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Peripheral nerve tumors
Handbook of Clinical Neurology, Vol. 105 (3rd series) Neuro-oncology W. Grisold and R. Soffietti, Editors # 2012 Elsevier B.V. All rights reserved
Chapter 44
Peripheral nerve tumors 1
JULIUS JULY 1,2 AND ABHIJIT GUHA1,3* Division of Neurosurgery, Toronto Western Hospital, University of Toronto, Toronto, Canada 2
Division of Neurosurgery, Padjadjaran University, Bandung, Indonesia
3
Arthur and Sonia Labatt Brain Tumor Center, Hospital for Sick Children Research Institute, University of Toronto, Toronto, Canada
INTRODUCTION Peripheral nerve tumors (PNTs) fall under the broad category of soft-tissue tumors and are therefore managed by a large number of subdisciplines including plastic surgery, dermatology, orthopedics, and neurosurgery. However, PNTs arise or are in close proximity to neural structures, so if not managed properly can lead to significant neurological deficits well beyond the adjacent softtissue structures. To complicate matters further, PNTs are relatively rare, lack definitive imaging or other diagnostic modalities, have a relatively large differential diagnosis comprising of transformation of any of the cellular elements that constitute a peripheral nerve (Table 44.1) with a wide variety of clinical and biological manifestations and association with predisposition syndromes. In this chapter we will review the principles of diagnosis, which includes a family history for any predisposition syndrome such as neurofibromatosis (NF) types 1 and 2, a thorough focused and systemic physical examination, and radiological investigations, principal amongst which is magnetic resonance imaging (MRI). In this chapter we review the major management strategies, which include observation or surgical intervention, occasionally augmented with adjuvant treatment with radiation and chemotherapy. Intraoperative principles, aimed at minimizing the risk of postoperative neurological deficit, are discussed briefly in general and specific to the main subtypes of PNT.
PRINCIPLES OF DIAGNOSIS History and physical examination When a soft tissue mass is associated with sensory and/or motor symptoms supplied by a known peripheral nerve, the suspicion of a PNT is readily apparent. However, the
majority of PNTs will present without any fixed neurological deficit or pain, and be brought to the patient’s attention simply as a palpable mass with an occasional Tinel’s sign upon contact. Like any mass, questions regarding any noticed growth alterations and associated clinical symptoms are of importance. In a suspected PNT, one needs to ask whether the mass is isolated, does the patient have any other prior malignancies, and is there a family history of such masses or cancer? Although some patients may not be aware, a direct question regarding their knowledge of the existence in their family for NF1 or NF2 is sometimes fruitful. Physical examination should be directed at the mass and overlying soft tissue, associated neurological function supplied by neighboring nerves, and a systemic examination to investigate the presence of any other masses or integumentary changes which are often associated with NF. Several features of the examination that suggests a tumor of peripheral nerve origin include: ● ●
●
PNTs are mobile perpendicularly but not along the longitudinal axis of a known peripheral nerve. Palpation or percussion (Tinel’s sign) of a PNT may elicit sensory stimuli radiating along the distribution of the nerve of origin. A mass in a patient with a genetic predisposition such as NF most likely represents a PNT.
Diagnostic investigations Nerve conduction and electromyographic (EMG) evaluation are generally not performed in the management of PNTs as they are not diagnostic and do not help in the management decision; however, intraoperative electrophysiology is crucial, as discussed under surgical
*Correspondence to: Abhijit Guha, MD FRCSC FACS, 4W-446, Western Hospital, 399 Bathurst Street, Toronto, Ontario M5T 2S8, Canada. Tel: (416) 603-5740, Fax: (416) 603-5298, E-mail: [email protected]
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Table 44.1 Peripheral nerve tumors: simplified classification scheme Benign
Malignant
Neural elements Schwannoma Neurofibroma Perineuroma
Neural elements Malignant peripheral nerve sheath tumor (MPNST) Primary peripheral nerve lymphoma Non-neural elements Pancoast tumor Soft tissue sarcoma Carcinoma
Non-neural elements Desmoid Ganglion cyst Fibrolipomatous hamartoma Lipoma Neuromuscular choristoma
management. Plain X-rays and computed tomography are occasionally helpful, especially to demonstrate remodeling of adjacent bony structures. Angiography or MR angiography is rarely required, and restricted to large PNTs at the base of the neck, chest, or retroperitoneum, where close proximity and or rarely vascular invasion may be present. Rarely nerve conduction velocity and EMG are performed prior to operations/interventions in order to delineate the preoperative function of peripheral nerve structures. MRI is the most useful and sensitive technique, often but not always revealing the nerve of origin (Figure 44.1). MRI may be highly suggestive but not diagnostic of the subtype of PNT, with elements of the history and physical examination often better at predicting whether the lesion is benign or malignant and the likely subtype of PNT
A
D
B
E
C
F
Fig. 44.1. Magnetic resonance images of common peripheral nerve tumors. (A) Median nerve schwannoma: sagittal and axial T1 gadolinium. (B) Neurofibromatosis type 1 (NF1) plexiform neurofibroma: axial and coronal T1 gadolinium. (C) Right brachial plexus lipoma: coronal T2 and fat saturation. (D) Tibia–fibula ganglion cyst: axial and sagittal T2. (E) NF1 sciatic nerve malignant peripheral nerve sheath tumor: (left) T1 þ gadolinium; (right) axial computed tomography–positron emission tomography (CT-PET) with high take-up in the tumor. (F) Left pancoast tumor: coronal and sagittal T1 þ gadolinium.
PERIPHERAL NERVE TUMORS present. Occasionally, MRI of schwannomas demonstrates the nerve(s) of origin, and the displaced passerby fascicles around the capsule, consistence with its typical ‘extrafascicular’ growth (Figure 44.1A). In contrast, neurofibromas are more fusiform (i.e., spindle-shaped) or multinodal, suggestive of their typical ‘intrafascicular’ growth (Figure 44.1B). Of note, a PNT in a patient with NF1 will most certainly be a neurofibroma, compared with a PNT in a patient with NF2, who likely harbors a schwannoma. Other PNTs with classical MRI findings include lipomas, which have the characteristic bright on T1 and T2 signal (Figure 44.1C). Ganglion cysts are bright on T2, with the origin traced to joint capsule in proximity to the nerve (Figure 44.1D). The ability to differentiate benign from malignant peripheral nerve sheath tumors (MPNSTs) by MRI remains problematic. PNTs may be of varying sizes, including extremely large tumors that grow in body cavities such as the abdomen and chest, with heterogeneous enhancement indicative of intratumor hemorrhage, necrosis, and/or cystic degeneration, but not malignant behavior. The differentiation of MPNSTs from benign PNTs is especially important in the management of patients with NF1, who may harbor many benign PNTs, although with an occasional risk of malignant conversion. The diagnosis of MPNST remains one of suspicion as a result of rapid clinical and radiological growth, progressive neurological deterioration, and, most importantly, onset of pain. Current investigations, including at our own institute, include investigation of the usefulness of positron emission tomography with [18F]fluorodeoxyglucose (18FDG-PET) (Figure 44.1E), although surgical– pathological diagnosis probably remains the definitive arbitrator (Lucas et al., 1998, Cardona et al., 2003).
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solitary tumors arising in middle-aged adults, with no sex predilection. Less than 5% of cases arise as part of predisposition syndromes such as NF2 or schwannomatosis, discussed in further detail below. Paraspinal schwannomas often have both intradural and extradural involvement with associated myelopathic and nerve root presentation. Management of these ‘dumbbell’ tumors involves prioritization of the intracanalicular portion and decompression of the spinal cord. Microscopic evaluation of a typical schwannoma reveals alternating areas of cellular Antoni A and loosely arranged Antoni B regions with occasional palisading organization of the nuclei, termed Verocay bodies (Figure 44.2A). Immunohistochemical characterization includes S-100 and anti-Leu-7 positivity (Burger et al., 2002). Immunostaining for glial fibrillary acidic protein (GFAP) and epithelial membrane antigen (EMA) is variably positive (Kleihues and Cavenee, 2000). The main feature differentiating schwannomas from neurofibromas is their extrafascicular growth, with absence of functional axons within the tumor substance.
SPECIFIC TYPES AND CLASSIFICATION OF PERIPHERAL NERVE TUMORS (TABLE 44.1) Benign tumors Benign PNTs that originate from transformation of Schwann cells are most common. However, the majority of these PNTs comprise not only the transformed Schwann cell, but also other stromal (endothelial cells, fibroblasts, pericytes, etc.) and sometimes inflammatory (mast cells, macrophages, etc.) cells, all of which contribute to the overall biology of the PNT.
SCHWANNOMAS Schwannomas are the most common PNT in adults. It is a benign tumor comprised of cells with the histological, ultrastructural, and antigenic characteristics of Schwann cells. The majority of schwannomas are spontaneous and
Fig. 44.2. Pathology of schwannoma and neurofibroma (hematoxylin and eosin stain). (A) Schwannoma: Antoni A cellular region, with Antoni B sparsely cellular region. (B) Neurofibroma: loose myxoid background with spindle cell nuclei and intratumoral nerve fascicles.
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Several atypical schwannomas exist, all usually with a benign course. Ancient schwannomas are characterized by cystic and calcified degenerative centers. These tumors, due to their inhomogeneous radiological features and occasionally rapid expansion (cystic degeneration), are suggestive of malignant behavior but are completely benign and curable. Cellular schwannomas may pose a pathological diagnostic challenge due to their hypercellularity, but nuclear atypia is usually mild with a modestly raised proliferation rate of up to 4–5 mitotic figures per 10 high-power fields. An exception to this benign nature of atypical schwannomas are the rare psammomatous melanotic schwannomas, which are packed with melanin and calcephorites. These may occur sporadically or as part of the extremely rare Carney syndrome, which includes Cushing disease and atrial myxomas (Carney, 1990). On rare occasions, these melanotic schwannomas can become malignant with metastasis (Noubari et al., 1998), but the histological criteria for malignancy are not well defined (Scheithauer et al., 1999). Most schwannomas are sporadic but multiple schwannomas are seen in patients with NF2 (Table 44.2), where they may occur in addition to vestibular schwannomas and other intracranial gliomas. In some patients with multiple schwannomas, intracranial tumors are absent and the patient may harbor a second distinct predisposition syndrome called schwannomatosis or NF3 (Table 44.2). NF2 is a rare autosomal dominant disease (incidence 1 in 37 000 live births), in which 50% of the patients have inherited a mutated NF2 gene from one of their parents and the other 50% represent a de novo germline mutation. The hallmark of the disease is bilateral vestibular schwannoma, which occurs in approximately 75% of patients with NF2, with a smaller subset of patients harboring multiple spinal and intracranial gliomas plus spinal and peripheral schwannomas (Martuza and Eldridge, 1988). The NF2 gene, identified in 1993, is located on chromosome 22 and is a typical tumor suppressor gene-mediated cancer predisposition syndrome. The NF2 gene encodes the protein Merlin or Schwannomin, which is completely absent in the Schwann cells of NF2-associated tumors due to a germline mutation in one NF2 allele with subsequent somatic inactivation of the normal NF2 allele (Trofatter et al., 1993). The exact transforming mechanism due to loss of Merlin/ Schwannomin that promotes transformation is not known, but it likely involves loss of normal regulation of cellular proliferation and motility (Shaw et al., 2001; Xiao et al., 2003). Management of schwannomas may be observation alone, especially when the tumor is asymptomatic or in the elderly or high-risk patients. Reassurance that the overwhelming majority of these tumors do not undergo malignant transformation is often critical for the patient to accept nonsurgical intervention. If symptoms
Table 44.2 National Institutes of Health diagnostic criteria for neurofibromatosis types 1 and 2, and schwannomatosis Neurofibromatosis type 1 Two or more of the following give the clinical diagnosis of NF1: ● Six or more cafe´ au lait spots (98%)* ● Two of more neurofibromas of any type, or one plexiform neurofibroma (95%)* ● Axillary freckling (88%)* ● Optic nerve gliomas (20%)* ● Two or more Lisch nodules ● Osseous lesions with or without pseudoarthrosis ● First-degree relative with NF1. Neurofibromatosis type 2 Definitive criteria: ● Bilateral vestibular schwannomas (bilateral acoustic neurofibromatosis, BANF), or ● A family history of NF2 in a first-degree relative, and: ● Unilateral vestibular schwannoma diagnosed at age less than 30 years, or ● Two of more of the following: meningioma, glioma, schwannoma, juvenile posterior subcapsular lenticular opacities/juvenile cortical cataract. Presumptive criteria: ● Unilateral vestibular schwannoma at age less than 30 years, and one of the following: ● Meningioma glioma, schwannoma, juvenile posterior subcapsular lenticular opacities/juvenile cortical cataract. ● Multiple meningiomas and unilateral vestibular schwannoma at age less than 30 years, or one of the following: ● Meningioma, glioma, schwannoma, juvenile posterior subcapsular lenticular opacities/juvenile cortical cataract. Schwannomatosis or NF3 Definitive criteria: ● Two or more pathologically proven schwannomas, and ● Lack of radiographic evidence of vestibular nerve tumors at age over 18 years. Presumptive criteria: ● Two or more pathologically proven schwannomas, without symptoms of VIIIth nerve dysfunction, at age over 30 years, or ● Two or more pathologically proven schwannomas in an anatomically limited distribution (single limb or segment of the spine), without symptoms of VIIIth nerve dysfunction, at any age. *Approximate incidence. NF, neurofibromatosis.
and/or growth are present, microneurosurgical removal is warranted with intraoperative electrophysiological monitoring. Using some of the surgical principles outlined briefly below, the extrafascicular growth of schwannomas usually allows isolation of the nerve of origin and exit, leading to gross total resection with minimal neurological deficits (Figure 44.3A)
PERIPHERAL NERVE TUMORS
A
B
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C
* D
E
F
Fig. 44.3. Surgical principles for schwannoma and ganglion cyst. Schwannoma: (A) incision and draping should allow dissection of the normal proximal and distal nerve plus the intervening tumor (T); (B) isolation of the proximal and distal normal nerves (arrowheads); (C) visual and electrophysiological mapping of passer-by functioning fasicles splayed around the tumor capsule; (D) microneurosurgical isolation of nonfunctioning nerve of origin (arrowhead) and exit to undertake tumor and capsule removal. Ganglion cyst: (E) common peroneal nerve with adhered ganglion cyst (arrowheads); (F) resection of ganglion cyst right with cauterization of origin in tibia–fibula joint (*) and decompression of the anterior tibial and superficial peroneal branches of the common peroneal nerve (arrowheads).
NEUROFIBROMAS Neurofibromas are benign PNTs, and are also due to primary transformation of Schwann cells, although additional stromal cells such as pericytes, fibroblasts, and mast cells are quite prevalent and contribute to the overall growth of the neurofibroma. In contrast to schwannomas, neurofibromas have a loose myxoid matrix of collagen fibrils. Wavy interlacing hyperchromatic spindle-shaped transformed Schwann cell nuclei are interspersed with normal nerve fibers within the tumor (see Figure 44.2B). The transformed Schwann cells stain positive for S-100 and Leu-7, but not as prominently as schwannomas. The presence of axons within the tumor substance, as demonstrated by axon-specific stains, is the cardinal intrafascicular growth of neurofibromas. Neurofibromas arise spontaneously, but in about half of the patients occur in the context of NF1, a disease first named by von Recklinghausen in 1882. NF1, like NF2, is also an autosomal dominant disorder, but is approximately 10 times more common, with an incidence of 1 in 3500 live births. The clinical criteria, as set by the National Institutes of Health, remain the most reliable and clinically practical means for making a diagnosis of NF1 (Stumpf et al., 1988) (see Table 44.2), although we now know much more about its molecular genetics. Like NF2, 50% of patients with NF1 have
inherited a mutated NF1 gene from one of their parents, with the other 50% due to a germline mutation. This represents an extremely high spontaneous mutation rate for a gene, perhaps related to its extremely large size (Karnes, 1998; Kluwe et al., 2003). The chromosomal location for the NF1 gene is 17q12 (Schmidt et al., 2000), encoding for the protein neurofibromin, which belongs to the Ras-GAP (Ras-GTPase activating protein) family (Gutmann and Collins, 1993) involved in inactivating Ras. The activation of Ras is a pivotal intracellular mechanism of signal transduction utilized by many growth factor receptors (Egan and Weinberg, 1993), with neurofibromin and other related family members hydrolyzing active Ras to its inactive state. As predicted, we have demonstrated levels of activated Ras to be markedly increased in NF1-associated neurofibromas and MPNSTs, compared with schwannomas and normal nerves (Guha et al., 1996). The importance of this molecular understanding is that pharmacological agents that target activated Ras or its downstream effector proteins may be promising as biologically targeted therapies for these tumors (Kohl et al., 1993). Clinically, neurofibromas are divided into several subtypes based on their location and gross appearance (Kleihues and Cavenee, 2000). Cutaneous or dermal neurofibromas, which may number in the hundreds in patients with NF1, are rarely a cosmetic and/or local
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irritation problem. For the most part, these dermal neurofibromas should not be operated on, with reassurance to the patients that these neurofibromas almost never undergo malignant transformation. Plexiform neurofibromas arise from deeper and larger nerves, with multiple tumors in patients with NF1. Again, clinical and radiological observation is most prudent, especially in the setting of NF1, because the intrafascicular growth lends itself to neurological deficit if radical resection is attempted. Indications for surgery are solitary plexiform neurofibromas in patients without NF1, or tumors that demonstrate progressive growth, neurological symptoms, and especially pain. Indications for surgery in these cases are not only partial debulking for potential amelioration of the clinical symptoms, but also to exclude malignant transformation. Malignant transformation may occur in 3–5% of plexiform neurofibromas in patients without NF1, and in as many as 8–13% of patients with NF1 (Sorensen et al., 1986; Perrin and Guha, 2004; Tucker et al., 2005). In general, if the plexiform neurofibroma is benign on quick section, one can undertake subtotal but often radical debulking, with careful attention at sparing functioning intratumoral fascicles. However, if the pathologist queries malignant transformation, it is best to close, confirm the diagnosis, and undertake delayed nonnerve-sparing surgery, as described below.
GANGLION
CYSTS
These non-neoplastic lesions often occur near joints or tendon sheaths and may cause compression of adjacent nerves (Rosenberg et al., 1991). The median and ulnar nerve at the wrist, the posterior interosseus nerve at the elbow, and the common peroneal nerve at the knee are most commonly affected. At surgery, special effort should be made not only to decompress the nerve but also to find and completely resect the portion of the cyst originating from the joint capsule, to prevent recurrence (see Figure 44.3B).
FIBROLIPOMATOUS
HAMARTOMA OR LIPOMA
These are benign neoplasms arising from adipocytes or fibrofatty tissue with associated infiltration of the nerve (Guthikonda et al., 1994). Diagnosis can usually be made by the unique characteristics of fat on MRI (see Figure 44.1C). Fibrolipomatous hamartomas have a relatively higher proportion of fibrous tissue to fat in the proximal and distal segments of the lesions (Scheithauer et al., 1999). Conservative management of these lesions is usually recommended, with symptomatic lesions requiring only decompression of any associated entrapment point (e.g., carpal tunnel, etc.) or subtotal resection, making sure there is no intertwined functioning fascicles within the lipoma.
PERINEUROMA
NEUROMUSCULAR
These rare tumors are recognized based on their unique immunohistochemical and ultrastructural characteristics, identifying the perineural cell as the cell of origin (Tsang et al., 1992; Giannini et al., 1997). Clinically they are benign, occur in the middle-aged with a slightly higher incidence in women, typically arise in the deep soft tissues of the extremities, and are not associated with NF1 or NF2. Pathologically, these lesions are composed of cells with a wavy bipolar cytoplasm and elongated nuclei in a collagen or myxoid stroma, and stain positively for EMA. The ultrastructural features are characteristic with an incomplete basal lamina and abundant pinocytic vesicles in the predominant transformed perineural cells. Management principles are similar to those outlined above for schwannomas.
These are rare benign neoplasms in which welldifferentiated muscle is found within a mature neural element (Maher et al., 2002). Most cases present as single lesions and affect large nerves, with neurological deficit, muscle atrophy, and limb deformity (Maher et al., 2002). The regrowth rate after first surgery is low.
DESMOIDS These are fibrous mesenchymal tumors arising from muscles that can encase or infiltrate peripheral nerves and nearby vascular structures (Lusk et al., 1987; Rosenberg et al., 1991). Although they do not metastasize, desmoids are locally aggressive with a high recurrence rate, especially when the brachial plexus is involved.
CHORISTOMA
Malignant tumors Malignant tumors of peripheral nerves can be primary, resulting from primary malignant transformation of Schwann cells – collectively termed malignant peripheral nerve sheath tumors (MPNSTs) – or secondary to infiltration or metastasis of lymphomas, carcinomas, or sarcomas.
MALIGNANT
PERIPHERAL NERVE SHEATH TUMOR
MPNSTs account for 3–10% of all soft-tissue sarcomas, with half of the cases originating at an earlier age in patients with NF1 (King et al., 2000). As discussed above, the risk of malignant transformation of a benign plexiform neurofibroma is quite substantial in patients with NF1, which is a source of diagnostic and psychological stress in these patients. Progressive
PERIPHERAL NERVE TUMORS enlargement, incapacitating pain, and increasing neurological deficit in a plexiform neurofibroma should raise suspicion and lead to definitive steps in pathological diagnosis, as current noninvasive diagnostic tests are often inconclusive. The ideal management of MPNSTs remains controversial, with our institute recommending a multidisciplinary management strategy requiring collaboration with orthopedic oncology colleagues, physiotherapy and occupational therapists (Angelov et al., 1998) (Figure 44.4A). Clinical suspicion is followed by four-quadrant open biopsy (Figure 44.4B). We prefer an open biopsy to fine-needle or percutaneous TruCut biopsy, so as to obtain more representative tissue, as the malignant foci in the nerve are often mixed with benign regions, and also to minimize pain and neurological deficits from a blind procedure. If, at surgery, the quick sections are all negative for malignancy, we proceed to a nerve-sparing subtotal debulking, hopefully to obtain symptomatic relief. If the quick section of any of the specimens is suspicious for malignancy, we close, as discussed preoperatively with the patient, to facilitate pathological confirmation of MPNST, which can often be troublesome in these rare tumors. Subsequent to definitive confirmation and grading of the MPNST, the patient is referred to our sarcoma clinic for preoperative assessment for metastasis and radiation to the tumor and surrounding soft-tissue margins. This is followed by a thorough discussion with the patient by the neurosurgeon, orthopedic oncology surgeon, physiotherapy and occupational therapist regarding the expected neurological and functional deficits after a radical non-nervesparing procedure with adjacent soft-tissue planes. The overall objective is to obtain tumor-free margins as determined by intraoperative quick sections, which can be usually achieved without requiring limb amputation. In our experience, such a staged multidisciplinary approach has served well not only for tumor control, but also for the patient to retain a good quality of life. However, the prognosis remains guarded, as approximately 50% of the patients have succumbed to pulmonary and visceral metastasis by 5 years, despite multiple surgeries and systemic chemotherapy (Angelov et al., 1999; Ferner et al., 2002). Adverse prognostic factors include: size (> 5 cm), higher tumor grade, advanced histology, non-tumor-free surgical margins, and MPNSTs in association with NF1. Hence there is continued need for research and search of biologically targeted therapies to augment the current management of MPNSTs. Assessment of these novel therapies in these rare tumors will likely require formation of multi-institutional and multinational consortiums.
PRIMARY
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PERIPHERAL NERVE LYMPHOMA
Only a few cases have been reported so far of primary peripheral nerve lymphoma without systemic evidence of lymphoma, the latter being termed neurolymphomatosis, which is a part of the systemic manifestation of lymphoma. The majority of these are of B-cell type, affecting the sciatic nerve. Treatment includes surgical biopsy for diagnosis, followed by radiation and/or chemotherapy (Misdraji et al., 2000).
COMPRESSION
AND/OR INFILTRATION
FROM PRIMARY MALIGNANCY
Peripheral nerves may be secondarily compressed from adjacent tumors or their metastasis to lymph nodes. Rarely there may be direct longitudinal invasion of epineurium of the nerve by a carcinoma or sarcoma, resulting in pain or neurological symptoms. Pulmonary or breast carcinomas are the most common secondary tumors to involve the brachial plexus (Lusk et al., 1987). In cases of brachial plexopathy following mastectomy and radiotherapy, which is often associated with pain and rapid motor weakness, it is sometimes hard to differentiate from carcinoma recurrence and invasion versus radiation plexopathy. External neurolysis to obtain tissue for pathological examination and provide pain relief may be indicated, although return of motor function does not usually occur.
PRINCIPLES OF SURGICAL MANAGEMENT OF PERIPHERAL NERVE TUMORS If surgery is warranted, the preoperative goals (total excision versus subtotal debulking versus biopsy) and associated risks must be thoroughly discussed. Microneurosurgical techniques, intraoperative magnification, and electrophysiological monitoring without neuromuscular paralysis are essential prerequisites. The affected limb should be positioned and draped to allow evaluation of the distal muscles supplied by the relevant nerve or audible EMG electrodes inserted into those muscles. The incision should be long enough to expose the proximal and distal normal nerve (see Figure 44.3A). If the PNT is close to a natural entrapment point such as the carpal tunnel or fibular head, prophylactic release of the nerve traversing through these regions should be undertaken to defray delayed entrapment syndromes. Exposure commences with isolation of the normal proximal and distal segments of the nerve of origin, which are confirmed electrophysiologically. The presence of passer-by fascicles, which may be splayed across the tumor capsule, is highly suggestive of the extrafascicular growth of schwannomas, and
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J. JULY AND A. GUHA Suspected MPNST History/Examination/Radiology
Referral to tertiary center
Four-quadrant open biopsy and pathological verification/grading
Metastasis screening and informed consent
Metastasis not detected
Metastasis detected
Multidisciplinary approach Surgery for tumor margin (local control) Pre-/postoperative radiation therapy
Palliative tumor debulking Radiation Chemotherapy
A
Follow-up (local/systemic)
B
C
Fig. 44.4. (A) Management strategy for malignant peripheral nerve sheath tumor (MPNST) (University of Toronto Multidisciplinary Sarcoma Group). (B) Initial four-quadrant open biopsy of sciatic nerve neurofibroma in a patient with neurofibromatosis type 1 (see Figure 44.1E for MRI and CT-PET), which was confirmed pathologically to be a MPNST. The wound was closed and the tumor bed and margins are irradiated. (C) Second en bloc resection of the MPNST, adjacent nerve, and soft tissue, with intraoperative sampling to ensure tumor free margins.
visual and electrical localization of these fascicles is important (see Figure 44.3A). An area that is electrically silent, hence representing only tumor, is then chosen to obtain a quick section. If the macroscopic and pathological examination is consistent with the diagnosis of a schwannoma, then total removal is to be expected, whereas subtotal but radical debulking can be
accomplished with neurofibromas. Often the exact differentiation of the PNT subtype cannot be made on the quick section, requiring use of good clinical judgment to maximize tumor removal with minimal deficits. The majority of small to medium-sized PNTs can be removed completely, although removal of larger tumors or those adjacent to vital structures such as the spinal
PERIPHERAL NERVE TUMORS canal may first require intratumoral decompression followed by resection of the capsule from adjacent functioning neural and non-neural structures. Microneurosurgical dissection, combined with electrophysiological monitoring, is continued until the nerve fascicle of origin and exit is identified and electrically isolated, and demonstrated to be nonfunctional (see Figure 44.3A). Total capsular removal is often achievable, once the passer-by fasicles have been identified and protected. The need for nerve grafts after resection of PNTs is extremely rare. If the quick section is suggestive of malignancy, the main objective of surgery is localized tumor control rather than nerve-sparing, as discussed above.
FUTURE DIRECTIONS Although rare, PNTs form a diverse group of tumors, which vary in their pathology, biological, and clinical behavior. Due to their rarity, referral to tertiary centers is recommended for optimal care. Not all patients with PNTs require surgery, especially patients predisposed to these tumors. Management objectives may change with the natural history of the tumor and require thorough discussion with the patient. Careful surgical management can be achieved, where indicated, with minimal morbidity. MPNST remains an incurable tumor, which will require further molecular understanding and biological adjuvant therapies in the future.
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Giannini C, Scheithauer BW, Jenkins RB et al. (1997). Soft tissue perineurioma. Evidence for an abnormality of chromosome 22, criteria for diagnosis, and review of the literature. Am J Surg Pathol 21: 164–173. Guha A, Lau N, Gutmann D et al. (1996). Ras-GTP levels are elevated in human NF1 peripheral nerve tumors. Oncogene 12: 507–513. Guthikonda M, Rengachary SS, Balko MG et al. (1994). Lipofibromatous hamartoma of the median nerve: case report with magnetic resonance imaging correlation. Neurosurgery 35: 127–132. Gutmann D, Collins F (1993). The neurofibromatosis type 1 gene and its protein product, neurofibromin. Neuron 10: 335–343. Karnes PS (1998). Neurofibromatosis: a common neurocutaneous disorder. Mayo Clin Proc 73: 1071–1076. King AA, Debaun MR, Riccardi VM et al. (2000). Malignant peripheral nerve sheath tumors in neurofibromatosis 1. Am J Med Genet 93: 388–392. Kleihues P, Cavenee WK (2000). Pathology and Genetics of Tumours of the Nervous System. World Health Organization Classification of Tumour, IARC Press, Lyons. Kluwe L, Tatagiba M, Funsterer C et al. (2003). NF1 mutations and clinical spectrum in patients with spinal neurofibromas. J Med Genet 40: 368–371. Kohl NE, Mosser SD, deSolms SJ et al. (1993). Selective inhibition of ras-dependent transformation by a farnesyltransferase inhibitor. Science 260: 1934–1937. Lucas JD, O’Doherty MJ, Wong JCH et al. (1998). Evaluation of fluorodeoxyglucose positron emission tomography in the management of soft tissue sarcomas. J Bone Joint Surg Br 80-B: 441–447. Lusk M, Kline D, Garcia C (1987). Tumors of the brachial plexus. Neurosurgery 21: 439–453. Maher CO, Spinner RJ, Giannic C et al. (2002). Neuromuscular choristoma of the sciatic nerve. J Neurosurg 96: 1123–1126. Martuza RL, Eldridge R (1988). Neurofibromatosis 2 (bilateral acoustic neurofibromatosis). N Engl J Med 318: 684–688. Misdraji J, Ino Y, Louis DN et al. (2000). Primary lymphoma of peripheral nerve: report of four cases. Am J Surg Pathol 24: 1257–1265. Noubari BA, Chiaramonte I, Magro G et al. (1998). Spinal malignant melanotic schwannoma Case report.. J Neurosurg Sci 42: 245–249. Perrin R, Guha A (2004). Management of malignant peripheral nerve tumors. Neurosurg Clin N Am 15: 203–216. Rosenberg A, Dick H, Botte M (1991). Nerve tumors. In: R Gilberman (Ed.), Operative Nerve Repair and Reconstruction. J.B, Lippincott, Philadelphia. Scheithauer BW, Woodruff JM, Erlandson RA (1999). Tumors of Peripheral Nervous System. Vol. 24. Armed Forces Institute of Pathology, Washington, DC, pp. 29–104. Schmidt H, Taubert H, Meye A et al. (2000). Gains in chromosomes 7, 8q, 15q, and 17q are characteristic changes in malignant but not in benign peripheral nerve sheath tumors from patients with Recklinghausen’s disease. Cancer Lett 155: 181–190.
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Shaw RJ, Paez JG, Curto M et al. (2001). The Nf-2 tumor suppressor, merlin, functions in Rac-dependent signaling. Dev Cell 1: 63–72. Sorensen S, Mulvhill J, Nielsen A (1986). Longterm follow up of von Recklinghausen neurofibromatosis Survival and malignant neoplasms.. N Engl J Med 314: 1010–1015. Stumpf S, Alksne JF, Annegers JF et al. (1988). Neurofibromatosis Conference statement. National Institutes of Health Consensus Development Conference.. Arch Neurol 45: 575–578. Trofatter JA, MacCollin MM, Rutter JL et al. (1993). A novel moesin-, ezrin-, radixin-like gene is a candidate for the neurofibromatosis 2 tumor suppressor. Cell 72: 791–800.
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Chapter 44
Peripheral nerve tumors 1
JULIUS JULY 1,2 AND ABHIJIT GUHA1,3* Division of Neurosurgery, Toronto Western Hospital, University of Toronto, Toronto, Canada 2
Division of Neurosurgery, Padjadjaran University, Bandung, Indonesia
3
Arthur and Sonia Labatt Brain Tumor Center, Hospital for Sick Children Research Institute, University of Toronto, Toronto, Canada
INTRODUCTION Peripheral nerve tumors (PNTs) fall under the broad category of soft-tissue tumors and are therefore managed by a large number of subdisciplines including plastic surgery, dermatology, orthopedics, and neurosurgery. However, PNTs arise or are in close proximity to neural structures, so if not managed properly can lead to significant neurological deficits well beyond the adjacent softtissue structures. To complicate matters further, PNTs are relatively rare, lack definitive imaging or other diagnostic modalities, have a relatively large differential diagnosis comprising of transformation of any of the cellular elements that constitute a peripheral nerve (Table 44.1) with a wide variety of clinical and biological manifestations and association with predisposition syndromes. In this chapter we will review the principles of diagnosis, which includes a family history for any predisposition syndrome such as neurofibromatosis (NF) types 1 and 2, a thorough focused and systemic physical examination, and radiological investigations, principal amongst which is magnetic resonance imaging (MRI). In this chapter we review the major management strategies, which include observation or surgical intervention, occasionally augmented with adjuvant treatment with radiation and chemotherapy. Intraoperative principles, aimed at minimizing the risk of postoperative neurological deficit, are discussed briefly in general and specific to the main subtypes of PNT.
PRINCIPLES OF DIAGNOSIS History and physical examination When a soft tissue mass is associated with sensory and/or motor symptoms supplied by a known peripheral nerve, the suspicion of a PNT is readily apparent. However, the
majority of PNTs will present without any fixed neurological deficit or pain, and be brought to the patient’s attention simply as a palpable mass with an occasional Tinel’s sign upon contact. Like any mass, questions regarding any noticed growth alterations and associated clinical symptoms are of importance. In a suspected PNT, one needs to ask whether the mass is isolated, does the patient have any other prior malignancies, and is there a family history of such masses or cancer? Although some patients may not be aware, a direct question regarding their knowledge of the existence in their family for NF1 or NF2 is sometimes fruitful. Physical examination should be directed at the mass and overlying soft tissue, associated neurological function supplied by neighboring nerves, and a systemic examination to investigate the presence of any other masses or integumentary changes which are often associated with NF. Several features of the examination that suggests a tumor of peripheral nerve origin include: ● ●
●
PNTs are mobile perpendicularly but not along the longitudinal axis of a known peripheral nerve. Palpation or percussion (Tinel’s sign) of a PNT may elicit sensory stimuli radiating along the distribution of the nerve of origin. A mass in a patient with a genetic predisposition such as NF most likely represents a PNT.
Diagnostic investigations Nerve conduction and electromyographic (EMG) evaluation are generally not performed in the management of PNTs as they are not diagnostic and do not help in the management decision; however, intraoperative electrophysiology is crucial, as discussed under surgical
*Correspondence to: Abhijit Guha, MD FRCSC FACS, 4W-446, Western Hospital, 399 Bathurst Street, Toronto, Ontario M5T 2S8, Canada. Tel: (416) 603-5740, Fax: (416) 603-5298, E-mail: [email protected]
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Table 44.1 Peripheral nerve tumors: simplified classification scheme Benign
Malignant
Neural elements Schwannoma Neurofibroma Perineuroma
Neural elements Malignant peripheral nerve sheath tumor (MPNST) Primary peripheral nerve lymphoma Non-neural elements Pancoast tumor Soft tissue sarcoma Carcinoma
Non-neural elements Desmoid Ganglion cyst Fibrolipomatous hamartoma Lipoma Neuromuscular choristoma
management. Plain X-rays and computed tomography are occasionally helpful, especially to demonstrate remodeling of adjacent bony structures. Angiography or MR angiography is rarely required, and restricted to large PNTs at the base of the neck, chest, or retroperitoneum, where close proximity and or rarely vascular invasion may be present. Rarely nerve conduction velocity and EMG are performed prior to operations/interventions in order to delineate the preoperative function of peripheral nerve structures. MRI is the most useful and sensitive technique, often but not always revealing the nerve of origin (Figure 44.1). MRI may be highly suggestive but not diagnostic of the subtype of PNT, with elements of the history and physical examination often better at predicting whether the lesion is benign or malignant and the likely subtype of PNT
A
D
B
E
C
F
Fig. 44.1. Magnetic resonance images of common peripheral nerve tumors. (A) Median nerve schwannoma: sagittal and axial T1 gadolinium. (B) Neurofibromatosis type 1 (NF1) plexiform neurofibroma: axial and coronal T1 gadolinium. (C) Right brachial plexus lipoma: coronal T2 and fat saturation. (D) Tibia–fibula ganglion cyst: axial and sagittal T2. (E) NF1 sciatic nerve malignant peripheral nerve sheath tumor: (left) T1 þ gadolinium; (right) axial computed tomography–positron emission tomography (CT-PET) with high take-up in the tumor. (F) Left pancoast tumor: coronal and sagittal T1 þ gadolinium.
PERIPHERAL NERVE TUMORS present. Occasionally, MRI of schwannomas demonstrates the nerve(s) of origin, and the displaced passerby fascicles around the capsule, consistence with its typical ‘extrafascicular’ growth (Figure 44.1A). In contrast, neurofibromas are more fusiform (i.e., spindle-shaped) or multinodal, suggestive of their typical ‘intrafascicular’ growth (Figure 44.1B). Of note, a PNT in a patient with NF1 will most certainly be a neurofibroma, compared with a PNT in a patient with NF2, who likely harbors a schwannoma. Other PNTs with classical MRI findings include lipomas, which have the characteristic bright on T1 and T2 signal (Figure 44.1C). Ganglion cysts are bright on T2, with the origin traced to joint capsule in proximity to the nerve (Figure 44.1D). The ability to differentiate benign from malignant peripheral nerve sheath tumors (MPNSTs) by MRI remains problematic. PNTs may be of varying sizes, including extremely large tumors that grow in body cavities such as the abdomen and chest, with heterogeneous enhancement indicative of intratumor hemorrhage, necrosis, and/or cystic degeneration, but not malignant behavior. The differentiation of MPNSTs from benign PNTs is especially important in the management of patients with NF1, who may harbor many benign PNTs, although with an occasional risk of malignant conversion. The diagnosis of MPNST remains one of suspicion as a result of rapid clinical and radiological growth, progressive neurological deterioration, and, most importantly, onset of pain. Current investigations, including at our own institute, include investigation of the usefulness of positron emission tomography with [18F]fluorodeoxyglucose (18FDG-PET) (Figure 44.1E), although surgical– pathological diagnosis probably remains the definitive arbitrator (Lucas et al., 1998, Cardona et al., 2003).
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solitary tumors arising in middle-aged adults, with no sex predilection. Less than 5% of cases arise as part of predisposition syndromes such as NF2 or schwannomatosis, discussed in further detail below. Paraspinal schwannomas often have both intradural and extradural involvement with associated myelopathic and nerve root presentation. Management of these ‘dumbbell’ tumors involves prioritization of the intracanalicular portion and decompression of the spinal cord. Microscopic evaluation of a typical schwannoma reveals alternating areas of cellular Antoni A and loosely arranged Antoni B regions with occasional palisading organization of the nuclei, termed Verocay bodies (Figure 44.2A). Immunohistochemical characterization includes S-100 and anti-Leu-7 positivity (Burger et al., 2002). Immunostaining for glial fibrillary acidic protein (GFAP) and epithelial membrane antigen (EMA) is variably positive (Kleihues and Cavenee, 2000). The main feature differentiating schwannomas from neurofibromas is their extrafascicular growth, with absence of functional axons within the tumor substance.
SPECIFIC TYPES AND CLASSIFICATION OF PERIPHERAL NERVE TUMORS (TABLE 44.1) Benign tumors Benign PNTs that originate from transformation of Schwann cells are most common. However, the majority of these PNTs comprise not only the transformed Schwann cell, but also other stromal (endothelial cells, fibroblasts, pericytes, etc.) and sometimes inflammatory (mast cells, macrophages, etc.) cells, all of which contribute to the overall biology of the PNT.
SCHWANNOMAS Schwannomas are the most common PNT in adults. It is a benign tumor comprised of cells with the histological, ultrastructural, and antigenic characteristics of Schwann cells. The majority of schwannomas are spontaneous and
Fig. 44.2. Pathology of schwannoma and neurofibroma (hematoxylin and eosin stain). (A) Schwannoma: Antoni A cellular region, with Antoni B sparsely cellular region. (B) Neurofibroma: loose myxoid background with spindle cell nuclei and intratumoral nerve fascicles.
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Several atypical schwannomas exist, all usually with a benign course. Ancient schwannomas are characterized by cystic and calcified degenerative centers. These tumors, due to their inhomogeneous radiological features and occasionally rapid expansion (cystic degeneration), are suggestive of malignant behavior but are completely benign and curable. Cellular schwannomas may pose a pathological diagnostic challenge due to their hypercellularity, but nuclear atypia is usually mild with a modestly raised proliferation rate of up to 4–5 mitotic figures per 10 high-power fields. An exception to this benign nature of atypical schwannomas are the rare psammomatous melanotic schwannomas, which are packed with melanin and calcephorites. These may occur sporadically or as part of the extremely rare Carney syndrome, which includes Cushing disease and atrial myxomas (Carney, 1990). On rare occasions, these melanotic schwannomas can become malignant with metastasis (Noubari et al., 1998), but the histological criteria for malignancy are not well defined (Scheithauer et al., 1999). Most schwannomas are sporadic but multiple schwannomas are seen in patients with NF2 (Table 44.2), where they may occur in addition to vestibular schwannomas and other intracranial gliomas. In some patients with multiple schwannomas, intracranial tumors are absent and the patient may harbor a second distinct predisposition syndrome called schwannomatosis or NF3 (Table 44.2). NF2 is a rare autosomal dominant disease (incidence 1 in 37 000 live births), in which 50% of the patients have inherited a mutated NF2 gene from one of their parents and the other 50% represent a de novo germline mutation. The hallmark of the disease is bilateral vestibular schwannoma, which occurs in approximately 75% of patients with NF2, with a smaller subset of patients harboring multiple spinal and intracranial gliomas plus spinal and peripheral schwannomas (Martuza and Eldridge, 1988). The NF2 gene, identified in 1993, is located on chromosome 22 and is a typical tumor suppressor gene-mediated cancer predisposition syndrome. The NF2 gene encodes the protein Merlin or Schwannomin, which is completely absent in the Schwann cells of NF2-associated tumors due to a germline mutation in one NF2 allele with subsequent somatic inactivation of the normal NF2 allele (Trofatter et al., 1993). The exact transforming mechanism due to loss of Merlin/ Schwannomin that promotes transformation is not known, but it likely involves loss of normal regulation of cellular proliferation and motility (Shaw et al., 2001; Xiao et al., 2003). Management of schwannomas may be observation alone, especially when the tumor is asymptomatic or in the elderly or high-risk patients. Reassurance that the overwhelming majority of these tumors do not undergo malignant transformation is often critical for the patient to accept nonsurgical intervention. If symptoms
Table 44.2 National Institutes of Health diagnostic criteria for neurofibromatosis types 1 and 2, and schwannomatosis Neurofibromatosis type 1 Two or more of the following give the clinical diagnosis of NF1: ● Six or more cafe´ au lait spots (98%)* ● Two of more neurofibromas of any type, or one plexiform neurofibroma (95%)* ● Axillary freckling (88%)* ● Optic nerve gliomas (20%)* ● Two or more Lisch nodules ● Osseous lesions with or without pseudoarthrosis ● First-degree relative with NF1. Neurofibromatosis type 2 Definitive criteria: ● Bilateral vestibular schwannomas (bilateral acoustic neurofibromatosis, BANF), or ● A family history of NF2 in a first-degree relative, and: ● Unilateral vestibular schwannoma diagnosed at age less than 30 years, or ● Two of more of the following: meningioma, glioma, schwannoma, juvenile posterior subcapsular lenticular opacities/juvenile cortical cataract. Presumptive criteria: ● Unilateral vestibular schwannoma at age less than 30 years, and one of the following: ● Meningioma glioma, schwannoma, juvenile posterior subcapsular lenticular opacities/juvenile cortical cataract. ● Multiple meningiomas and unilateral vestibular schwannoma at age less than 30 years, or one of the following: ● Meningioma, glioma, schwannoma, juvenile posterior subcapsular lenticular opacities/juvenile cortical cataract. Schwannomatosis or NF3 Definitive criteria: ● Two or more pathologically proven schwannomas, and ● Lack of radiographic evidence of vestibular nerve tumors at age over 18 years. Presumptive criteria: ● Two or more pathologically proven schwannomas, without symptoms of VIIIth nerve dysfunction, at age over 30 years, or ● Two or more pathologically proven schwannomas in an anatomically limited distribution (single limb or segment of the spine), without symptoms of VIIIth nerve dysfunction, at any age. *Approximate incidence. NF, neurofibromatosis.
and/or growth are present, microneurosurgical removal is warranted with intraoperative electrophysiological monitoring. Using some of the surgical principles outlined briefly below, the extrafascicular growth of schwannomas usually allows isolation of the nerve of origin and exit, leading to gross total resection with minimal neurological deficits (Figure 44.3A)
PERIPHERAL NERVE TUMORS
A
B
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C
* D
E
F
Fig. 44.3. Surgical principles for schwannoma and ganglion cyst. Schwannoma: (A) incision and draping should allow dissection of the normal proximal and distal nerve plus the intervening tumor (T); (B) isolation of the proximal and distal normal nerves (arrowheads); (C) visual and electrophysiological mapping of passer-by functioning fasicles splayed around the tumor capsule; (D) microneurosurgical isolation of nonfunctioning nerve of origin (arrowhead) and exit to undertake tumor and capsule removal. Ganglion cyst: (E) common peroneal nerve with adhered ganglion cyst (arrowheads); (F) resection of ganglion cyst right with cauterization of origin in tibia–fibula joint (*) and decompression of the anterior tibial and superficial peroneal branches of the common peroneal nerve (arrowheads).
NEUROFIBROMAS Neurofibromas are benign PNTs, and are also due to primary transformation of Schwann cells, although additional stromal cells such as pericytes, fibroblasts, and mast cells are quite prevalent and contribute to the overall growth of the neurofibroma. In contrast to schwannomas, neurofibromas have a loose myxoid matrix of collagen fibrils. Wavy interlacing hyperchromatic spindle-shaped transformed Schwann cell nuclei are interspersed with normal nerve fibers within the tumor (see Figure 44.2B). The transformed Schwann cells stain positive for S-100 and Leu-7, but not as prominently as schwannomas. The presence of axons within the tumor substance, as demonstrated by axon-specific stains, is the cardinal intrafascicular growth of neurofibromas. Neurofibromas arise spontaneously, but in about half of the patients occur in the context of NF1, a disease first named by von Recklinghausen in 1882. NF1, like NF2, is also an autosomal dominant disorder, but is approximately 10 times more common, with an incidence of 1 in 3500 live births. The clinical criteria, as set by the National Institutes of Health, remain the most reliable and clinically practical means for making a diagnosis of NF1 (Stumpf et al., 1988) (see Table 44.2), although we now know much more about its molecular genetics. Like NF2, 50% of patients with NF1 have
inherited a mutated NF1 gene from one of their parents, with the other 50% due to a germline mutation. This represents an extremely high spontaneous mutation rate for a gene, perhaps related to its extremely large size (Karnes, 1998; Kluwe et al., 2003). The chromosomal location for the NF1 gene is 17q12 (Schmidt et al., 2000), encoding for the protein neurofibromin, which belongs to the Ras-GAP (Ras-GTPase activating protein) family (Gutmann and Collins, 1993) involved in inactivating Ras. The activation of Ras is a pivotal intracellular mechanism of signal transduction utilized by many growth factor receptors (Egan and Weinberg, 1993), with neurofibromin and other related family members hydrolyzing active Ras to its inactive state. As predicted, we have demonstrated levels of activated Ras to be markedly increased in NF1-associated neurofibromas and MPNSTs, compared with schwannomas and normal nerves (Guha et al., 1996). The importance of this molecular understanding is that pharmacological agents that target activated Ras or its downstream effector proteins may be promising as biologically targeted therapies for these tumors (Kohl et al., 1993). Clinically, neurofibromas are divided into several subtypes based on their location and gross appearance (Kleihues and Cavenee, 2000). Cutaneous or dermal neurofibromas, which may number in the hundreds in patients with NF1, are rarely a cosmetic and/or local
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irritation problem. For the most part, these dermal neurofibromas should not be operated on, with reassurance to the patients that these neurofibromas almost never undergo malignant transformation. Plexiform neurofibromas arise from deeper and larger nerves, with multiple tumors in patients with NF1. Again, clinical and radiological observation is most prudent, especially in the setting of NF1, because the intrafascicular growth lends itself to neurological deficit if radical resection is attempted. Indications for surgery are solitary plexiform neurofibromas in patients without NF1, or tumors that demonstrate progressive growth, neurological symptoms, and especially pain. Indications for surgery in these cases are not only partial debulking for potential amelioration of the clinical symptoms, but also to exclude malignant transformation. Malignant transformation may occur in 3–5% of plexiform neurofibromas in patients without NF1, and in as many as 8–13% of patients with NF1 (Sorensen et al., 1986; Perrin and Guha, 2004; Tucker et al., 2005). In general, if the plexiform neurofibroma is benign on quick section, one can undertake subtotal but often radical debulking, with careful attention at sparing functioning intratumoral fascicles. However, if the pathologist queries malignant transformation, it is best to close, confirm the diagnosis, and undertake delayed nonnerve-sparing surgery, as described below.
GANGLION
CYSTS
These non-neoplastic lesions often occur near joints or tendon sheaths and may cause compression of adjacent nerves (Rosenberg et al., 1991). The median and ulnar nerve at the wrist, the posterior interosseus nerve at the elbow, and the common peroneal nerve at the knee are most commonly affected. At surgery, special effort should be made not only to decompress the nerve but also to find and completely resect the portion of the cyst originating from the joint capsule, to prevent recurrence (see Figure 44.3B).
FIBROLIPOMATOUS
HAMARTOMA OR LIPOMA
These are benign neoplasms arising from adipocytes or fibrofatty tissue with associated infiltration of the nerve (Guthikonda et al., 1994). Diagnosis can usually be made by the unique characteristics of fat on MRI (see Figure 44.1C). Fibrolipomatous hamartomas have a relatively higher proportion of fibrous tissue to fat in the proximal and distal segments of the lesions (Scheithauer et al., 1999). Conservative management of these lesions is usually recommended, with symptomatic lesions requiring only decompression of any associated entrapment point (e.g., carpal tunnel, etc.) or subtotal resection, making sure there is no intertwined functioning fascicles within the lipoma.
PERINEUROMA
NEUROMUSCULAR
These rare tumors are recognized based on their unique immunohistochemical and ultrastructural characteristics, identifying the perineural cell as the cell of origin (Tsang et al., 1992; Giannini et al., 1997). Clinically they are benign, occur in the middle-aged with a slightly higher incidence in women, typically arise in the deep soft tissues of the extremities, and are not associated with NF1 or NF2. Pathologically, these lesions are composed of cells with a wavy bipolar cytoplasm and elongated nuclei in a collagen or myxoid stroma, and stain positively for EMA. The ultrastructural features are characteristic with an incomplete basal lamina and abundant pinocytic vesicles in the predominant transformed perineural cells. Management principles are similar to those outlined above for schwannomas.
These are rare benign neoplasms in which welldifferentiated muscle is found within a mature neural element (Maher et al., 2002). Most cases present as single lesions and affect large nerves, with neurological deficit, muscle atrophy, and limb deformity (Maher et al., 2002). The regrowth rate after first surgery is low.
DESMOIDS These are fibrous mesenchymal tumors arising from muscles that can encase or infiltrate peripheral nerves and nearby vascular structures (Lusk et al., 1987; Rosenberg et al., 1991). Although they do not metastasize, desmoids are locally aggressive with a high recurrence rate, especially when the brachial plexus is involved.
CHORISTOMA
Malignant tumors Malignant tumors of peripheral nerves can be primary, resulting from primary malignant transformation of Schwann cells – collectively termed malignant peripheral nerve sheath tumors (MPNSTs) – or secondary to infiltration or metastasis of lymphomas, carcinomas, or sarcomas.
MALIGNANT
PERIPHERAL NERVE SHEATH TUMOR
MPNSTs account for 3–10% of all soft-tissue sarcomas, with half of the cases originating at an earlier age in patients with NF1 (King et al., 2000). As discussed above, the risk of malignant transformation of a benign plexiform neurofibroma is quite substantial in patients with NF1, which is a source of diagnostic and psychological stress in these patients. Progressive
PERIPHERAL NERVE TUMORS enlargement, incapacitating pain, and increasing neurological deficit in a plexiform neurofibroma should raise suspicion and lead to definitive steps in pathological diagnosis, as current noninvasive diagnostic tests are often inconclusive. The ideal management of MPNSTs remains controversial, with our institute recommending a multidisciplinary management strategy requiring collaboration with orthopedic oncology colleagues, physiotherapy and occupational therapists (Angelov et al., 1998) (Figure 44.4A). Clinical suspicion is followed by four-quadrant open biopsy (Figure 44.4B). We prefer an open biopsy to fine-needle or percutaneous TruCut biopsy, so as to obtain more representative tissue, as the malignant foci in the nerve are often mixed with benign regions, and also to minimize pain and neurological deficits from a blind procedure. If, at surgery, the quick sections are all negative for malignancy, we proceed to a nerve-sparing subtotal debulking, hopefully to obtain symptomatic relief. If the quick section of any of the specimens is suspicious for malignancy, we close, as discussed preoperatively with the patient, to facilitate pathological confirmation of MPNST, which can often be troublesome in these rare tumors. Subsequent to definitive confirmation and grading of the MPNST, the patient is referred to our sarcoma clinic for preoperative assessment for metastasis and radiation to the tumor and surrounding soft-tissue margins. This is followed by a thorough discussion with the patient by the neurosurgeon, orthopedic oncology surgeon, physiotherapy and occupational therapist regarding the expected neurological and functional deficits after a radical non-nervesparing procedure with adjacent soft-tissue planes. The overall objective is to obtain tumor-free margins as determined by intraoperative quick sections, which can be usually achieved without requiring limb amputation. In our experience, such a staged multidisciplinary approach has served well not only for tumor control, but also for the patient to retain a good quality of life. However, the prognosis remains guarded, as approximately 50% of the patients have succumbed to pulmonary and visceral metastasis by 5 years, despite multiple surgeries and systemic chemotherapy (Angelov et al., 1999; Ferner et al., 2002). Adverse prognostic factors include: size (> 5 cm), higher tumor grade, advanced histology, non-tumor-free surgical margins, and MPNSTs in association with NF1. Hence there is continued need for research and search of biologically targeted therapies to augment the current management of MPNSTs. Assessment of these novel therapies in these rare tumors will likely require formation of multi-institutional and multinational consortiums.
PRIMARY
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PERIPHERAL NERVE LYMPHOMA
Only a few cases have been reported so far of primary peripheral nerve lymphoma without systemic evidence of lymphoma, the latter being termed neurolymphomatosis, which is a part of the systemic manifestation of lymphoma. The majority of these are of B-cell type, affecting the sciatic nerve. Treatment includes surgical biopsy for diagnosis, followed by radiation and/or chemotherapy (Misdraji et al., 2000).
COMPRESSION
AND/OR INFILTRATION
FROM PRIMARY MALIGNANCY
Peripheral nerves may be secondarily compressed from adjacent tumors or their metastasis to lymph nodes. Rarely there may be direct longitudinal invasion of epineurium of the nerve by a carcinoma or sarcoma, resulting in pain or neurological symptoms. Pulmonary or breast carcinomas are the most common secondary tumors to involve the brachial plexus (Lusk et al., 1987). In cases of brachial plexopathy following mastectomy and radiotherapy, which is often associated with pain and rapid motor weakness, it is sometimes hard to differentiate from carcinoma recurrence and invasion versus radiation plexopathy. External neurolysis to obtain tissue for pathological examination and provide pain relief may be indicated, although return of motor function does not usually occur.
PRINCIPLES OF SURGICAL MANAGEMENT OF PERIPHERAL NERVE TUMORS If surgery is warranted, the preoperative goals (total excision versus subtotal debulking versus biopsy) and associated risks must be thoroughly discussed. Microneurosurgical techniques, intraoperative magnification, and electrophysiological monitoring without neuromuscular paralysis are essential prerequisites. The affected limb should be positioned and draped to allow evaluation of the distal muscles supplied by the relevant nerve or audible EMG electrodes inserted into those muscles. The incision should be long enough to expose the proximal and distal normal nerve (see Figure 44.3A). If the PNT is close to a natural entrapment point such as the carpal tunnel or fibular head, prophylactic release of the nerve traversing through these regions should be undertaken to defray delayed entrapment syndromes. Exposure commences with isolation of the normal proximal and distal segments of the nerve of origin, which are confirmed electrophysiologically. The presence of passer-by fascicles, which may be splayed across the tumor capsule, is highly suggestive of the extrafascicular growth of schwannomas, and
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J. JULY AND A. GUHA Suspected MPNST History/Examination/Radiology
Referral to tertiary center
Four-quadrant open biopsy and pathological verification/grading
Metastasis screening and informed consent
Metastasis not detected
Metastasis detected
Multidisciplinary approach Surgery for tumor margin (local control) Pre-/postoperative radiation therapy
Palliative tumor debulking Radiation Chemotherapy
A
Follow-up (local/systemic)
B
C
Fig. 44.4. (A) Management strategy for malignant peripheral nerve sheath tumor (MPNST) (University of Toronto Multidisciplinary Sarcoma Group). (B) Initial four-quadrant open biopsy of sciatic nerve neurofibroma in a patient with neurofibromatosis type 1 (see Figure 44.1E for MRI and CT-PET), which was confirmed pathologically to be a MPNST. The wound was closed and the tumor bed and margins are irradiated. (C) Second en bloc resection of the MPNST, adjacent nerve, and soft tissue, with intraoperative sampling to ensure tumor free margins.
visual and electrical localization of these fascicles is important (see Figure 44.3A). An area that is electrically silent, hence representing only tumor, is then chosen to obtain a quick section. If the macroscopic and pathological examination is consistent with the diagnosis of a schwannoma, then total removal is to be expected, whereas subtotal but radical debulking can be
accomplished with neurofibromas. Often the exact differentiation of the PNT subtype cannot be made on the quick section, requiring use of good clinical judgment to maximize tumor removal with minimal deficits. The majority of small to medium-sized PNTs can be removed completely, although removal of larger tumors or those adjacent to vital structures such as the spinal
PERIPHERAL NERVE TUMORS canal may first require intratumoral decompression followed by resection of the capsule from adjacent functioning neural and non-neural structures. Microneurosurgical dissection, combined with electrophysiological monitoring, is continued until the nerve fascicle of origin and exit is identified and electrically isolated, and demonstrated to be nonfunctional (see Figure 44.3A). Total capsular removal is often achievable, once the passer-by fasicles have been identified and protected. The need for nerve grafts after resection of PNTs is extremely rare. If the quick section is suggestive of malignancy, the main objective of surgery is localized tumor control rather than nerve-sparing, as discussed above.
FUTURE DIRECTIONS Although rare, PNTs form a diverse group of tumors, which vary in their pathology, biological, and clinical behavior. Due to their rarity, referral to tertiary centers is recommended for optimal care. Not all patients with PNTs require surgery, especially patients predisposed to these tumors. Management objectives may change with the natural history of the tumor and require thorough discussion with the patient. Careful surgical management can be achieved, where indicated, with minimal morbidity. MPNST remains an incurable tumor, which will require further molecular understanding and biological adjuvant therapies in the future.
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