Rom J Morphol Embryol 2014, 55(1):159164 [613847]
Rom J Morphol Embryol 2014, 55(1):159–164
ISSN (print) 1220–0522 ISSN (on-line) 2066–8279 CCAASSEE RREEPPOORRTT
Unusual median nerve schwannoma: a case presentation
ANDREA ANGHEL1,2), IRINA TUDOSE3), DANA TERZEA2,4), LAURA RĂDUCU5), RUXANDRA DIANA SINESCU1,2)
1)Department of Plastic Surgery and Reconstructive Microsurgery , “Elias” Emergency University Hospital, Bucharest, Romania
2)“Carol Davila” University of Medici ne and Pharmacy, Bucharest, Romania
3)Department of Pathology, “Elias” Emergenc y University Hospital , Bucharest, Romania
4)Oncoteam Diagnostic, Bucharest, Romania
5)Department of Plastic Surgery, “Prof. dr. Agrippa Ione scu” Military Emergency Ho spital, Bucharest, Romania
Abstract
Peripheral nerve sheath tumors are common soft tissue neoplasms and their characterization is often challenging. Although the s urgical
pathology defines some typical entities, some degree of controversy regarding the classification of these tumors still exists. Newer imagistic
and histopathological techniques are crucial for their accurate diagnosis and grading. We present an unusual case of median ner ve
schwannoma in a young patient, discussing the clinical, surgical and pathological elements, including immunohistochemistry.
Keywords : nervous tumors, schwannoma, immunohistochemistry.
Introduction
Schwannomas, also known as neurilemmomas, the
most common benign tumors of the peripheral nerves’ neural sheaths, are benign tumors originating from Schwann cells derived from the neural crest [1, 2].
Schwannoma usually affects patients aged 20–50
years without race or sex pr edilection and accounts for
approximately 5% of all benign soft tissue tumors [3].
The most common sites of involvement are the head
and neck, the flexor surfaces of the extremities, the mediastinum and the retroperitoneal space. Upper limb schwannomas (contributing 19% of all locations) [4] usually involve the ulnar nerve, only 6.8% of them being situated along the median nerve sheath [5].
Although they commonly appear as solitary lesions,
multiple tumors can occasi onally develop in schwanno-
matosis (one of the “candidate” genes is SMARCB1, a tumor-suppressor gene that regulates cell cycle, growth and differentiation, located on chromosome 22 a short
distance from the neurofibromatosis type 2 gene) [6, 7] or in association with neurofibromatosis type 2 (bilateral vestibular schwannoma is pathognomonic of neurofibro-matosis type 2) and neurofibromatosis type 1 [6]. They rarely undergo malignant transformation [8].
Solitary schwannoma is a slow-growing tumor and it
can present as a painless swelling for years before the onset of pain and neurological symptoms caused by nerve compression. Clinically, the tumor is well circumscribed and mobile transversely to the course to the nerve, but immobile in the longitudinal plane [9, 10].
Tumors with a long evolution and/or relatively large
dimensions can undergo degenerative changes such as cyst formation, calcificati on, hemorrhage and fibrosis
and are described as ancient schwannomas [11].
Macroscopically, a schwannoma is an oval yellowish
mass, typically eccentric to the nerve and enveloped in a true capsule, often covered by tortuous blood vessels.
This capsule consists of the perineurium of the nerve bundle of origin, surrounded by an onion-like condensation of the deepest layers of the epineurium. As such, it usually allows excision of the tumor without damage to the parent nerve. The extratumoral fascicles are stretched, attenuated and displaced over the dome of the mass. The rare plexiform variant of a schwannoma may infiltrate between nerve bundles and thus make excision difficult [12].
Microscopically, the tumor contains a variable mixture
of two distinctive areas: Antoni A (cellular areas with nuclei arranged in parallel rows termed “nuclear palisa-
ding”, Verocay bodies in which two rows of palisading
nuclei are separated by pink fibrillary material) and Antoni B (paucicellular, micr ocystic areas rich in macro-
phages and collagen fibers). Degenerative changes are
frequent. Ectatic, hyalinised, thrombosed blood vessels with associated hemorrhage and deposition of fibrin are
typically present. Cyst formation, hyalinization of the
matrix and focal calcificati on are also described. An
inflammatory infiltrate is usually present, including
numerous histiocytes. The nuclei of the Schwann cells
become hyperchromatic, enlarged and multilobed, but mitoses remain sparse [5].
By immunohistochemistry, schwannomas typically
show diffuse, strong expression of S100 protein, given the neuroectodermal origin of Schwann cells similar
with that of melanocytes [13, 14].
Folpe and Gowan (2001) have stated that immuno-
staining for this protein is so consistent and of such
intensity that it serves as an important diagnostic tool
[15].
Recent markers frequently used in the positive and
differential immunohistochemical diagnosis of schwannoma
include calretinin, CD34, neurofilament protein, Ki67, CD56 and factor XIIIa [16–18].
R J M E
Romanian Journal of
Morphology & Embryology
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Andrea Anghel et al.
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Here we report an unusual case of schwannoma of
the median nerve that, despite the classical description
as a well-defined tumor not including the patent nerve,
entrapped nerve bundles with intraoperative motor
response to electrical stimulation. We describe the
anamnestic and clinical pres entation, the MRI imaging,
the surgical findings and ther apy, the histopathological
and immunohistochemical diagnosis and the functional
outcome. The patient signed a full informed consent
form. This presentation received the approval of the
Scientific Research Ethics’ Committee of “Carol Davila”
University of Medicine and Ph armacy, Bucharest, Romania.
Patient, Methods and Results
We present the case of a 19-year-old male admitted
in our department for a soft tissue tumor located antero-medially in the proximal third of the left arm. The tumor had started growing slowly three years before and it was painless, but it associated paresthesias and numbness on the volar aspect of the second and third phalanges of the index and middle finger for the last few months. The patient had previously suffered a sports accident, the impact area matc hing the exact localization
of the tumor.
The patient’s medical history showed a Wolff–
Parkinson–White syndrome – posterior septal accessory fascicle – recently treated by radiofrequency ablation.
The clinical examination revealed a firm, painless
subcutaneous soft tissue tumor of about 3×2.5×1 cm, placed antero-laterally on the proximal left arm. The tumor could be mobilized transversely, but not axially or on the deep planes. The percussion of the median nerve at this level generated a positive Tinel sign over the volar distal phalanges of the second and third fingers.
Magnetic resonance imaging (MRI) showed a nodular,
well-demarcated tumor of the me dian nerve, with discreet
T2 signal, T1 signal and STIR hyperintense signal (Figure 1, a–c).
The median nerve conduction studies were completely
normal.
The patient underwent surgery under general anesthesia,
the tumor being dissected and excised with microscope magnification. It entrapped two nerve fascicles on the antero-medial aspect of the median nerve, which were
also resected. Since their el ectrical stimulation produced
some degree of flexion of the proximal interphalangeal joint of the index finger, the resulted defect was grafted using the medial brachial cu taneous nerve (located in
the same surgical field) as a donor (Figure 2, a–c).
No motor deficit was noted postoperatively. The
numbness of the index and middle finger subsided progressively, with significant improvement 12 months later.
The excision specimen was fo rmalin-fixed and paraffin-
embedded samples were examined histopathologically and immunohistochemicaly at Oncoteam Diagnostic, Bucharest. Serial 3 μm sections had been cut from paraffin blocks
and stained with Hematoxylin and Eosin (HE).
Histopathological evaluation
HE-stained sections showed the typical biphasic pattern
of Antoni A (Figure 3b) and
Antoni B (Figure 3a) areas, nuclear palisading (Figure 3c) and Verocay bodies, common
vascular ecstasies, some blood vessels with thickened
walls (Figure 3d), thrombosis and hyalinization with
moderate chronic inflammatory infiltrate (Figure 3e).
Immunohistochemistry method The immunohistochemistry (IHC) was performed on
3 μm sections from 10% formalin-fixed paraffin-embedded
tissues according to the IHC method an indirect bistadial
technique performed with a polymer-based detection
system (EnVision
TM Dual Link System-HRP, DAKO,
Carpinteria, CA, USA). Tissue sections were spread on
poly-L-Lysine-coated slides immersed in three changes
of xylene and rehydrated using a graded series of alcohol.
Antigen retrieval was performed in microwave oven.
In each section, endogenous peroxidase was blocked by
20 minutes incubation in 3% hydrogen peroxide. The
sections were incubated with primary antibody: S100
protein (DAKO, 1:400, polyclonal), Vimentin (Leica,
1:50, V9), Leu-7 (DAKO, 1:50, TB01), CD34 (DAKO,
1:50, QBend10) and Ki67 (DAKO, 1:100, Mib-1) at room
temperature for one hour. Th e DAKO EnVision Detection
System-HRP was then applied for 30 minutes. Finally,
the sections were incubated in 3,3’-diaminobenzidine for
5 minutes, counterstained with Meyer’s Hematoxylin and
mounted. The slides was examined and photographed
on Leica DM750 microscope. Negative controls were
obtained by replacing the primary antibody with non-
immune serum. As a positive control, a neural tissue
section was used.
Immunohistochemically, the tumor cells presented a
diffuse strong expression for S100 protein (Figure 4a)
and Vimentin (Figure 4c) with focal positive immuno-
staining for Leu7 (Figure 4d). CD34 was expressed only
in blood vessels (Figure 4b) and Ki67 was positive in
about 5% on the tumor cells (Figure 4e).
Discussion
Peripheral nerve sheath tumors include a spectrum of
clinical and pathological entities, ranging from benign
lesions such as schwannoma and neurofibroma to high-
grade malignant neoplasms such as malignant peripheral
nerve sheath tumors, but the main categories of solitary
benign peripheral nerve sheath tu mors consist of schwannoma
and neurofibroma.
Localized or solitary neurofibromas are slowly growing
fusiform lesions with a centrally entering and exiting
nerve. These lesions often lack a capsule and the tumor
tissue cannot be separated from normal nerve fibers.
Neurofibromas account for approximately 5% of all benign
soft tissue tumors and are usually observed in younger
individuals aged 20–30 years with no sex predilection [3].
The classical literature describes the schwannoma as
a slow-growing, well-encapsulated tumor that develops
eccentrically to the nerve fi bers, allowing complete
enucleation during excision. Despite these well-known
descriptions, recent studies ha ve revealed a significant
possibility of fascicle entrapment (even up to 75%) in the
schwannoma, possibility confirmed by the case depicted
in this paper [19–21].
Unusual median nerve schwannoma: a case presentation
161
Schwannomas arise from neural sheaths and, especially
in larger and/or longer history tumors [22, 23], the fascicles
surrounded by this part of the sheath can become embedded and may have to be excised – particularly in tumors located
in the proximal upper extremity and associated with
preoperative sensory disturbances (positive Tinel sign), as in our case [24].
The literature shows controversial results regarding
both the neurological deficit resulted after resection and the attitudes of various surgeons towards resection and
repair of the entrapped nerve fascicles. Sturzenegger et
al. reported six cases in which one or more fascicles disappeared in the tumor bulk and required resection, no
additional neurological deficit being reported after
excision [25]. On the other hand, Park et al. stated that
larger tumors tended to have more fascicles entering
the tumor bulk, thus being at a greater risk of major
neurological deficits after surgery. Oberle et al. observed
that schwannomas with long evolutions associated a greater
number of postoperative neurological complications.
Likewise, the study of Park et al. showed that 75% of
patients had immediate neurological deficits that seemed to
be determined by the transection of the fascicles that ran
through the tumor [22, 23].
Figure 1 – Large nodular tumor of the median nerve,
MRI: (a) STIR; (b) T1; (c) T2. Figure 2 – Intraoperative aspects: (a) Pre-excision; (b)
After partial excision of the tumor (distal end); (c) Nerve graft at the site of post-excisional nerve gap.
Figure 3 – HE staining: (a) Antoni B areas (ob. 4×); (b) Antoni A areas (ob. 10×); (c) Nuclear palisading (ob. 20×);
(d) Blood vessels with thickened walls (ob. 10×); (e) Ectatic, hyalinized, thrombosed blood vessels and chronic
inflammatory infiltrate (ob. 20×).
Andrea Anghel et al.
162
Figure 4 – Immunohistochemistry: (a) S100 staini ng (ob. 10×), diffuse positive; (b) CD34 (ob. 4×) in the blood vessels;
(c) Vimentin (ob. 10×); (d) Leu-7 (ob. 10×), zonal positive; (e) Ki67-positive in about 5% of the tumor cells (ob. 40×).
As mentioned above, the repair of resected nerve
fibers in schwannomas is somewhat controversial, too. Donner et al. stimulated the intratumoral fascicles and
recorded the action potentials across the tumors, resecting
only the fascicles that did not transmit nerve action
potentials [26]. Holdsworth opted for sural nerve grafts to repair the fascicles post-excision and achieved good results [27]. New or worsening pain after excision has been reported in 7.7–9.5% of cases and motor weakness in 7.7–10.5% [26, 28, 29]. Intraoperative electrical stimulation
of the involved fascicles can help in directing the surgical
attitude towards excision and/or repair of these fascicles [19]. When motor function loss is expected – after intra-operative nerve fascicle stimulation – nerve grafting is recommended [30].
In the case presented above, even if the MRI showed
at least one nerve bundle entering the tumor and the
surgery revealed that the tumor (localized in the proximal third of the arm, along the anterior aspect of the median nerve) entrapped two fascicles which produced a motor response at intraoperative el ectrical stimulation–flexion
of the proximal interphalangeal joint of the index finger,
both the histopathological exam and immunohistochemistry
confirmed the diagnosis of median nerve schwannoma. The classical histopathology description shows the typical biphasic pattern of Antoni A and Antoni B areas, Verocay bodies, common vascular ecstasies, some blood vessels with thrombosis, moderate polymorphic inflammatory
infiltrate and fibrosis with peripheral focal hyalinization. Immunohistochemically, the tumor presented a diffuse,
strong expression of S100 protein, a characteristic feature of schwannomas, given the neuroectodermal origin of Schwann cells similar with that of melanocytes [13, 14].
This protein is expressed by a great variety of human
cells and tissues including glial cells, neurons, chondrocytes, Schwann cells, melanocytes, macrophages, Langerhans cells and different epithelial tissues (especially those in the breast, sudoral glands and female genital tract) [16], but not by perineurial cells and endoneurial fibroblasts.
It is therefore useful for the differential diagnosis of
schwannomas that express S100 more than neurofibromas, but not sufficient because of some overlap in the expression of this marker between the two tumors.
Because the predominant cells found in a schwannoma
are the Schwann cells, while the neurofibroma presents
some additional types (endoneurial fibroblasts, perineurial-
like cells, etc.), CD34 or the human hematopoietic progenitor cell antigen is al so a useful stain in the
differential diagnosis of these tumors. Neurofibromas typically demonstrate a significant subpopulation of CD34-positive stromal cells, while schwannomas show
CD34 immunostaining most marked in Antoni B areas
and in the blood vessels (as in our case), given that CD34 is typically expressed by the embryonic cells of the hematopoietic system (endothelial cells and lymphoid/ myelogenous elements), but also by embryonary fibro-blasts, endoneurial fibroblasts [16, 31, 32].
The tumor cells of our patient presented also focal
Unusual median nerve schwannoma: a case presentation
163
positive immunostaining for Leu-7. Being a myelin-
associated glycoprotein present on Schwann cells (as well as on around 10 to 20% of lymphocytes, some epithelial and chromaffin cells), Leu-7 – also designated CD57 or HNK-1 – is part of a panel for identification of
neuroendocrine cells and neural cells and therefore for
differentiating neuroendocrine tumors from others [32, 33].
Vimentin is a 57-kD protein and is considered the most
ubiquitous of the intermediate filaments, being part of
the cytoplasmic cyto skeleton. Vimentin is expressed by
the great majority of mesenchymal cells (fibroblasts, endothelial cells, etc.), by many mesoderm-derived
epithelial cells ( e.g., Bowman capsule in kidney, endo-
metrium, myoepithelial cells of the breast, salivary and sweat glands, thyroid gland epithelium – in coexpression
with cytokeratin) and by cells from the neural crest
and tumors derived from these (malignant melanoma, schwannoma, glioma – in coexpression with glial fibrillary
acidic protein) [16, 32, 34].
Finally, the immunostaining for Ki67 (a nuclear antigen
expressed during the proliferating phases G1, S and G2
of the cell cycle), an indicator for the mitotic activity of
the cells and a measure for the tumor growth fraction, was assessed in our case and it was positive in approximately
5% of the tumor cells. This percentage is somewhat
borderline to malignancy, given that Kindblom et al.
reported a Ki67 index ranging from 5% to 65% in
malignant peripheral nerve sheath tumors, as opposed to
benign peripheral nerve sheath tumors in which the Ki67 index was lower than 5% [16]. If we consider the
idea that this marker may contribute to an earlier detection
of malignant transformation of benign neural tumors and that in our case the index Ki67 was 5%, the resection of
the whole tumor (including the entrapped functional
nerve bundles) becomes justified, even imperative.
Conclusions
Hereby we add another case of schwannoma that,
despite the classical description of this type of peripheral nerve sheath tumor, involved the bundles of the patent nerve and its treatment required complete excision and nerve grafting. At present, no clinical or imagistic
method can reliably predict the occurrence of fascicular
involvement. The histological and immunohistochemical exams are the ultimate diagnostic tools for the atypical cases.
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Corresponding author
Ruxandra Diana Sinescu, MD, PhD, Department of Plasti c Surgery and Reconstructive Microsurgery, “Elias”
Emergency University Hospital, 17 M ărăști Avenue, Sector 1, 011461 Bucharest, Romania; Phone +40722–545 830,
e-mail: ruxandrasinescu@gmail.com
Received: September 25, 2013
Accepted: February 5, 2014
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