Department Of Neurology
and Phsychiatry, Division of Neurosurgery, University of Rome ¡°Sapienza¡±, Viale
del Policlinico 155, 00100, Rome Italy. dott.alessandro.landi@gmail.com
Tel: +39-06-49979105
Received: Apirl 18, 2013
Revised: May 7, 2013
Accepted: May 9, 2013
Published
online: June 18, 2013
ABSTRACT
Schwannomas are encapsulated and
slow grooving benign peripheral nerve tumors. They represent about one third of
all benign primary spinal tumors. Most schwannomas occur as isolated lesions,
but it could be possible to find a multiple localization involving one or more
nerves. The presence of multiple schwannomas in a single patient is suggestive
of a genetic predisposition to tumorigenesis and a possible association with
syndromes such as neurofibromatosis (NF). Schwannomatosis is defined as an
extremely rare tumors syndrome characterized by the presence of multiple
schwannomas in the absence of typical signs of NF1 and NF2 syndromes. The
genetic and molecular analysis of the tumors, revealed, therefore, that it is
possible to frame schwannomatosis as distinct clinical and genetic syndrome.
Usually, patients with schwannomatosis develop cranial, spinal or peripheral
nerve schwannomas but do not develop vestibular lesions (VS), typical of NF2.
Moreover, even the genetic features are different respect to neurofibromatosis,
allowing to classify the disease as a distinct nosological entity. The
treatment, up to us, in case of symptomatic lesions is surgical removal; in
case of asymptomatic lesions is important, instead, to perform serial MRI
studies. Moreover, even the genetic features are different respect to
neurofibromatosis, allowing to classify the disease as a distinct nosological
entity. Furthermore given the high incidence of developing additional lesions
in patients with Schwannomatosis, it remains imperative to perform serial brain
and spinal cord MRI studies during follow-up time. Important is the differential
diagnosis including clinical and radiological criteria plus molecular genetic
analysis of tumor cells and lymphocyte DNA. The aim of this editorial is to
analyze the state of the art about diagnosis, treatment and follow-up about
this extremely rare pathology, often misdiagnosed or confused with other
pathologies such as NF syndromes, highlighting the extremely high relevance of
molecular genetic study to correctly identify it.
©
2013 ACT. All rights reserved.
Key words: Spinal schwannomatosis; Neurofibromatosis; Surgery;
Multiple schwannomas; NF syndrome; NF1; NF2
Landi A, Dugoni DE, Delfini R. Spinal
Schwannomatosis without NF Syndrome: State of the Art Editorial. Journal of tumor 2013; 1(1): 1-4
Available from: URL: http://www.ghrnet.org/index.php/jt
INTRODUCTION
Schwannomatosis is defined
as an extremely rare tumors syndrome characterized by the presence of
multiple schwannomas in the absence of typical signs of NF1 and NF2 syndromes.
Schwannomas are encapsulated and slow grooving benign peripheral nerve tumors.
They represent about one third of all benign primary spinal tumors. Most
schwannomas occur as isolated lesions, but it could be possible to find a
multiple localization of schwannomas involving one or more nerves. The presence
of multiple schwannomas in a single patient is suggestive of a genetic
predisposition to tumorigenesis and a possible association with syndromes such
as neurofibromatosis (NF).
NEUROFIBROMATOSIS
Neurofibromatoses are an heterogeneous group of genetic disorders predisposing
to various tumors of the nervous system. Among the different variants of NF
only for type 1 neurofibromatosis (NF1) and type 2 neurofibromatosis (NF2)[1],
National Institute of Health (NIH) have estabilished the guidelines for the
diagnosis as described in the literature. NF1 is the most common form, with an
incidence at birth of 1 / 2500. NF1
is a common autosomal dominant neurocutaneous disorder characterized by
multiple caf¨¦ au lait spots, axillary and inguinal freckling, multiple
cutaneous neurofibromas, and iris Lisch nodules[2]. NF-1 is caused
by loss of function mutations in the NF1 gene in 17q11.1. This leads to
defective production of neurofibromin, a guanosine triphosphatase-activating
protein that helps maintain the protooncogene Ras in its inactive form[3].
Loss of neurofibromin predisposes to increased tumorigenesis, and malignant
disease can appear in either childhood or adulthood, with malignant peripheral
nerve sheath tumours (MPNSTs) being most common[4]. Several pathways
are thought to be involved in the development of tumours associated with NF1:
rat sarcoma viral oncogene homologue (RAS)-mitogen-activated protein kinase
(MAPK), mammalian target of rapamycin (mTOR), and P21 protein
(Cdc42/Rac)-activated kinase 1 (PAK1)[5,6]. NF-1 patients have a
lifetime risk of 8-13% to develop MPNSTs, which are the leading cause of
NF1-related mortality. In current clinical practice the diagnosis of MPNST
should always be considered in NF-1 patients, especially those with persistent
pain (that lasts over 1 month or disturbs sleep), new neurological deficits, or
alteration in the characteristics of a known neurofibroma[7].
Surgical resection is the mainstay of treatment; however, because of increased
metastatic potential and resistance to chemotherapy and radiation the prognosis
is poor. Five-year survival rates still only reach 20-50%, despite latest
efforts to identify potential molecular targets[8]. MPNSTs should be
included in the differential diagnosis of persistent or atypical pain in a young
adult. Although rare, these malignancies are commonly associated with NF-1 and
can be the first manifestation of the disease, as this case illustrates. Early
diagnosis is paramount as survival rates are extremely poor in advanced stages
of the malignancy.
The NF2, much
less common than the previous one (incidence at birth of approximately 1 /
33000), is associated with significant morbidity and mortality due to the
frequent localization of the lesions in the brain and in the spinal cord. The
mutation in the NF2 gene maps to chromosome band 22q12. The NF2 is caused by a
¡°de novo¡± mutation at 22q12 in more than 50% of patients. It is a tumor
suppressor gene with a molecular weight of 110 kb, it consists of 16
consecutive exons and alternatively spliced exon. The protein encoded by NF2
gene is called Merlin. The Merlin has a similar structure to the family of
proteins that link cell surface glycoproteins to actin cytoskeleton. The most
important finding for the diagnosis of NF2 is the presence of bilateral
schwannomas involving the eighth cranial nerve, with an incidence of about 95%
of patients. Individuals with NF2 also have an increased risk of developing
single or multiple meningiomas and schwannomas of peripheral nerves[1].
SCHWANNOMATOSIS
A small subset of patients with multiple schwannomas without any
clinical signs and without any radiological evidence of vestibular lesions or
other characteristic features of NF2 has been identified.
The genetic
and molecular analysis performed on the tumors of these patients, revealed that
it is possible to frame schwannomatosis as distinct clinical and genetic
syndrome. Schwannomatosis is defined, therefore, as an extremely rare tumors
syndrome characterized by the presence of multiple schwannomas in the absence
of typical signs of NF1 and NF2 syndromes. Usually, patients with
schwannomatosis develop cranial, spinal or peripheral nerve schwannomas but do
not develop vestibular lesions (VS), typical of NF2. Moreover, even the genetic
features are different respect to neurofibromatosis, allowing to classify the
disease as a distinct nosological entity.
Diagnosis
An important aspect for the classification of Schwannomatosis is the
differential diagnosis with NF. In particular, we can define Schwannomatosis a
syndrome characterized by multiple schwannomas in the absence of VS, having no
characteristic of NF1 or NF2, having no familiarity and, having no
constitutional mutations of specific gene, as like 17q11.1 in NF1 and 22q12 in
NF2.
Clinical and
radiological: The Schwannomatosis has been described for the first time in the
1973 as neurofibromatosis type 3. The characteristic of this syndrome was the
presence of multiple skin and spinal¡¯s schwannomas in the absence of vestibular
involvement or other relevant features of NF1 and NF2. Over time, several
authors have reported cases of patients with multiple schwannomas without
vestibular lesions, suggesting the existence of a distinct syndrome from the
NF. Patients with schwannomatosis develop multiple schwannomas on cranial,
spinal and peripheral nerves, but they do not develop vestibular schwannomas.
The locations of the schwannomas included intraspinal (multiple sites),
paraspinal, brachial plexus, femoral nerve, sciatic nerve, calf, forearm,
retroperitoneum, and middle cranial/infratemporal fossa region. The prevalence
in the cervical inferior tract and the dorso-lumbar passage is interpreted by
the authors as being related to the presence of a higher concentration of roots
and directed to the superior and the inferior limbs at those levels. The mean
duration of symptoms ranges between 2 and 3 years. The common presenting
symptoms included paresthesias, pain, weakness, or palpable mass. Usually the
growth of the tumor was very slow, and the symptoms that were vague in the
beginning worsened very slowly. The age of its first manifestation was usually,
with exception to few cases and few sites, around the 3th and 4th
decade. No prevalence between male and female was found.
At this time
there are no NIH diagnostic criteria for schwannomatosis. Jacobi et al
have proposed clinical criteria for diagnosis of schwannomatosis: the presence
of two or more schwannomas in the absence of radiological evidence of
vestibular lesions in patients older than 18 years, is definitely indicative of
schwannomatosis. Michael et al have proposed an integration of these
diagnostic criteria, indicating the MRI exame as a fundamental instrument to
exclude the presence of vestibular schannomas and, more important is the
absence of constitutional NF2 mutations. Today, therefore, the first major
challenge to the diagnosis of schwannomatosis is the presence of two or more
non-intradermal schannomas in patients older than 30 years, in the absence of
vestibular lesions shown on the brain MRI with contrast enhancement and in the
absence of constitutional NF2 mutations. Second important aspect is the
presence of first-degree relative with a confirmed diagnosis of
schwannomastosis in a patient with multiple schwannomas in the absence of
vestibular lesions resulting on MRI imaging and genetic analysis, in this case,
without any limit of age.
The
electromyographic diagnosis is needed to determine with certainty the origin of
the lesion by a motor root and evaluate the extent of any damage.
Molecular
genetics; Several authors have studied the schwannomatosis molecular genetics.
Jacobi and McCollins analyzed alterations in the NF2 locus in patients with
schwannomatosis revealing in the tumor cell, a typical truncating mutations at
NF2 gene, with loss of heterozygosity of chromosome 22. They found that unlike
patients with NF2, no heterozygous NF2 gene changes were seen in normal
tissues. They identified 20 different somatic mutations in the NF2 gene, 18 of
which were truncating mutations. None of the mutations detected in tumour
specimens was detected in paired blood specimens. Lymphocyte DNA did not reveal
any NF2 mutation but the tumour DNA showed loss of heterozygosity and mutations
of NF2 gene. Tumors from these patients frequently had the same truncating
mutations and loss of heterozygosity at the Nf2 locus as NF2 patients. However,
normal tissue did not contain these changes, implying that the underlying
genetic mechanism of NF2 and schwannomatosis differs. They concluded that
schwannomatosis is a distinct entity from type 2 neurofibromatosis.
The SMARCB1
gene has been found to harbor germline alterations in both familia and sporadic
schwannomatosis patients. Several linkage studies performed in families
affected with schwannomatosis excluded NF2 as the germline-transmissible
schwannomatosis gene and suggested a location of this gene near marker
D22S1174, which is in the region on chromosome 22 centromeric to NF2. In this
region is the CABIN1 (also known as SMARCB1) gene, in which missense mutations
may contribute to the pathogenesis of both schwannomatosis and NF2. INI1 is an
attractive candidate gene, because it is a tumor-suppressor gene that is
located within a short distance (i.e., <360 kb) of marker D22S1174
[University of California Santa Cruz (UCSC) Genome Browser]. INI1 is a member
of the ATP-dependent SWI-SNF chromatin remodeling complex and affects the
expression of genes that regulate cell cycle, growth, and differentiation.
However further studies are needed to determine whether the inactivation of the
INI1 gene is the cause of
tumor
formation in cases of familial and sporadic schwannomatosis as well and to
elucidate the exact oncogenetic mechanisms and functional consequences of INI1
inactivation in these and other tumors. Surely as germline SMARCB1 mutations
have never been reported in cases of vestibular schwannomas, the presence of
multiple non-vestibular schwannomas appears a good criterion to first
investigate the SMARCB1 gene
Treatment
The treatment in case of symptomatic lesions is surgical removal;
Asymptomatic tumours can be monitored conservatively with serial MRI studies.
The surgical approach is usually due to back and can be performed using
classical laminectomy or, more frequently in young patients with laminothomy in
order than to restore the correct anatomical integrity of the spine. The
approach to the lesion provides, in cases of intradural lesions, the execution
of a median durotomy which allows exposure of the roots and the spinal cord. In
most cases schwannommas originate from the sensory root, for wich their
localization within the spinal canal is almost always posterolateral. In rare
cases, however, the origin is from the motor root resulting in more anterior
localization. The removal, in order to prevent recurrence, must be total and
possibly enbloc. In cases were the origin is from the sensory root, removal,
after careful dissection of the adjacent neural structures, occurs through the
section of the sensory root of origin. Clearly the same can not be executed in
case of origin from motor root. Only for thoracic motor roots is indicated
resection of the root. The procedure is always performed with micro-surgical
technique through the use of the surgical microscope. Another extremely
important tool is ultrasonic aspirator CUSA, wich allows the surgeon to a
fragmentation and an aspiration of the lesion, performing a debulking of the
lesion from the inside. In all cases, in our opinion, it is imperative to run
during the surgical procedure, intraoperative neurophysiological monitoring, in
order to make the procedure more safe. In cases were the lesion has efflux
intra-extraforaminal, for its removal may be necessary to remove the articular
mass to reach the intervertebral foramen and the extraforaminal portion; in
such cases it may be necessary to run an additional instrumented spine
stabilization procedure in order to correct the instability generated by the
bone removal. The complete removal of the tumor is the ultimate goal; in fact,
in our case reports, which confirmed other reported series, the recurrence
occurred in all the cases in which the excision was subtotal. Radiation therapy
is indicated in some cases of subtotal removal and malignant lesions. In any case, given the high incidence of
developing additional lesions in patients with Schwannomatosis, it remains
imperative, for all patients, to perform serial MRI studies during follow-up
time, usually at a yearly interval. It is important to consider genetic
testing. Molecular diagnosis rules out NF2 and appropriate genetic counseling
can be offered. Patients are advised to monitor themselves for any new
neurological problems.
CONCLUSIONS
The genetic and molecular analysis of the tumors described in this
article, revealed that it is possible to frame Schwannomatosis as distinct
clinical and genetic syndrome from NF syndrome, and this is the real innovation
about this pathology, because since now the differential diagnosis was
essentially clinical. The treatment in case of symptomatic lesions is surgical
removal; in case of asymptomatic lesions is important, instead, to perform
serial MRI studies. Given the high incidence of developing additional lesions
in patients with Schwannomatosis, it remains imperative to perform serial brain
and spinal cord MRI studies during follow-up time. Important is the
differential diagnosis including clinical and radiological criteria plus
molecular genetic analysis of tumor cells and lymphocyte DNA. Due to the recent
molecular and genetic innovations, in the next few years we expect that
advances in the research will provide us the use of new potential drug
therapies; this to reserve the surgical therapy only in selected cases.
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Peer reviewer: Xiang Zhang,
Professor, Department of Neurosurgery, Xijing Hospital, Fourth Military Medical
University, West Changle Road, No.127, Xi¡¯an, Shaanxi Province, 710032,
People's Republic of China.
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